Health Risks Associated with a Long-Term Gluten-Free Diet and the Potential Protective Role of Anthocyanins

Abstract

Gluten-free diets (GFDs) are gaining popularity worldwide. Originally, GFDs were designed for individuals with gluten intolerance, including conditions such as celiac disease, non-celiac gluten sensitivity, gluten ataxia, or dermatitis herpetiformis. However, many individuals without gluten sensitivity have subsequently adopted this diet, leading to a growing demand for gluten-free food products. Meanwhile, the health risks associated with a long-term gluten-free diet (LTGFD) and the inherent related issues, such as nutrient imbalances, remain uncertain. Scientific studies have indicated that obesity, non-alcoholic fatty liver disease (NAFLD), dysbiosis, and poor mental health represent the most probable health risks associated with a LTGFD. Moreover, high fat and simple carbohydrate content, increased calorie content, and vitamin deficiencies, including vitamin B derivatives (B1, B2, B3, B5, B6, B7, B9, and B12), vitamin D, and minerals (Fe, Mg, Se, and Zn), are key components in a GFD that are at the helm of health issues due to a LTGFD. Anthocyanins, a class of flavonoids found predominantly in red, purple, and blue fruits and vegetables, may provide a promising solution to alleviate health risks associated with a LTGFD due to their inherent antioxidant, anti-inflammatory, neuroprotective, anti-diabetic, and anti-obesity properties. Therefore, this review critically examines in vivo, in vitro, clinical, and mechanistic studies to explore the potential of anthocyanin-enriched GFDs in alleviating the health risks associated with a LTGFD, highlighting their significant advantages over regular GFDs.

Graphical abstract

Keywords

anthocyanin / dysbiosis / gluten-free diet / mental health / non-alcoholic fatty liver disease / obesity

1. Introduction

A gluten-free diet (GFD) is a popular global diet ranked among the top five most prominent diets worldwide [1]. Although a GFD was typically used to diagnose gluten-related disorders, it has recently become a leading dietary trend based on contentious beliefs. The promotion of weight loss through a GFD by celebrities, the endorsement of popular media and books, and the recommendations provided by health and fitness communities have been identified as the root causes of this fashionista [2, 3]. Arslain et al. [4] have investigated the main motivations of non-gluten-sensitive GFD adherents. They found that the most prevalent beliefs were that a GFD promotes weight loss, is healthier, gluten-free (GF) products are more nutritious, gluten can cause diseases in non-sensitive individuals, and can alleviate acne. The idea was supported by book publications [3] and research that found accumulation of fat and stimulation of insulin hormone which triggers fat accumulation on long-term wheat consumption [5]. Furthermore, going GF made consumers omit processed high-caloric wheat products with high glycemic index such as bread, pasta, cookies, and snacks which promoted weight loss, reduced metabolic risks, and alleviated acne [6]. Moreover, a “gluten-free” label on packed food products was a key determinant of the purchase decision [7].

Gluten is a group of prolamins found in wheat and some other grains such as rye, barley, their cross-linked grains, and possibly in oats. Prolamins are the key components responsible for celiac disease, non-celiac gluten sensitivity, gluten ataxia, and dermatitis herpetiformis. To date, a GFD followed by all patients with gluten disorders has been identified as the most successful treatment [8]. Furthermore, GFD has continued to appeal to the regular community as a lifestyle choice in the absence of any gluten sensitivity. Based on the previous study by Kamiński et al. [1], the compliance rate of GFD was 11.11% of the relative study volume.

Just as if, several studies have identified issues of long-term gluten-free diet (LTGFD).

Considering the nutritional status of a GFD, several nutrient deficiencies and excesses have been identified through research. Siminiuc and Țurcanu [9] found that communities following a GFD commonly experience deficiencies in protein, fiber, vitamin A, vitamin D, vitamin E, vitamin B, vitamin B1, vitamin B2, vitamin B3, vitamin B5, vitamin B6, vitamin B12, folic acid, Ca, Fe, Mg, Zn, Mn, and Na in all age groups. Concurrently, adhering to a GFD is associated with high amounts of fat, sugar, and salt, consistent with the high glycemic index of GF processed food [10, 11, 12]. Long-term intake of GF food products can lead to various health defects such as hyperlipidemia, overweight and obesity, hepatic steatosis, increased risk of cardiovascular diseases, and deprived mental health, especially depression [13]. However, the dilemma of the beneficial health impact of a GFD on communities sensitive to gluten or with celiac disease and the detrimental health impacts on community adhering to a GFD without any diagnosed symptoms of gluten sensitivity (asymptomatic community) does not clearly address some health issues such as osteoporosis, infertility, growth failure, and delayed puberty in children.

Anthocyanins are a class of flavonoids that function as plant pigments [14]. Flowers, dark-colored fruits, vegetables, and grains could be identified as rich sources of anthocyanins [15]. Usually, anthocyanins are predominant in red, purple, and blue fruits and vegetables such as mulberries, chokeberries, black elderberries, black currants, blackberries, blueberries, pomegranate, purple corn, purple sweet potato, red cabbage, black carrots, eggplants. Anthocyanins are a widespread group of compounds that promote a wide range of health benefits with their antioxidant [16], anticancer [17], anti-inflammatory activities [16], neuroprotective activities [18], anti-obesity [19], antidiabetic activities [20], antiatherosclerosis activity [21] and ability to prevent cardiovascular diseases [17]. Thus, although anthocyanins may not serve as a direct solution to address nutritional imbalances of a GFD, they may offer a potential solution for preventing or reducing the health complications associated with LTGFD. This review assesses the potential use of anthocyanins in alleviating the clinical effects of LTGFD. Fig. 1 demonstrates the potential of anthocyanins to address the health risks of a LTGFD. In this context, a GFD enriched with anthocyanins is always more beneficial than one lacking these bioactive compounds due to their proven efficacy.

Several studies have highlighted various sources of anthocyanins and their beneficial effects on human health. While few review studies have highlighted the downside of the LTGFD intake [2, 22], there is a lack of solid evidence supporting the role of anthocyanins in addressing these issues. Hence, this review aims to explore the potential of anthocyanins to alleviate health risks due to LTGFD, thereby opening new avenues for future research. Recent literature linking GFD with obesity, overweight, non-alcoholic fatty liver disease, dysbiosis, mental health, and therapeutic effects of anthocyanins were comprehensively reviewed. To the best of our knowledge, this study is the first to provide an exclusive account of the potential use of anthocyanins to alleviate LTGFD-associated health risks.

2. Health Defects Concomitant With Long-Term GFD (LTGFD)

Adhering to GFD is the most efficacious therapy for treating celiac disease, non-celiac gluten sensitivity, gluten ataxia, and dermatitis herpetiformis [23]. Nonetheless, it remains uncertain whether adopting GFD confers advantages among individuals who abstain from gluten without celiac disease or non-coeliac gluten sensitivity. Despite this uncertainty, the number of GFD devotees is constantly increasing contributing to the growing demand for GF products [3]. Nutrient imbalance is a core dispute that has been identified as related to a GFD through a study that can cause several health defects inadvertently. Salazar Quero et al. [24] reported a higher intake of lipids especially monounsaturated fatty acids, in a group of 69 celiac-diseased patients of 1–13 years. Barone et al. [25] also report a significantly higher intake of lipids by celiac-diseased adults representing both sexes. Melini and Melini [12] identified various nutritional deficiencies and excessive intake through a review done using 105 research articles. These include iron, calcium, selenium, zinc, and magnesium deficiencies, as well as low intake of vitamin B12, folate, vitamin C, and vitamin D deficiency [12]. Furthermore, there is evidence of low intake of dietary fiber and controversial protein intake as well as excess intake of fat and sugar. Similar conclusions were drawn in previous studies by Cardo et al. [26] and Perrin et al. [27]. The nutritional quality of GFD has always been questioned by the scientific community due to the higher fat composition, higher glycemic index, and high salt content of GF food on the market [28]. These imbalances can cause intricate health risks associated with LTGFD. This could be more intricate with the community adapted to processed GF food rather than for a natural GFD. So, it is important to understand that having a properly planned, nutritious, and equilibrated GFD with naturally whole foods and fortified products, can offer adequate nutrients and therapeutic benefits beyond celiac disease.

Overweight, non-alcoholic fatty liver disease (NAFLD), dysbiosis, and psychological defects are some identified possible health risks of a LTGFD. Though LTGFD could play a crucial role in these health risks, other factors such as genetic factors, biological determinants, behavioral factors, environmental factors, and sociodemographic factors interplay collectively for the cause of these health defects. Scientific research is scarce on the prolonged impact of following a GFD due to the majority of studies being conducted for brief intervals ranging from 6 months to 2–3 years. Additionally, the available literature predominantly concentrates on celiac disease gluten-sensitive groups with few studies focusing on the asymptomatic community of GFD adherents. It is important to distinguish between GFD adherents with gluten sensitivity and those who voluntarily follow a GFD as the long-term health impacts may differ significantly.

2.1 LTGFD and Obesity

Overweight and obesity are global health crises that have led to a rise in the number of obese people worldwide and an increased risk of other non-communicable diseases [29]. A study has identified possible correlations between the GFD and overweight and obesity among individuals who adhere to a strict GFD. These interactions may be attributed to increased food intake, improved intestinal absorption due to intestinal mucosal injuries, and high calories and fat content in most processed GF food products [30].

A study conducted with 39 followers of a GFD revealed a general trend toward increased body mass index (BMI) after following the GFD. Specifically, followers with a normal BMI experienced a significant weight gain, and did not switch to the overweight or obese category within the approximately two-year study period [25]. Kabbani et al. [31] examined BMI and risk of obesity in communities with celiac disease and found a significant increase in BMI over an average of 39.5 years of study. Specifically, 21.2% of the cohort adhering to a strict GFD experienced an increase in BMI by more than two units, and 17% of the cohort became overweight or obese [31]. A study by Perrin et al. [27] on asymptomatic French adults found that individuals who partially avoided gluten or non-strict adherents of a GFD exhibited a higher energy intake than non-avoiders (regular community) and total avoiders. Ciccone et al. [32] and Kozioł-Kozakowska et al. [33] also observed a significant increase in BMI after a GFD.

Asri et al. [34] conducted a study to investigate the impact of a GFD on the body weight and BMI of Iranian patients across three time periods: after less than 6 months, after 6 months to 2 years, and after more than 3 years of GFD. The results showed that within the first six months of starting a GFD, 50% of the underweight participants had achieved normal weight. After 6 months to 2 years, 33.3% of the underweight individuals and 5.17% of those with normal weight had achieved normal and overweight status respectively. Of the participants who adhered to a GFD for over 2 years, 64.7% of the underweight, 6.25% of the normal weight, and 25% of the overweight transitioned to the normal weight, overweight, and obese BMI categories respectively. Nevertheless, a few cases experienced a reduction in body weight and BMI, whereas a significant number of subjects maintained their initial BMI level throughout the study. However, this study observed a positive correlation between a GFD, and an increase in body weight [34].

When studying children, Więch et al. [35] discovered a notable rise in body weight and BMI during their evaluation of the effects of a GFD on the body composition of children with celiac disease. Lionetti et al. [36] did not detect any substantial differences in energy intake, weight, height, BMI, physical activity, or sedentary behavior between children adhering to a GFD and non-adherents. Amirikian et al. [37] found no significant effect on the BMI of children, but a trend toward higher BMI after GFD adherence was observed in adolescents. The study suggested that the increased amenability of adolescents towards more convenient processed food over the health aspects was the most possible reason.

It is contentious whether a GFD contributes to overweight, and obesity as certain studies have concluded that such a diet has no detrimental or even favorable impact on BMI or body weight [38]. These effects can be influenced by other factors such as gender, age, occupation, type of residence, income, marital status, and educational level [39]. In addition, other contributors including lack of physical activity, sedentarism, genetic predisposition, pathophysiological conditions (such as hormonal imbalances, and physical disabilities), and medications (such as diabetic treatments, steroids, and antidepressants) and psychological health are strongly correlated with overweight and obesity. While it is a proven fact that GF processed food products contain excess fat and sugar, following a GFD poses a clear vulnerability to develop or succor overweight and obesity over a lifetime, either independently or in conjunction with other contributing factors [34]. Importantly, maintaining a proper GFD rich with GF whole food over processed GF alternatives combined with adequate physical activities could significantly reduce the risk of obesity.

2.2 LTGFD and NAFLD

Non-alcoholic fatty liver disease (NAFLD) is a set of conditions linked to metabolic dysfunction of the liver and is recognized as the most widespread chronic liver disease affecting about 25% of the adult population worldwide [40]. NAFLD is closely associated with metabolic syndrome in a bidirectional way [41]. Therefore, NAFLD has been identified as another risk factor of LTGFD exposure. This was confirmed by Tovoli et al. [42], who conducted a human clinical study in individuals with coeliac disease after GFD and controls. The demographic and clinical factors such as age, gender, BMI, diabetes, cholesterol, and triglycerides were matched across the study groups. The study found a positive correlation between the risk of NAFLD and communities with celiac disease especially among overweight patients with celiac disease. Therefore, Tovoli et al. [42] reported a three-fold higher risk of NAFLD among patients with celiac disease who followed a GFD compared to the control group. Reilly et al. [43] also reported an increased risk of NAFLD among patients with celiac disease compared with the regular population in a study conducted over 15 years. Age, sex, calendar year, and county of residence at the time of biopsy were matched. According to the study, the risk of NAFLD is the highest within the first year after diagnosis, and then reduces in magnitude, but persists beyond 15 years of diagnosis [43]. Although the study revealed patients with celiac disease following a GFD, no relation between GFD and NAFLD was made. As for the study conducted by Imperatore et al. [44], 23.9% of metabolic syndrome and 37.2% of hepatic steatosis occurrences were found in a cohort of 301 patients with celiac disease after one year of GFD treatment. During the study, the dietary quality was maintained through a professional dietitian with a patient-tailored approach based on the daily calorie requirements [44].

The elevated prevalence of NAFLD following the adoption of a GFD among those with gluten sensitivity has been attributed to the absorption of more nutrients due to mucosal recovery post-GFD as well as consumption of high-calorie foodstuff that are rich in fats and simple carbohydrates [45]. These suggestions may be more accurate with long-term exposure to a GFD. Excessive fatty acids consumption through a GFD can lead to adipocyte exhaustion and liver damage progress through inhibition of adiponectin and stimulation of production of proinflammatory adipokines, leptin, resistin, TNF-\alpha, and IL-6. The inhibited action of adiponectin leads to further accumulation of fat in the liver. However, increased amounts of leptin, resistin, and proinflammatory cytokines (TNF-\alpha, and IL-6) promote hepatic inflammation and fibrosis leading to severe conditions of NAFLD [46].

Vitamin and micronutrient deficiencies resulting from a GFD in communities with celiac disease have an impact on liver health. Vitamin A, D, E, B12, B6, folate (vitamin B9), and Zn deficiencies are especially significant with notable effects on the liver. However, these nutrients insufficiencies have been identified in celiac disease communities after adopting a GFD [47]. Vitamin A, an antioxidant in the liver, induces oxidative stress at insufficient levels. Vitamin A deficiency is associated with the progression of cirrhosis and the appearance of hepatic encephalopathy, a brain dysfunction condition caused by toxins produced due to liver malfunctioning [48]. Vitamin D deficiency is also associated with cirrhosis despite causing chronic liver disease. These effects can lead to fibrosis, resulting in infections, hepatocellular carcinoma, and mortality. Vitamin D deficiency is also associated with metabolic syndrome and NAFLD is considered as the hepatic expression of metabolic syndrome. However, research has demonstrated that vitamin D can enhance liver health through its anti-proliferative, anti-inflammatory, and antifibrotic properties. In contrast, vitamin D deficiency is associated with the progression of chronic liver diseases such as NAFLD [49]. Vitamin E is a vital nutrient with antioxidant and immunomodulating properties. Vitamin E deficiency can induce oxidative stress in the liver leading to the progress of liver inflammations [50]. Vitamin B12 is another important vitamin that plays a vital role in the maintenance of liver health. Vitamin B12 deficiency concomitant with pernicious anemia, an autoimmune gastritis condition can lead to liver damage and cirrhosis [51]. On the contrary, vitamin B12 deficiency inhibits the synthesis of S-adenosylmethionine, the main cellular antioxidant in hepatocytes where liver damage and differentiation can occur in the absence [52]. Furthermore, vitamin B12 deficiency can lead to reduced liver detoxification and restoration of damaged hepatocytes, and aid in the progression of chronic liver disorders, including cirrhosis and NAFLD [51]. Folate has a significant effect on liver health, and low serum folate levels can lead to NAFLD [53]. Vitamin B6 is a vital antioxidant that can cause oxidative stress in the liver during deficiency by limiting glutathione synthesis [54]. Vitamin B6 deficiency also leads to endoplasmic reticulum stress and de novo lipid synthesis resulting in increased lipid deposition in the liver and NAFLD [46]. Besides vitamin deficiencies, the scarcity of minerals such as Zn affects liver health. Zn deficiency also causes endoplasmic reticulum stress and hepatocyte apoptosis. In contrast, Zn deficiency induces insulin resistance, enhancing metabolic syndrome and NAFLD [55]. However, studies have revealed that restoring recommended levels of vitamins A, D, E, B6, B9, B12, and Zn can effectively combat NAFLD [46, 48, 52, 53, 56].

Accordingly, a GFD can expose consumers to a higher risk of liver-related disorders including NAFLD during long-term consumption. Focusing on the intake of gluten-free whole food over gluten-free processed options may help to minimize these risks. However, it is difficult to establish that adherence to a LTGFD is the sole cause of NAFLD following the adoption of a GFD.

2.3 LTGFD and Dysbiosis

Symbiotic bacteria colonize the human body, with the skin, mouth, gut, and vagina being the primary sites of colonization. Numerous bacteria, archaea, microeukaryotes, and viruses inhabit the human microbiome. The highest proportion of this microbiota inhabits the gut, which is estimated to have ten trillion symbionts. The microbiome, which is 150 times larger than the human genome, has evolved from collective microbial genes. The microbiome can be affected by the genotype of the host, the environment, and the diet [57].

The term ‘eubiosis’ is used to describe a well-balanced intestinal microbial ecosystem whereas per contra is described as ‘dysbiosis’. The balance of the intestinal microbiota or eubiotic state is maintained by potentially beneficial species of microbiota, whereas potentially pathogenic species are also present in small numbers. Potentially beneficial bacteria were primarily from two bacterial phyla, Firmicutes and Bacteroidetes (more than 90%) and potentially pathogenic species, such as those from the phylum Proteobacteria (Enterobacteriaceae), were present at low levels [58].

The gut microbiome is a symbiotic, ubiquitous organ that performs different important functions in the human body. A few key functions of the gut microbiome include, but are not limited to production of bioactive metabolites that aid in the regulation of immunity and defense against pathogens [59], the production of bioactive compounds for energy homeostasis [60], the metabolism of nutrients and other food components [61], regulation of gut epithelial development [62], maintenance and protection of normal gut physiology and gut health [62], influence on neural development, cognition, behavior, and mental health through interactions with the gut-brain axis [63], regulation of gut-brain communication in immune-related neurological disorders [63], and contribution to the formation of fecal bulk, and dilution and elimination of toxins through fecal bulk [64]. Dysbiosis influences these functions and can cause other conditions including inflammatory bowel disorders and metabolic disorders like obesity and type II diabetes. Dysbiosis may also precede conditions such as Parkinson’s disease and facilitate the development of various other immune-mediated, metabolic, neurological, and psychiatric disorders [65].

Diet is a major cause of dysbiosis. The composition of a diet such as amounts of fat, sugar, proteins, and fiber affects the intestinal gut microbiota composition. Unbalanced diets, specifically rich in animal protein, saturated fats, and low dietary fiber, have been shown to decrease beneficial bacteria while increasing potentially harmful bacteria [66]. The rapid absorption of saturated fats and sugars in the small intestine, leaving no substrate for microbiota to ferment, and alteration of gut ecosystem promotes dysbiosis [67, 68]. As for the research, GFD also causes dysbiosis in GFD adherents. De Palma et al. [69] analyzed the effects of GFD on gut microbiota in 10 healthy individuals over one month. Results showed a decrease in beneficial gut microbiota, such as Bifidobacterium, Bifidobacterium longum, and Lactobacillus, and an increase in pathogens such as Escherichia coli and total Enterobacteriaceae [69]. The decreased availability of polysaccharides in the GFD, which act as a habitat for the gut microbiota is believed to be the primary factor behind the decline in Bifidobacterium and Lactobacillus levels [69]. In a study conducted by Bonder et al. [70], the gut microbiome of 21 healthy individuals were tested after undergoing a GFD for four weeks, followed by a habitual diet for an additional four weeks. Age, gender, BMI, nationality, and pre-antibiotic treatments of the study group were considered. The results showed a significant variation in bacterial diversity, including a significant reduction of Veillonellaceae, Ruminococcus bromii, and Roseburia faecis and a significant increase in Victivallaceae, Clostridiaceae, Coriobacteriaceae, and Slackia when comparing bacterial counts in different intervals [70]. Hansen et al. [71] conducted a crossover study by introducing a low-gluten diet (2 g gluten per day) for 8 weeks, and a high-gluten diet (18 g gluten per day) for another 8 weeks, with a regular diet (12 g gluten per day) for 6 weeks as a washout period in 60 adults with no identified diseases. Consequently, the low-gluten diet was more proficient for dysbiosis than the high-gluten diet, with a diminished relative and absolute availability of Bifidobacterium spp. [71].

Morrison et al. [72] conducted an animal-based study introducing a GFD into wild-type mice. A significant deviation in the gut microbiome of mice was observed compared to wild-type control mice fed a regular diet. A decrease in the Shannon diversity index with a significantly lower number of bacterial species was observed compared to the control group. Furthermore, Atopobiacae, Streptococcaceae, and Erysipelotrichaceae were prominent in GFD mice, whereas the Lactobacillaceae family and unidentified Lactobacillales were characterized in mice fed a normal diet. Despite this, the Actinobacteria count was significantly increased by introducing a GFD to wild-type mice [72].

Di Cagno et al. [73] conducted a study to investigate the microbiome of 19 children with celiac disease who had followed a GFD for 2 years compared to children without celiac disease. Duodenal biopsies and fecal samples revealed that cell counts of Lactobacillus, Enterococcus, and Bifidobacterium were significantly lower, whereas levels of pathogenic microbes such as Bacteroides, Staphylococcus, Salmonella, Shigella, and Klebsiella like were significantly higher in children with celiac disease after a GFD than in healthy controls. Furthermore, Di Cagno et al. [73] highlight the inability of a GFD to rehabilitate eubiosis even after two years of adherence in patients with celiac disease. Dysbiosis due to a GFD is also proved by Zopf et al. [74].

While diet is a major intrinsic factor affecting the gut microbial composition, various other factors also play a significant role, including physiological, genetic, mental, environmental, and lifestyle factors. The causative dietary factors include alcohol consumption, food additives, and dietary changes [75]. Physiological influences comprise the use of antibiotics and other medications [76], infections [77], gene mutations, chronic diseases such as obesity [78] and diabetes [79], and aging [80]. Mental health factors such as psychological stress and anxiety also lead to dysbiosis [81]. Environmental influences include hygiene practices [82], chemical exposure [83], and early-life factors such as cesarean delivery, formula feeding instead of breastfeeding, and early exposure to antibiotics [84]. Additionally, lifestyle factors such as lack of sleep [85] and nicotine use [86] contribute to dysbiosis.

2.4 LTGFD and Deprived Mental Health

GFD is the only available treatment for coeliac disease and non-coeliac gluten sensitivity. However, adherence to a strict GFD is challenging due to inevitable changes in eating patterns, lifestyle, and daily routine activities. Consequently, subjects may encounter stressful and difficult-to-accept conditions, followed by psycho-social-behavioral disorders [2].

Celiac disease is correlated with behavioral and psychiatric disorders such as anxiety, depression, dysthymia, attention-deficit hyperactive disorders, social adjustment disorder, sleep disorders, mood disorders, addictive and neurocognitive disorders, feeding and eating disorders, autistic spectrum disorders, schizophrenia, learning disabilities, and suicide attempts, among which depression found to be strongly correlated [87, 88]. A strict GFD may worsen these mental health issues and a study shows that community with celiac disease has a higher suicide rate compared to the general population [89]. Furthermore, celiac disease is associated with a higher intake of psychiatric drugs [88]. Despite the nutrient and vitamin deficiency associated with LTGFD, potential causes of mental health deprivation from adherence to the diet, including immune dysregulation, cerebral hypo perfusion, and stress have been proposed but not yet scientifically proven [2].

A poor diet is associated with poor psychiatric health. In contrast, LTGFD is associated with nutrient deficiencies, such as vitamin and mineral deficiencies which play vital roles in maintaining physical and mental health. Vitamin B derivatives are essential nutrients that improve brain health and mood and increase the risk of depression in their dearth [90]. Vitamin B deficiency can also affect memory, and cause cognitive impairment, and dementia [91]. Vitamin B1 deficiency is also directly associated with anxiety, mood disorders, and depression [92]. Vitamin B2 or riboflavin deficiency can affect fetal development causing congenital impairments [93] and poor cognitive outcomes, depression, and adverse personality changes due to changes in the central nervous system in adults [94]. Vitamin B3 (niacin) deficiency is strongly associated with depression and niacin supplementation has reduced depression symptoms. Furthermore, schizophrenia, manic depression, benign depression, anxiety, and pellagra are associated with niacin shortage. Vitamin B5 or pantothenic acid, also called ‘anti-stress factor’ causes depression and fatigue when deficient [95]. Vitamin B5 is widely used to treat anxiety, depression, and mood disorders [96]. Vitamin B6 or pyridoxine is vital for the regulation of anxiety and depression, and its shortage results in high serum homocysteine levels. Higher levels of homocysteine are associated with migraine, anxiety, and depression [97]. Vitamin B7 (biotin) is also used to treat severe depression; however, its mechanisms of action have not yet been scientifically proven [98]. Vitamin B9 (folate) deficiency is directly related to depression and behavioral disorders [99] where sufficient folate intake leads to antidepressant activities, such as the regulation of serotonin and noradrenalin receptors [100]. Vitamin B12 or cobalamin deficiency can cause acute depression, suicidal behavior, mood disorders, poor cognition, mental fatigue, mania, psychosis, and severe agitation. Vitamin B12 is widely used in the treatment of psychiatric disorders [101]. Besides vitamin B, vitamin D is also crucial for mental health. Vitamin D plays an indispensable role in neurocognitive function and functions as an antidepressant via gene transcription in the brain, in which serotonin synthesis induces and increases serotonin in the central nervous system [102]. Vitamin D deficiency is associated with a higher risk of depression, anxiety, autism, and dementia [103]. Vitamin D deficiency has also been associated with sleep and mood disorders [104].

Besides vitamins, minerals, such as iron, magnesium, selenium, and zinc play an important role in maintaining psychiatric health. Iron deficiency is responsible for mental, social, behavioral, emotional, neurophysiological, and neurocognitive impairments in all age groups [105]. Depression, anxiety, sleep disorders, and psychotic disorders are associated with iron deficiency among adults and affect the hippocampus, corpus striatum, and precise neurotransmitters such as serotonin, noradrenaline, and dopamine [106]. Magnesium deficiency causes anxiety, depression, and attention deficit hyperactivity disorder [107]. Dysregulation of the hypothalamic-pituitary-adrenal axis, increased calcium ions in the brain, and increased inflammatory responses have been suggested as possible mechanisms [108]. Selenium deficiency is directly correlated with depression, mood disorders, and autism and selenium supplementation improves symptoms of depressive disorders [107, 109]. Proposed explanations include the ability of selenium to induce thyroid function and modulate hormonal activity and neurotransmitters in the brain (serotonin, dopamine, noradrenalin) [108, 109]. Zinc deficiency leads to neuropsychological disorders, anxiety, and depression in severe deficit conditions. Increased cortisol levels, decreased neurogenesis and neural plasticity, and downregulated glutamate homeostasis are believed to contribute to zinc deficiency-associated depression [108]. Because all the micronutrient deficiencies are held by GF food products, a LTGFD can easily cause severe micronutrient deficiencies and their consequences such as an increased risk of mental disorders.

Inflammation can cause anxiety, stress, and depression [110]. Linking depression with inflammation, proinflammatory cytokines such as IL-6 and TNF-\alpha have been studied [111]. Metabolic syndrome, obesity connected with LTGFD, and celiac disease are prevalent causes of inflammation.

The gut microbiota regulates the gut-brain axis, through which they play functional roles in the regulation of brain functions, including mood, behavior, and emotional processing [112]. Research has found that dysbiosis is strongly related to anxiety and depression [113] where dysbiosis occurs due to a GFD [71]. Dysbiosis is also associated with mood disorders and autism [114].

However, it is important to understand that a wide range of other causative factors may affect mental health beyond following a GFD. These include genetic predispositions [115], hormonal imbalances [116], neurochemical changes [117], chronic stress, social isolation, traumatic experiences, and pre-existing psychological disorders [118]. Other determinants such as environmental stress factors, socioeconomic status, and lifestyle factors such as poor sleep quality and lack of physical activity can affect the mental well-being of a person [115, 118]. As mental health depends upon a complex interplay of numerous biological, psychological, and social factors, a GFD does not fully account for the mental well-being of a GFD adherent. Regardless, it is proven that adhering to a GFD can significantly affect mental well-being.

3. Anthocyanins as a Viable Solution

To date, more than 700 anthocyanins have been identified as they have garnered scientific interest due to their therapeutic significance beyond their roles as plant pigments. Extensive research including in vitro, in vivo, and clinical studies recognize anthocyanins as bioactive compounds with potent antioxidant and anti-inflammatory properties that foster a wide range of biological effects. In regards, anthocyanins can be identified as a potential solution that can alleviate the above-discussed health risks due to a LTGFD. Although not a direct remedy for nutrient imbalances associated with a GFD, anthocyanins may serve as a promising strategy to reduce the risk of discussed health risks due to a LTGFD.

3.1 Inhibitory Effect of Anthocyanins Opposed to Obesity and Overweight

Anthocyanins are a highly effective bioactive compound in combating several health defects including overweight and obesity [119]. Studies have recently shown the potential benefits of anthocyanins in mitigating obesity risk. Three potential protective effects of anthocyanins against obesity were identified: regulation of lipid metabolism, regulation of inflammatory pathways, and regulation of neurohormonal activities involved in energy homeostasis.

3.1.1 Regulation of Lipid Metabolism

Adipose tissue is functional for energy storage as lipids for future consumption [120]. With continuous storage of lipids in adipose tissue, they expand and generate anorexic signals that inhibit further energy intake [121]. However, when the adipose tissues reach the limit of lipid storage, hyperlipidemia occurs. Furthermore, they trigger the production of proinflammatory cytokines and the activation of leukocytes [122]. With their potential to reduce plasma cholesterol levels and to improve adipocyte function, anthocyanins are functional compounds that play a role in lipid metabolism regulation [21]. Anthocyanins’ primary function in the regulation of lipid metabolism can be attributed to decreasing accumulation of fat and serum lipids, activation of 5^′ adenosine monophosphate-activated protein kinase (AMPK) regulator [123], suppression of fatty acid synthase (FAS), triggered expression of lipid-metabolism related genes such as peroxisome proliferator-activated receptors \gamma and \alpha(PPAR\gamma and PPAR\alpha) [124], and suppression of sterol regulatory element-binding protein-1c (SREBP-1c) [125].

AMPK is a mammalian energy sensor that is activated when the cellular ATP levels decrease. Its responsibilities include lipid synthesis, lipolysis, and fatty acid oxidation [126]. Upregulation and activation of AMPK regulators induce the oxidation of fatty acids to generate ATP [127]. PPAR\gamma is a type of PPAR that is highly expressed in adipocytes and macrophages. Lipid metabolism through activation of the AMPK pathway is a major function of PPAR\gamma. It also stimulates the expression of genes that encode proteins involved in the metabolism of lipids and glucose. PPAR\gamma also acts as an anti-inflammatory agent that inhibits the production of proinflammatory markers (discussed in section 3.1.2) [128]. PPAR\alpha is another isomer that is responsible for suppressing the de novo synthesis of complex lipids called sphingolipids [127]. PPAR\alpha is highly effective in the liver and skeletal muscles and regulates the expression of genes that encode enzymes and transport proteins involved in lipid homeostasis [129]. SREBP-1c is an isomer of the SREBP transcription factor family that oversees the regulation of expression of enzymes involved in the synthesis of fatty acids, triacylglycerols, phospholipids, and cholesterol. SREBP suppression is a key factor in the AMPK pathway which regulates lipid metabolism [130]. Table 1 (Ref. [124, 125, 126, 131, 132, 133, 134, 135, 136, 137, 138, 139, 140]) summarizes the various sources of anthocyanins researched for their effectiveness in lipid metabolism.

3.1.2 Regulation of Inflammatory Pathways

Obesity is associated with chronic low-grade inflammation, called “meta-inflammation”. In response, proinflammatory cytokines are produced by innate immune cells in adipose tissues. Interleukin-6 (IL-6), interleukin-1\beta (IL-1\beta), C-reactive protein (CRP), and tumor necrosis factor-\alpha (TNF-\alpha) are identified as the major proinflammatory cytokines produced in response to obesity [141]. Furthermore, obesity triggers a phenotypic transformation of M2 macrophages in adipose tissues to M1 macrophages. While M2 macrophages have an anti-inflammatory function, M1 macrophages induce proinflammation by producing more cytokines [142] which are found in higher levels in obese individuals than in healthy individuals [143, 144]. However, meta-inflammation also acts as a precursor to obesity by inducing weight gain through weight cycling [145].

Anthocyanin as an anti-inflammatory agent, can interfere with meta-inflammation. Therefore, anthocyanins decrease the expression of proinflammatory markers mentioned above [119]. Table 2 (Ref. [122, 124, 132, 136, 138, 139, 146, 147, 148, 149, 150, 151, 152]) summarizes the various sources of anthocyanins researched for their effectiveness in reducing proinflammatory markers and presenting positive outcomes.

3.1.3 Regulation of Neurohormonal Activities Involved in Energy Homeostasis

Insulin resistance and hyperinsulinemia are implicated in triggering obesity [153]. Insulin, a vital hormone, plays a crucial role in the onset of obesity. Anthocyanins have the potential to modulate the central nervous system by regulating insulin thereby alleviating insulin-resistant conditions and enhancing insulin sensitivity. The mechanisms through which anthocyanins activate the AMPK regulatory pathway, decrease phosphorylation of insulin receptor substrate 1 (IRS-1), and reduce expression of retinol-binding protein 4 (RBP4) and sterol regulatory element-binding protein 1 (SREBP-1) are primarily responsible for regulating energy homeostasis. The fatty acid and triacylglycerol synthesizing enzymes are downregulated and are the lipogenic factors. Furthermore, the upregulation of lipolytic enzymes, reducing the concentration of high sensitivity C-reactive protein (hs-CRP), and upregulation of PPAR\gamma followed by an enhanced translocation were other underlying mechanisms [154].

Leptin is a hormone secreted by white adipocytes that plays a vital role in lipolysis. It also regulates the food intake by reducing the appetite [155]. Although leptin helps prevent body weight gain, Różańska and Regulska-Ilow [154] found it ineffective in obese individuals. However, leptin is positively correlated with proinflammatory cytokines increasing the production of IL-6, IL-12, and TNF-\alpha. In contrast, inflammatory cytokines such as IL-1 and TNF-\alpha stimulate the expression of adipocytes and increase plasma leptin levels. Thus, a loop is created that fosters meta-inflammation [156]. Several studies have demonstrated the efficacy of anthocyanins in controlling plasma leptin levels.

Several researchers have reported the influence of anthocyanins on the secretion of adiponectin. Adiponectin is another hormone that regulates glucose homeostasis through various mechanisms mainly in the liver and skeletal muscles. In vitro, adiponectin has been shown to improve insulin secretion and insulin sensitivity, suppress gluconeogenesis in the liver, lower blood glucose levels, and suppress fatty acid oxidation and lipogenesis [157]. Table 3 (Ref. [136, 138, 140, 152, 158, 159, 160, 161, 162]) summarizes the different sources of anthocyanin together and their effects on neurohormones involved in energy homeostasis.

3.2 Anthocyanins Against Non-Alcoholic Fatty Liver Disease (NAFLD)

NAFLD involves a range of liver disorders that result from fat buildup in the absence of excessive alcohol consumption. The spectrum ranges from simple steatosis to non-alcoholic steatohepatitis, fibrosis, cirrhosis, or hepatocellular carcinoma [163]. Disturbances in liver homeostasis (glucose and lipid metabolism), mitochondrial and endoplasmic reticulum dysfunction, and subsequent oxidative stress due to the production of reactive oxygen species (ROS) can explain the mechanisms underlying NAFLD and its progression [46].

Several studies have found an accumulation of dysfunctional mitochondria in the liver which release excessive amounts of ROS. ROS mediate signaling in metabolic pathways, leading to changes in those pathways that impact the development and progression of liver disorders. Furthermore, oxidative stress in the liver results in cell death, fibrogenesis, inflammation, and heightened susceptibility to infections [164]. In contrast, excessive ROS activates the NLR family pyrin domain containing 3 (NLRP3) inflammasome. NLRP3 activates Caspase 1 which induces the production of proinflammatory cytokines IL-1\beta and IL-18 that aggravate hepatic steatosis [165]. Mitochondria-specific autophagy (mitophagy) clears dysfunctional mitochondria [166] and PTEN induced kinase 1 (PINK1) pathway is a common regulator of mitophagy [167]. Anthocyanins (Cyanidin-3-O-glucoside) can induce the expression of PINK1 pathway-related proteins and mitochondrial localization thereby promoting mitophagy. Consequently, anthocyanins attenuate hepatic steatosis, oxidative stress, and activation of the NLRP3 pathway [168].

Superoxide dismutase and glutathione peroxidase are first-line antioxidants capable of scavenging ROS and free radicals [169]. Anthocyanins increase the activities of these enzymes and reduce the oxidative stress in the liver [169, 170, 171]. Furthermore, anthocyanins can inhibit lipid peroxidation, and the activity of enzymes associated with free radicals which inhibit ROS generation [169, 172, 173, 174, 175]. Moreover, anthocyanins mitigate NAFLD by improving lipid oxidation in the liver, inhibiting de nova synthesis of lipids in the liver, inhibiting fat deposition in hepatocytes, activating the AMPK pathway, and inhibiting proinflammatory cytokine expression (Tables 1,2). Table 4 (Ref. [122, 168, 170, 171, 172, 173, 174, 176, 177, 178, 179, 180, 181, 182, 183, 184]) summarizes different sources of anthocyanins and their functions in alleviating NAFLD.

3.3 Anthocyanins as a Succor to Improve Gut Microbiome

Maintaining the balance of the gut microbiota is vital for human health. Anthocyanins are recognized as beneficial for maintaining eubiosis by regulating microorganisms. Anthocyanins not only ameliorate the beneficial gut bacteria but also reduce harmful bacteria. In addition, the gut microbiota participates in the metabolism of anthocyanin, the synthesis of vitamins, and carbohydrate catabolism as reported by Tian et al. [185]. Anthocyanins may enhance the proliferation of beneficial microorganisms in vitro and in human subjects including species of Bifidobacterium and Lactobacillus-Enterococcus [186]. Table 5 (Ref. [148, 187, 188, 189, 190, 191, 192, 193, 194]) summarizes the impact of anthocyanins from different sources on the gut microbiota.

3.4 Anthocyanins as a Therapy for Deprived Mental Health

Anthocyanins play an important role in preserving mental health and may alleviate numerous health issues. These compounds demonstrate efficacy against major depressive disorders, anxiety, attention-deficit hyperactivity disorder, and schizophrenia. Proposed mechanisms underlying the efficacy of anthocyanins against these psychiatric disorders include mitigating inflammation, oxidative stress, and dysbiosis [195]. Although anthocyanins cannot solve nutrient deficiency issues associated with LTGFD, they will probably reduce the impact of nutrient deficiencies on mental health through their mechanisms of action.

Depression and anxiety, the most abundant and expected to be the most prevalent psychiatric problems, present with various symptoms, including feelings of distress, a persistently low mood, impaired cognitive function, and a loss of interest [196]. Monoamines, such as serotonin, dopamine, and adrenaline play a crucial role in maintaining mental well-being. Reduced synthesis of monoamine and impaired monoamine functioning are two primary contributors to depression and anxiety. Monoamine oxidase is responsible for this phenomenon [197]. Anthocyanins can inhibit the action of monoamine oxidases, specifically monoamine oxidase A and monoamine oxidase B [198, 199, 200]. Table 6 (Ref. [198, 199, 200, 201, 202, 203, 204, 205]) provides evidence for anthocyanins as a therapy for psychiatric disorders, especially depression and anxiety.

4. Anthocyanins After Ingestion

4.1 Anthocyanin Intake and Metabolism

Since anthocyanins are considered as non-essential nutrients, none of the major health authorities have established universal dietary recommendations. Researchers have found different dietary intake limits that are beneficial over discussed pathological issues. Sources of anthocyanins and their effective dosages found during clinical studies are included in Tables 1,2,3,4,5,6.

Once anthocyanins are consumed, they undergo an extremely complex in vivo metabolism due to their extreme sensitivity to the outside environment and susceptibility to degradation. Their metabolism is further influenced by factors such as food matrix, food processing methods, enzyme concentrations, gut microbiota, and genetic factors [206].

Absorption of anthocyanins starts from the oral cavity where saliva, oral epithelial cells, and oral microbiome contribute to their metabolism. Saliva partially degrades anthocyanins, with the resulting metabolites primarily influenced by oral microbiota. Once ingested, anthocyanins are rapidly absorbed in the stomach without undergoing hydrolysis as the acidic gastric environment (pH 1.5–4) provides optimum conditions for their absorption and stability of most anthocyanins other than highly active anthocyanins such as pelargonidin. In the small intestine, the alkaline pH (7.5–8) breaks down the stability of anthocyanins converting them to hemiketal and chalcone. Most anthocyanins are hydrolyzed by the hydrolytic enzymes in the jejunum, while limited absorption takes place in the duodenum and none in the ileum or colon. Two major mechanisms facilitating the absorption of anthocyanin glycosides in the intestine are sodium-glucose co-transporter 1 (SGLT1) and glucose transporter 2 (GLUT2). Unabsorbed anthocyanins are metabolized by the gut microbiota which possess enzymatic capabilities for de-glycosylation and hydrolysis. In the liver, anthocyanins are subjected to metabolic transformation through two phases where Phase I involves demethylation and hydrolysis, whereas Phase II includes glucuronidation, sulfation, and methylation occurring primarily in the liver or kidney [185, 207].

4.2 Potential Limitations

Although anthocyanins play an array of health properties in the human body, their effectiveness can be limited by low bioavailability and their extensive metabolic processing within the body. The low bioavailability of anthocyanins has notoriously been claimed by research. However, Lila et al. [208] state that anthocyanins are far more available than originally envisioned, as anthocyanins undergo enterohepatic recycling where the metabolites last longer performing functional properties in different physiological systems. Gui et al. [207] identify key challenges in fully understanding anthocyanin metabolism and bioavailability, including shortage of anthocyanin monomers, complex metabolism affected by many internal and external factors, and limitation of detection technology. Nonetheless, the dose of intake remains crucial for rewarding results. Although different gluten-free foods enriched with anthocyanins have been produced, a sparse of studies address their functional activity within conventional gluten-free products.

5. Key Insights and Constraints

The review comprehensively explores the health risks associated with a LTGFD, particularly those that arise due to nutrient imbalances. It emphasizes the importance of adapting to a well-planned, balanced GFD that embodies natural, whole GF foods over processed GF alternatives. Furthermore, it highlights the potential of anthocyanins in alleviating the health risks concomitant with a LTGFD, offering a detailed account of their mechanisms of action. It summarizes the evidence from in vivo, in vitro, and human clinical studies that support the efficacy of anthocyanins in addressing the discussed health risks.

However, based on current research, it is challenging to directly claim that the GFD alone can be responsible for the discussed health risks, as this review does not delve into other contributory factors such as demographic, physiological, economic, and social influences. Moreover, though anthocyanins remained promising, evidence supporting the use of anthocyanin-enriched GFD or its efficacy is limited, and further studies are essential to validate their functional efficacy along with a LTGFD. Therefore, this review not only identifies this gap but also gives insights for further research, highlighting the need for scientific investigations to prove the role of anthocyanins in alleviating the potential health risks of a LTGFD. It also highlights the need for the development of functional GF products in the market rather than general alternatives for conventional processed food.

6. Conclusions

Consuming a GFD over a prolonged period may increase various health risks, particularly when the diet is mainly composed of processed gluten-free foods high in fat, simple carbs, salt, and calories. Such foods may exacerbate micronutrient deficiencies, leading to conditions such as obesity, NAFLD, dysbiosis, and psychiatric disorders including depression. However, it is also important to note that not all GF processed foods are inherently unhealthy and a well-planned GFD can provide a well-balanced nutritional diet that brings functional benefits beyond the nutrition. However, research has shown that anthocyanins can address the potential health risks mentioned above. Therefore, anthocyanins can be researched as a dietary supplement for all adherents to GFD, regardless of their symptomatic or asymptomatic background. Furthermore, anthocyanins can help alleviate potential health risks from LTGFD. However, anthocyanins are not to mitigate the causative factors of a GFD such as nutrient imbalances, but to minimize the effect of a LTGFD on the cause of discussed health risks. Consequently, more scientific studies are required to claim the clinical efficacy of anthocyanins in addressing the potential health risks of a LTGFD.

References

[1] Kamiński M, Skonieczna-Żydecka K, Nowak JK, Stachowska E. Global and local diet popularity rankings, their secular trends, and seasonal variation in Google Trends data. Nutrition 2020; 79–80: 110759. https://doi.org/10.1016/j.nut.2020.110759.

[2] Lerner A, O’Bryan T, Matthias T. Navigating the Gluten-Free Boom: The Dark Side of Gluten Free Diet. Frontiers in Pediatrics. 2019; 7: 414. https://doi.org/10.3389/fped.2019.00414.

[3] Newberry C, McKnight L, Sarav M, Pickett-Blakely O. Going Gluten Free: the History and Nutritional Implications of Today’s Most Popular Diet. Current Gastroenterology Reports. 2017; 19: 54. https://doi.org/10.1007/s11894-017-0597-2.

[4] Arslain K, Gustafson CR, Baishya P, Rose DJ. Determinants of gluten-free diet adoption among individuals without celiac disease or non-celiac gluten sensitivity. Appetite. 2021; 156: 104958. https://doi.org/10.1016/j.appet.2020.104958.

[5] Guo H, Ding J, Liang J, Zhang Y. Associations of Whole Grain and Refined Grain Consumption with Metabolic Syndrome. A Meta-Analysis of Observational Studies. Frontiers in Nutrition. 2021; 8: 695620. https://doi.org/10.3389/fnut.2021.695620.

[6] Vriesekoop F, Wright E, Swinyard S, De Koning W. Gluten-free products in the UK retail environment. availability, pricing, consumer opinions in a longitudinal study. International Journal of Celiac Disease. 2020; 8: 95–103. https://doi.org/10.12691/ijcd-8-3-5.

[7] Piec K, Jancza-Smuga M. Assessment of Consumer Knowledge of Gluten-Free Food. Engineering Sciences and Technologies. 2022; 2022: 164–185. https://doi.org/10.15611/nit.2022.38.10. (In Polish)

[8] Jamieson JA, Gougeon L. Adults following a gluten-free diet report little dietary guidance in a pilot survey exploring relationships between dietary knowledge, management, and adherence in Nova Scotia, Canada. Nutrition Research. 2019; 66: 107–114. https://doi.org/10.1016/j.nutres.2019.02.005.

[9] Siminiuc R, Țurcanu D. Certain Aspects of Nutritional Security of People with Gluten-Related Disorders. Food and Nutrition Sciences. 2020; 11: 1012–1031. https://doi.org/10.4236/fns.2020.1111072.

[10] Myhrstad MCW, Slydahl M, Hellmann M, Garnweidner-Holme L, Lundin KEA, Henriksen C, et al. Nutritional quality and costs of gluten-free products: a case-control study of food products on the Norwegian marked. Food & Nutrition Research. 2021; 65: 10.29219/fnr.v65.6121. https://doi.org/10.29219/fnr.v65.6121.

[11] Fry L, Madden AM, Fallaize R. An investigation into the nutritional composition and cost of gluten-free versus regular food products in the UK. Journal of Human Nutrition and Dietetics. 2018; 31: 108–120. https://doi.org/10.1111/jhn.12502.

[12] Melini V, Melini F. Gluten-Free Diet: Gaps and Needs for a Healthier Diet. Nutrients. 2019; 11: 170. https://doi.org/10.3390/nu11010170.

[13] Al-Sunaid FF, Al-Homidi MM, Al-Qahtani RM, Al-Ashwal RA, Mudhish GA, Hanbazaza MA, et al. The influence of a gluten-free diet on health-related quality of life in individuals with celiac disease. BMC Gastroenterology. 2021; 21: 330. https://doi.org/10.1186/s12876-021-01908-0.

[14] Huang R, Su Y, Shen H, Liu W, Huang J, Kuang Z, et al. Integrative Transcriptome and Metabolome Analysis to Reveal Red Leaf Coloration in Shiya Tea (Adinandra nitida). Frontiers in Bioscience-Landmark. 2023; 28: 236. https://doi.org/10.31083/j.fbl2810236.

[15] Fan M, Kim SA, Choi YJ, Tang Y, Yang HP, Kim EK. Anthocyanin oligomer (grape skin extract) administration improves dry eye disease: A randomised, double-blind, placebo-controlled study. Clinical & Experimental Ophthalmology. 2023; 51: 122–130. https://doi.org/10.1111/ceo.14207.

[16] Szymanowska U, Baraniak B. Antioxidant and Potentially Anti-Inflammatory Activity of Anthocyanin Fractions from Pomace Obtained from Enzymatically Treated Raspberries. Antioxidants. 2019; 8: 299. https://doi.org/10.3390/antiox8080299.

[17] Li D, Wang P, Luo Y, Zhao M, Chen F. Health benefits of anthocyanins and molecular mechanisms: Update from recent decade. Critical Reviews in Food Science and Nutrition. 2017; 57: 1729–1741. https://doi.org/10.1080/10408398.2015.1030064.

[18] Zhang Y, Yin L, Huang L, Tekliye M, Xia X, Li J, et al. Composition, antioxidant activity, and neuroprotective effects of anthocyanin-rich extract from purple highland barley bran and its promotion on autophagy. Food Chemistry. 2021; 339: 127849. https://doi.org/10.1016/j.foodchem.2020.127849.

[19] Xie L, Su H, Sun C, Zheng X, Chen W. Recent advances in understanding the anti-obesity activity of anthocyanins and their biosynthesis in microorganisms. Trends in Food Science & Technology. 2018; 72: 13–24. https://doi.org/10.1016/j.tifs.2017.12.002.

[20] Les F, Cásedas G, Gómez C, Moliner C, Valero MS, López V. The role of anthocyanins as antidiabetic agents: from molecular mechanisms to in vivo and human studies. Journal of Physiology and Biochemistry. 2021; 77: 109–131. https://doi.org/10.1007/s13105-020-00739-z.

[21] Aboonabi A, Meyer RR, Gaiz A, Singh I. Anthocyanins in berries exhibited anti-atherogenicity and antiplatelet activities in a metabolic syndrome population. Nutrition Research. 2020; 76: 82–93. https://doi.org/10.1016/j.nutres.2020.02.011.

[22] Niland B, Cash BD. Health Benefits and Adverse Effects of a Gluten-Free Diet in Non-Celiac Disease Patients. Gastroenterology & Hepatology. 2018; 14: 82–91.

[23] Lerner A, Freire de Carvalho J, Kotrova A, Shoenfeld Y. Gluten-free diet can ameliorate the symptoms of non-celiac autoimmune diseases. Nutrition Reviews. 2022; 80: 525–543. https://doi.org/10.1093/nutrit/nuab039.

[24] Salazar Quero JC, Espín Jaime B, Rodríguez Martínez A, Argüelles Martín F, García Jiménez R, Rubio Murillo M, et al. Nutritional assessment of gluten-free diet. Is gluten-free diet deficient in some nutrient? Anales De Pediatria. 2015; 83: 33–39. https://doi.org/10.1016/j.anpedi.2014.08.011.

[25] Barone M, Della Valle N, Rosania R, Facciorusso A, Trotta A, Cantatore FP, et al. A comparison of the nutritional status between adult celiac patients on a long-term, strictly gluten-free diet and healthy subjects. European Journal of Clinical Nutrition. 2016; 70: 23–27. https://doi.org/10.1038/ejcn.2015.114.

[26] Cardo A, Churruca I, Lasa A, Navarro V, Vázquez-Polo M, Perez-Junkera G, et al. Nutritional Imbalances in Adult Celiac Patients Following a Gluten-Free Diet. Nutrients. 2021; 13: 2877. https://doi.org/10.3390/nu13082877.

[27] Perrin L, Allès B, Buscail C, Ravel C, Hercberg S, Julia C, et al. Gluten-free diet in French adults without coeliac disease: sociodemographic characteristics, motives and dietary profile. The British Journal of Nutrition. 2019; 122: 231–239. https://doi.org/10.1017/S0007114519001053.

[28] Krupa-Kozak U, Lange E. (). The Gluten-Free Diet and Glycaemic Index in the Management of Coeliac Disease Associated with Type 1 Diabetes. Food Reviews International. 2019; 35: 587–-608. https://doi.org/10.1080/87559129.2019.1584902.

[29] Hadjispyrou S, Dinas PC, Delitheos SM, Koumprentziotis IA, Chryssanthopoulos C, Philippou A. The Effect of High-Intensity Interval Training on Mitochondrial-Associated Indices in Overweight and Obese Adults: A Systematic Review and Meta-Analysis. Frontiers in Bioscience-Landmark. 2023; 28: 281. https://doi.org/10.31083/j.fbl2811281.

[30] Anafy A, Cohen S, Ben Tov A, Amir A, Weintraub Y, Moran-Lev H, et al. The effect of gluten-free diet on body mass index in paediatric celiac disease. Acta Paediatrica. 2021; 110: 2233–2239. https://doi.org/10.1111/apa.15787.

[31] Kabbani TA, Goldberg A, Kelly CP, Pallav K, Tariq S, Peer A, et al. Body mass index and the risk of obesity in coeliac disease treated with the gluten-free diet. Alimentary Pharmacology & Therapeutics. 2012; 35: 723–729. https://doi.org/10.1111/j.1365-2036.2012.05001.x.

[32] Ciccone A, Gabrieli D, Cardinale R, Di Ruscio M, Vernia F, Stefanelli G, et al. Metabolic Alterations in Celiac Disease Occurring after Following a Gluten-Free Diet. Digestion. 2019; 100: 262–268. https://doi.org/10.1159/000495749.

[33] Kozioł-Kozakowska A, Salamon D, Grzenda-Adamek Z, Krawczyk A, Duplaga M, Gosiewski T, et al. Changes in Diet and Anthropometric Parameters in Children and Adolescents with Celiac Disease-One Year of Follow-Up. Nutrients. 2021; 13: 4306. https://doi.org/10.3390/nu13124306.

[34] Asri N, Taraghikhah N, Baniasadi R, Ishaq S, Rezaei-Tavirani M, Sadeghi A, et al. The Effect of Gluten-Free Diet Duration on Body Mass Index of Iranian Patients with Celiac Disease. Middle East Journal of Digestive Diseases. 2022; 14: 323–329. https://doi.org/10.34172/mejdd.2022.290.

[35] Więch P, Chmiel Z, Bazaliński D, Sałacińska I, Bartosiewicz A, Mazur A, et al. The Relationship between Body Composition and a Gluten Free Diet in Children with Celiac Disease. Nutrients. 2018; 10: 1817. https://doi.org/10.3390/nu10111817.

[36] Lionetti E, Antonucci N, Marinelli M, Bartolomei B, Franceschini E, Gatti S, et al. Nutritional Status, Dietary Intake, and Adherence to the Mediterranean Diet of Children with Celiac Disease on a Gluten-Free Diet: A Case-Control Prospective Study. Nutrients. 2020; 12: 143. https://doi.org/10.3390/nu12010143.

[37] Amirikian K, Sansotta N, Guandalini S, Jericho H. Effects of the Gluten-free Diet on Body Mass Indexes in Pediatric Celiac Patients. Journal of Pediatric Gastroenterology and Nutrition. 2019; 68: 360–363. https://doi.org/10.1097/MPG.0000000000002190.

[38] Barone M, Iannone A, Cristofori F, Dargenio VN, Indrio F, Verduci E, et al. Risk of obesity during a gluten-free diet in pediatric and adult patients with celiac disease: a systematic review with meta-analysis. Nutrition Reviews. 2023; 81: 252–266. https://doi.org/10.1093/nutrit/nuac052.

[39] de Oliveira PM, Zandonadi RP, Cutrim AMV, Nakano EY, de Queiroz FLN, Botelho RBA, et al. Eating Competence and Aspects Related to a Gluten-Free Diet in Brazilian Adults with Gluten-Related Disorders. Nutrients. 2022; 14: 2815. https://doi.org/10.3390/nu14142815.

[40] Wang Z, Sun T, Yu J, Li S, Gong L, Zhang Y. FGF21: A Sharp Weapon in the Process of Exercise to Improve NAFLD. Frontiers in Bioscience-Landmark. 2023; 28: 351. https://doi.org/10.31083/j.fbl2812351.

[41] Lonardo A, Ballestri S, Marchesini G, Angulo P, Loria P. Nonalcoholic fatty liver disease: a precursor of the metabolic syndrome. Digestive and Liver Disease. 2015; 47: 181–190. https://doi.org/10.1016/j.dld.2014.09.020.

[42] Tovoli F, Negrini G, Farì R, Guidetti E, Faggiano C, Napoli L, et al. Increased risk of nonalcoholic fatty liver disease in patients with coeliac disease on a gluten-free diet: beyond traditional metabolic factors. Alimentary Pharmacology & Therapeutics. 2018; 48: 538–546. https://doi.org/10.1111/apt.14910.

[43] Reilly NR, Lebwohl B, Hultcrantz R, Green PHR, Ludvigsson JF. Increased risk of non-alcoholic fatty liver disease after diagnosis of celiac disease. Journal of Hepatology. 2015; 62: 1405–1411. https://doi.org/10.1016/j.jhep.2015.01.013.

[44] Imperatore N, Tortora R, Testa A, Gerbino N, Caporaso N, Rispo A. Proton pump inhibitors as risk factor for metabolic syndrome and hepatic steatosis in coeliac disease patients on gluten-free diet. Journal of Gastroenterology. 2018; 53: 507–516. https://doi.org/10.1007/s00535-017-1381-7.

[45] Larussa T, Abenavoli L, Procopio AC, Iannelli C, Polimeni N, Spagnuolo R, et al. The role of gluten-free diet in nonalcoholic fatty liver disease development. European Review for Medical and Pharmacological Sciences. 2021; 25: 6613–6618. https://doi.org/10.26355/eurrev_202111_27104.

[46] Abe RAM, Masroor A, Khorochkov A, Prieto J, Singh KB, Nnadozie MC, et al. The Role of Vitamins in Non-Alcoholic Fatty Liver Disease: A Systematic Review. Cureus. 2021; 13: e16855. https://doi.org/10.7759/cureus.16855.

[47] Tokgöz Y, Terlemez S, Karul A. Fat soluble vitamin levels in children with newly diagnosed celiac disease, a case control study. BMC Pediatrics. 2018; 18: 130. https://doi.org/10.1186/s12887-018-1107-x.

[48] Koop AH, Mousa OY, Pham LE, Corral-Hurtado JE, Pungpapong S, Keaveny AP. An Argument for Vitamin D, A, and Zinc Monitoring in Cirrhosis. Annals of Hepatology. 2018; 17: 920–932. https://doi.org/10.5604/01.3001.0012.7192.

[49] Izadi A, Aliasghari F, Gargari BP, Ebrahimi S. Strong association between serum Vitamin D and Vaspin Levels, AIP, VAI and liver enzymes in NAFLD patients. International Journal for Vitamin and Nutrition Research. 2020; 90: 59–66. https://doi.org/10.1024/0300-9831/a000443.

[50] Chung E, Mo H, Wang S, Zu Y, Elfakhani M, Rios SR, et al. Potential roles of vitamin E in age-related changes in skeletal muscle health. Nutrition Research. 2018; 49: 23–36. https://doi.org/10.1016/j.nutres.2017.09.005.

[51] Yan X, Gao R, Hu Y, Jin J. Pernicious anemia associated with cryptogenic cirrhosis: Two case reports and a literature review. Medicine. 2018; 97: e12547. https://doi.org/10.1097/MD.0000000000012547.

[52] Ouyang Y, Wu Q, Li J, Sun S, Sun S. S-adenosylmethionine: A metabolite critical to the regulation of autophagy. Cell Proliferation. 2020; 53: e12891. https://doi.org/10.1111/cpr.12891.

[53] Sid V, Siow YL, O K. Role of folate in nonalcoholic fatty liver disease. Canadian Journal of Physiology and Pharmacology. 2017; 95: 1141–1148. https://doi.org/10.1139/cjpp-2016-0681.

[54] Lu SC. Dysregulation of glutathione synthesis in liver disease. Liver Research. 2020; 4: 64–73. https://doi.org/10.1016/j.livres.2020.05.003.

[55] Liang T, Zhang Q, Sun W, Xin Y, Zhang Z, Tan Y, et al. Zinc treatment prevents type 1 diabetes-induced hepatic oxidative damage, endoplasmic reticulum stress, and cell death, and even prevents possible steatohepatitis in the OVE26 mouse model: Important role of metallothionein. Toxicology Letters. 2015; 233: 114–124. https://doi.org/10.1016/j.toxlet.2015.01.010.

[56] Zhang Z, Thorne JL, Moore JB. Vitamin D and nonalcoholic fatty liver disease. Current Opinion in Clinical Nutrition and Metabolic Care. 2019; 22: 449–458. https://doi.org/10.1097/MCO.0000000000000605.

[57] Lee SY, Lee DY, Kang HJ, Kang JH, Cho MG, Jang HW, et al. Differences in the gut microbiota between young and elderly persons in Korea. Nutrition Research. 2021; 87: 31–40. https://doi.org/10.1016/j.nutres.2020.12.013.

[58] Iebba V, Totino V, Gagliardi A, Santangelo F, Cacciotti F, Trancassini M, et al. Eubiosis and dysbiosis: the two sides of the microbiota. The New Microbiologica. 2016; 39: 1–12.

[59] Levy M, Blacher E, Elinav E. Microbiome, metabolites and host immunity. Current Opinion in Microbiology. 2017; 35: 8–15. https://doi.org/10.1016/j.mib.2016.10.003.

[60] Arora T, Sharma R. Fermentation potential of the gut microbiome: implications for energy homeostasis and weight management. Nutrition Reviews. 2011; 69: 99–106. https://doi.org/10.1111/j.1753-4887.2010.00365.x.

[61] Rowland I, Gibson G, Heinken A, Scott K, Swann J, Thiele I, et al. Gut microbiota functions: metabolism of nutrients and other food components. European Journal of Nutrition. 2018; 57: 1–24. https://doi.org/10.1007/s00394-017-1445-8.

[62] Monda V, Villano I, Messina A, Valenzano A, Esposito T, Moscatelli F, et al. Exercise Modifies the Gut Microbiota with Positive Health Effects. Oxidative Medicine and Cellular Longevity. 2017; 2017: 3831972. https://doi.org/10.1155/2017/3831972.

[63] Mohajeri MH, La Fata G, Steinert RE, Weber P. Relationship between the gut microbiome and brain function. Nutrition Reviews. 2018; 76: 481–496. https://doi.org/10.1093/nutrit/nuy009.

[64] Coryell M, McAlpine M, Pinkham NV, McDermott TR, Walk ST. The gut microbiome is required for full protection against acute arsenic toxicity in mouse models. Nature Communications. 2018; 9: 5424. https://doi.org/10.1038/s41467-018-07803-9.

[65] Schmidt NS, Lorentz A. Dietary restrictions modulate the gut microbiota: Implications for health and disease. Nutrition Research. 2021; 89: 10–22. https://doi.org/10.1016/j.nutres.2021.03.001.

[66] Losso JN. Food Processing, Dysbiosis, Gastrointestinal Inflammatory Diseases, and Antiangiogenic Functional Foods or Beverages. Annual Review of Food Science and Technology. 2021; 12: 235–258. https://doi.org/10.1146/annurev-food-062520-090235.

[67] Martinez JE, Kahana DD, Ghuman S, Wilson HP, Wilson J, Kim SCJ, et al. Unhealthy Lifestyle and Gut Dysbiosis: A Better Understanding of the Effects of Poor Diet and Nicotine on the Intestinal Microbiome. Frontiers in Endocrinology. 2021; 12: 667066. https://doi.org/10.3389/fendo.2021.667066.

[68] Brown K, DeCoffe D, Molcan E, Gibson DL. Diet-induced dysbiosis of the intestinal microbiota and the effects on immunity and disease. Nutrients. 2012; 4: 1095–1119. https://doi.org/10.3390/nu4081095.

[69] De Palma G, Nadal I, Collado MC, Sanz Y. Effects of a gluten-free diet on gut microbiota and immune function in healthy adult human subjects. The British Journal of Nutrition. 2009; 102: 1154–1160. https://doi.org/10.1017/S0007114509371767.

[70] Bonder MJ, Tigchelaar EF, Cai X, Trynka G, Cenit MC, Hrdlickova B, et al. The influence of a short-term gluten-free diet on the human gut microbiome. Genome Medicine. 2016; 8: 45. https://doi.org/10.1186/s13073-016-0295-y.

[71] Hansen LBS, Roager HM, Søndertoft NB, Gøbel RJ, Kristensen M, Vallès-Colomer M, et al. A low-gluten diet induces changes in the intestinal microbiome of healthy Danish adults. Nature Communications. 2018; 9: 4630. https://doi.org/10.1038/s41467-018-07019-x.

[72] Morrison HA, Liu Y, Eden K, Nagai-Singer MA, Wade PA, Allen IC. NLRX1 Deficiency Alters the Gut Microbiome and Is Further Exacerbated by Adherence to a Gluten-Free Diet. Frontiers in Immunology. 2022; 13: 882521. https://doi.org/10.3389/fimmu.2022.882521.

[73] Di Cagno R, De Angelis M, De Pasquale I, Ndagijimana M, Vernocchi P, Ricciuti P, et al. Duodenal and faecal microbiota of celiac children: molecular, phenotype and metabolome characterization. BMC Microbiology. 2011; 11: 219. https://doi.org/10.1186/1471-2180-11-219.

[74] Zopf Y, Reljic D, Dieterich W. Dietary Effects on Microbiota-New Trends with Gluten-Free or Paleo Diet. Medical Sciences. 2018; 6: 92. https://doi.org/10.3390/medsci6040092.

[75] Bishehsari F, Moossavi S, Engen PA, Liu X, Zhang Y. Abnormal Food Timing Promotes Alcohol-Associated Dysbiosis and Colon Carcinogenesis Pathways. Frontiers in Oncology. 2020; 10: 1029. https://doi.org/10.3389/fonc.2020.01029.

[76] Ojima M, Shimizu K, Motooka D, Ishihara T, Nakamura S, Shintani A, et al. Gut Dysbiosis Associated with Antibiotics and Disease Severity and Its Relation to Mortality in Critically Ill Patients. Digestive Diseases and Sciences. 2022; 67: 2420–2432. https://doi.org/10.1007/s10620-021-07000-7.

[77] Aktas B, Aslim B. Gut-lung axis and dysbiosis in COVID-19. Turkish Journal of Biology. 2020; 44: 265–272. https://doi.org/10.3906/biy-2005-102.

[78] Gao R, Zhu C, Li H, Yin M, Pan C, Huang L, et al. Dysbiosis Signatures of Gut Microbiota Along the Sequence from Healthy, Young Patients to Those with Overweight and Obesity. Obesity. 2018; 26: 351–361. https://doi.org/10.1002/oby.22088.

[79] Huang Y, Wang Z, Ma H, Ji S, Chen Z, Cui Z, et al. Dysbiosis and Implication of the Gut Microbiota in Diabetic Retinopathy. Frontiers in Cellular and Infection Microbiology. 2021; 11: 646348. https://doi.org/10.3389/fcimb.2021.646348.

[80] Thevaranjan N, Puchta A, Schulz C, Naidoo A, Szamosi JC, Verschoor CP, et al. Age-Associated Microbial Dysbiosis Promotes Intestinal Permeability, Systemic Inflammation, and Macrophage Dysfunction. Cell Host & Microbe. 2017; 21: 455–466.e4. https://doi.org/10.1016/j.chom.2017.03.002.

[81] Borrego-Ruiz A, Borrego JJ. An updated overview on the relationship between human gut microbiome dysbiosis and psychiatric and psychological disorders. Progress in Neuro-Psychopharmacology & Biological Psychiatry. 2024; 128: 110861. https://doi.org/10.1016/j.pnpbp.2023.110861.

[82] Finlay BB, Amato KR, Azad M, Blaser MJ, Bosch TCG, Chu H, et al. The hygiene hypothesis, the COVID pandemic, and consequences for the human microbiome. Proceedings of the National Academy of Sciences of the United States of America. 2021; 118: e2010217118. https://doi.org/10.1073/pnas.2010217118.

[83] Sen P, Fan Y, Schlezinger JJ, Ehrlich SD, Webster TF, Hyötyläinen T, et al. Exposure to environmental toxicants is associated with gut microbiome dysbiosis, insulin resistance and obesity. Environment International. 2024; 186: 108569. https://doi.org/10.1016/j.envint.2024.108569.

[84] Li P, Chang X, Chen X, Wang C, Shang Y, Zheng D, et al. Early-life antibiotic exposure increases the risk of childhood overweight and obesity in relation to dysbiosis of gut microbiota: a birth cohort study. Annals of Clinical Microbiology and Antimicrobials. 2022; 21: 46. https://doi.org/10.1186/s12941-022-00535-1.

[85] Neroni B, Evangelisti M, Radocchia G, Di Nardo G, Pantanella F, Villa MP, et al. Relationship between sleep disorders and gut dysbiosis: what affects what? Sleep Medicine. 2021; 87: 1–7. https://doi.org/10.1016/j.sleep.2021.08.003.

[86] Chen Y, Zhao M, Ji K, Li J, Wang S, Lu L, et al. Association of nicotine dependence and gut microbiota: a bidirectional two-sample Mendelian randomization study. Frontiers in Immunology. 2023; 14: 1244272. https://doi.org/10.3389/fimmu.2023.1244272.

[87] van Hees NJM, Giltay EJ, Tielemans SMAJ, Geleijnse JM, Puvill T, Janssen N, et al. Essential amino acids in the gluten-free diet and serum in relation to depression in patients with celiac disease. PLoS ONE. 2015; 10: e0122619. https://doi.org/10.1371/journal.pone.0122619.

[88] Lebwohl B, Haggård L, Emilsson L, Söderling J, Roelstraete B, Butwicka A, et al. Psychiatric Disorders in Patients With a Diagnosis of Celiac Disease During Childhood From 1973 to 2016. Clinical Gastroenterology and Hepatology. 2021; 19: 2093–2101.e13. https://doi.org/10.1016/j.cgh.2020.08.018.

[89] Quarpong W, Card TR, West J, Solaymani-Dodaran M, Logan RF, Grainge MJ. Mortality in people with coeliac disease: Long-term follow-up from a Scottish cohort. United European Gastroenterology Journal. 2019; 7: 377–387. https://doi.org/10.1177/2050640618814662.

[90] Wu Y, Li S, Wang W, Zhang D. Associations of dietary B vitamins intakes with depression in adults. International Journal for Vitamin and Nutrition Research. 2023; 93: 142–153. https://doi.org/10.1024/0300-9831/a000720.

[91] Kris-Etherton PM, Petersen KS, Hibbeln JR, Hurley D, Kolick V, Peoples S, et al. Nutrition and behavioral health disorders: depression and anxiety. Nutrition Reviews. 2021; 79: 247–260. https://doi.org/10.1093/nutrit/nuaa025.

[92] Dhir S, Tarasenko M, Napoli E, Giulivi C. Neurological, Psychiatric, and Biochemical Aspects of Thiamine Deficiency in Children and Adults. Frontiers in Psychiatry. 2019; 10: 207. https://doi.org/10.3389/fpsyt.2019.00207.

[93] Gramer G, Hoffmann GF, Hennermann JB. Maternal vitamin deficiency mimicking multiple acyl-CoA dehydrogenase deficiency on newborn screening. Molecular Genetics and Metabolism Reports. 2021; 27: 100738. https://doi.org/10.1016/j.ymgmr.2021.100738.

[94] Mikkelsen K, Apostolopoulos V. B Vitamins and Ageing. Sub-Cellular Biochemistry. 2018; 90: 451–470. https://doi.org/10.1007/978-981-13-2835-0_15.

[95] Mikkelsen K, Stojanovska L, Prakash M, Apostolopoulos V. The effects of vitamin B on the immune/cytokine network and their involvement in depression. Maturitas. 2017; 96: 58–71. https://doi.org/10.1016/j.maturitas.2016.11.012.

[96] Mahdavifar B, Hosseinzadeh M, Salehi-Abargouei A, Mirzaei M, Vafa M. Dietary intake of B vitamins and their association with depression, anxiety, and stress symptoms: A cross-sectional, population-based survey. Journal of Affective Disorders. 2021; 288: 92–98. https://doi.org/10.1016/j.jad.2021.03.055.

[97] Wu Y, Zhang L, Li S, Zhang D. Associations of dietary vitamin B1, vitamin B2, vitamin B6, and vitamin B12 with the risk of depression: a systematic review and meta-analysis. Nutrition Reviews. 2022; 80: 351–366. https://doi.org/10.1093/nutrit/nuab014.

[98] Kafeshani M, Feizi A, Esmaillzadeh A, Keshteli AH, Afshar H, Roohafza H, et al. Higher vitamin B₆ intake is associated with lower depression and anxiety risk in women but not in men: A large cross-sectional study. International Journal for Vitamin and Nutrition Research. 2020; 90: 484–492. https://doi.org/10.1024/0300-9831/a000589.

[99] Cicero AF, Minervino A. Combined action of SAMe, Folate, and Vitamin B12 in the treatment of mood disorders: a review. European Review for Medical and Pharmacological Sciences. 2022; 26: 2443–2459. https://doi.org/10.26355/eurrev_202204_28479.

[100] De Berardis D, Orsolini L, Serroni N, Girinelli G, Iasevoli F, Tomasetti C, et al. A comprehensive review on the efficacy of S-Adenosyl-L-methionine in Major Depressive Disorder. CNS & Neurological Disorders Drug Targets. 2016; 15: 35–44. https://doi.org/10.2174/1871527314666150821103825.

[101] Batista KS, Cintra VM, Lucena PAF, Manhães-de-Castro R, Toscano AE, Costa LP, et al. The role of vitamin B12 in viral infections: a comprehensive review of its relationship with the muscle-gut-brain axis and implications for SARS-CoV-2 infection. Nutrition Reviews. 2022; 80: 561–578. https://doi.org/10.1093/nutrit/nuab092.

[102] Almuqbil M, Almadani ME, Albraiki SA, Alamri AM, Alshehri A, Alghamdi A, et al. Impact of Vitamin D Deficiency on Mental Health in University Students: A Cross-Sectional Study. Healthcare. 2023; 11: 2097. https://doi.org/10.3390/healthcare11142097.

[103] Föcker M, Antel J, Ring S, Hahn D, Kanal Ö Öztürk D, et al. Vitamin D and mental health in children and adolescents. European Child & Adolescent Psychiatry. 2017; 26: 1043–1066. https://doi.org/10.1007/s00787-017-0949-3.

[104] Muscogiuri G, Barrea L, Scannapieco M, Di Somma C, Scacchi M, Aimaretti G, et al. The lullaby of the sun: the role of vitamin D in sleep disturbance. Sleep Medicine. 2019; 54: 262–265. https://doi.org/10.1016/j.sleep.2018.10.033.

[105] Ferreira A, Neves P, Gozzelino R. Multilevel Impacts of Iron in the Brain: The Cross Talk between Neurophysiological Mechanisms, Cognition, and Social Behavior. Pharmaceuticals. 2019; 12: 126. https://doi.org/10.3390/ph12030126.

[106] Shah HE, Bhawnani N, Ethirajulu A, Alkasabera A, Onyali CB, Anim-Koranteng C, et al. Iron Deficiency-Induced Changes in the Hippocampus, Corpus Striatum, and Monoamines Levels That Lead to Anxiety, Depression, Sleep Disorders, and Psychotic Disorders. Cureus. 2021; 13: e18138. https://doi.org/10.7759/cureus.18138.

[107] Shayganfard M. Are Essential Trace Elements Effective in Modulation of Mental Disorders? Update and Perspectives. Biological Trace Element Research. 2022; 200: 1032–1059. https://doi.org/10.1007/s12011-021-02733-y.

[108] Wang J, Um P, Dickerman BA, Liu J. Zinc, Magnesium, Selenium and Depression: A Review of the Evidence, Potential Mechanisms and Implications. Nutrients. 2018; 10: 584. https://doi.org/10.3390/nu10050584.

[109] Czaderny K. Risk factors for depression. New evidence on selenium deficiency and depressive disorders. Psychiatria Polska. 2020; 54: 1109–1121. https://doi.org/10.12740/PP/112967.

[110] Paolucci EM, Loukov D, Bowdish DME, Heisz JJ. Exercise reduces depression and inflammation but intensity matters. Biological Psychology. 2018; 133: 79–84. https://doi.org/10.1016/j.biopsycho.2018.01.015.

[111] Colasanto M, Madigan S, Korczak DJ. Depression and inflammation among children and adolescents: A meta-analysis. Journal of Affective Disorders. 2020; 277: 940–948. https://doi.org/10.1016/j.jad.2020.09.025.

[112] Simpson CA, Diaz-Arteche C, Eliby D, Schwartz OS, Simmons JG, Cowan CSM. The gut microbiota in anxiety and depression - A systematic review. Clinical Psychology Review. 2021; 83: 101943. https://doi.org/10.1016/j.cpr.2020.101943.

[113] Bear TLK, Dalziel JE, Coad J, Roy NC, Butts CA, Gopal PK. The Role of the Gut Microbiota in Dietary Interventions for Depression and Anxiety. Advances in Nutrition. 2020; 11: 890–907. https://doi.org/10.1093/advances/nmaa016.

[114] Mangiola F, Ianiro G, Franceschi F, Fagiuoli S, Gasbarrini G, Gasbarrini A. Gut microbiota in autism and mood disorders. World Journal of Gastroenterology. 2016; 22: 361–368. https://doi.org/10.3748/wjg.v22.i1.361.

[115] Vermeulen MCM, van der Heijden KB, Kocevska D, Treur JL, Huppertz C, van Beijsterveldt CEM, et al. Associations of sleep with psychological problems and well-being in adolescence: causality or common genetic predispositions? Journal of Child Psychology and Psychiatry, and Allied Disciplines. 2021; 62: 28–39. https://doi.org/10.1111/jcpp.13238.

[116] Gupta JK, Goyal A, Saraf B, Thareja K. Scientific basis for deplorable women’s behaviour: A connection with hormonal imbalance. Indian Journal of Science and Technology. 2019; 12: 1–7. https://doi.org/10.17485/ijst/2019/v12i16/143844.

[117] Cowen PJ. Neuroendocrine and Neurochemical Processes in Depression. Psychopathology Review. 2016; 3: 3–15. https://doi.org/10.5127/pr.034513.

[118] Laustsen LM, Lasgaard M, Momen NC, Chen D, Gradus JL, Grønkjær MS, et al. Social disconnectedness, subsequent medical conditions, and, the role of pre-existing mental disorders: a population-based cohort study. Epidemiology and Psychiatric Sciences. 2024; 33: e81. https://doi.org/10.1017/S2045796024000829.

[119] Sandoval-Ramírez BA, Catalán Ú Fernández-Castillejo S, Pedret A, Llauradó E, Solà R. Cyanidin-3-glucoside as a possible biomarker of anthocyanin-rich berry intake in body fluids of healthy humans: a systematic review of clinical trials. Nutrition Reviews. 2020; 78: 597–610. https://doi.org/10.1093/nutrit/nuz083.

[120] Bordoni L, Perugini J, Petracci I, Di Mercurio E, Lezoche G, Guerrieri M, et al. Mitochondrial DNA in Visceral Adipose Tissue in Severe Obesity: From Copy Number to D-Loop Methylation. Frontiers in Bioscience-Landmark. 2022; 27: 172. https://doi.org/10.31083/j.fbl2706172.

[121] van der Heijden RA, Morrison MC, Sheedfar F, Mulder P, Schreurs M, Hommelberg PPH, et al. Effects of Anthocyanin and Flavanol Compounds on Lipid Metabolism and Adipose Tissue Associated Systemic Inflammation in Diet-Induced Obesity. Mediators of Inflammation. 2016; 2016: 2042107. https://doi.org/10.1155/2016/2042107.

[122] Popović D, Kocić G, Katić V, Zarubica A, Veličković LJ, Ničković VP, et al. Anthocyanins Protect Hepatocytes against CCl₄-Induced Acute Liver Injury in Rats by Inhibiting Pro-inflammatory mediators, Polyamine Catabolism, Lipocalin-2, and Excessive Proliferation of Kupffer Cells. Antioxidants. 2019; 8: 451. https://doi.org/10.3390/antiox8100451.

[123] Escalante-Aburto A, Mendoza-Córdova MY, Mahady GB, Luna-Vital DA, Gutiérrez-Uribe JA, Chuck-Hernández C. Consumption of dietary anthocyanins and their association with a reduction in obesity biomarkers and the prevention of obesity. Trends in Food Science & Technology. 2023; 140: 104140. https://doi.org/10.1016/j.tifs.2023.104140.

[124] Aboonabi A, Aboonabi A. Anthocyanins reduce inflammation and improve glucose and lipid metabolism associated with inhibiting nuclear factor-kappaB activation and increasing PPAR-γ gene expression in metabolic syndrome subjects. Free Radical Biology & Medicine. 2020; 150: 30–39. https://doi.org/10.1016/j.freeradbiomed.2020.02.004.

[125] Han MH, Kim HJ, Jeong JW, Park C, Kim BW, Choi YH. Inhibition of Adipocyte Differentiation by Anthocyanins Isolated from the Fruit of Vitis coignetiae Pulliat is Associated with the Activation of AMPK Signaling Pathway. Toxicological Research. 2018; 34: 13–21. https://doi.org/10.5487/TR.2018.34.1.013.

[126] Lee M, Sorn SR, Park Y, Park HK. Anthocyanin Rich-Black Soybean Testa Improved Visceral Fat and Plasma Lipid Profiles in Overweight/Obese Korean Adults: A Randomized Controlled Trial. Journal of Medicinal Food. 2016; 19: 995–1003. https://doi.org/10.1089/jmf.2016.3762.

[127] Rodríguez C, Muñoz M, Contreras C, Prieto D. AMPK, metabolism, and vascular function. The FEBS Journal. 2021; 288: 3746–3771. https://doi.org/10.1111/febs.15863.

[128] Choi MJ, Lee EJ, Park JS, Kim SN, Park EM, Kim HS. Anti-inflammatory mechanism of galangin in lipopolysaccharide-stimulated microglia: Critical role of PPAR-γ signaling pathway. Biochemical Pharmacology. 2017; 144: 120–131. https://doi.org/10.1016/j.bcp.2017.07.021.

[129] Jia Y, Wu C, Kim YS, Yang SO, Kim Y, Kim JS, et al. A dietary anthocyanin cyanidin-3-O-glucoside binds to PPARs to regulate glucose metabolism and insulin sensitivity in mice. Communications Biology. 2020; 3: 514. https://doi.org/10.1038/s42003-020-01231-6.

[130] Wang Q, Liu S, Zhai A, Zhang B, Tian G. AMPK-Mediated Regulation of Lipid Metabolism by Phosphorylation. Biological & Pharmaceutical Bulletin. 2018; 41: 985–993. https://doi.org/10.1248/bpb.b17-00724.

[131] Lim SM, Lee HS, Jung JI, Kim SM, Kim NY, Seo TS, et al. Cyanidin-3-O-galactoside-enriched Aronia melanocarpa extract attenuates weight gain and adipogenic pathways in high-fat diet-induced obese C57BL/6 mice. Nutrients. 2019; 11: 1190. https://doi.org/10.3390/nu11051190.

[132] Wu T, Gao Y, Guo X, Zhang M, Gong L. Blackberry and Blueberry Anthocyanin Supplementation Counteract High-Fat-Diet-Induced Obesity by Alleviating Oxidative Stress and Inflammation and Accelerating Energy Expenditure. Oxidative Medicine and Cellular Longevity. 2018; 2018: 4051232. https://doi.org/10.1155/2018/4051232.

[133] Niesen S, Göttel C, Becker H, Bakuradze T, Winterhalter P, Richling E. Fractionation of Extracts from Black Chokeberry, Cranberry, and Pomegranate to Identify Compounds That Influence Lipid Metabolism. Foods. 2022; 11: 570. https://doi.org/10.3390/foods11040570.

[134] Song H, Shen X, Wang F, Li Y, Zheng X. Black Current Anthocyanins Improve Lipid Metabolism and Modulate Gut Microbiota in High-Fat Diet-Induced Obese Mice. Molecular Nutrition & Food Research. 2021; 65: e2001090. https://doi.org/10.1002/mnfr.202001090.

[135] Herrera-Balandrano DD, Chai Z, Hutabarat RP, Beta T, Feng J, Ma K, et al. Hypoglycemic and hypolipidemic effects of blueberry anthocyanins by AMPK activation: In vitro and in vivo studies. Redox Biology. 2021; 46: 102100. https://doi.org/10.1016/j.redox.2021.102100.

[136] Wu T, Yin J, Zhang G, Long H, Zheng X. Mulberry and cherry anthocyanin consumption prevents oxidative stress and inflammation in diet-induced obese mice. Molecular Nutrition & Food Research. 2016; 60: 687–694. https://doi.org/10.1002/mnfr.201500734.

[137] Briskey D, Malfa GA, Rao A. Effectiveness of ”Moro” Blood Orange Citrus sinensis Osbeck (Rutaceae) Standardized Extract on Weight Loss in Overweight but Otherwise Healthy Men and Women-A Randomized Double-Blind Placebo-Controlled Study. Nutrients. 2022; 14: 427. https://doi.org/10.3390/nu14030427.

[138] Luna-Vital D, Luzardo-Ocampo I, Cuellar-Nuñez ML, Loarca-Piña G, Gonzalez de Mejia E. Maize extract rich in ferulic acid and anthocyanins prevents high-fat-induced obesity in mice by modulating SIRT1, AMPK and IL-6 associated metabolic and inflammatory pathways. The Journal of Nutritional Biochemistry. 2020; 79: 108343. https://doi.org/10.1016/j.jnutbio.2020.108343.

[139] Wu T, Yang L, Guo X, Zhang M, Liu R, Sui W. Raspberry anthocyanin consumption prevents diet-induced obesity by alleviating oxidative stress and modulating hepatic lipid metabolism. Food & Function. 2018; 9: 2112–2120. https://doi.org/10.1039/c7fo02061a.

[140] da Costa GF, Santos IB, de Bem GF, Cordeiro VSC, da Costa CA, de Carvalho LCRM, et al. The Beneficial Effect of Anthocyanidin-Rich Vitis vinifera L. Grape Skin Extract on Metabolic Changes Induced by High-Fat Diet in Mice Involves Antiinflammatory and Antioxidant Actions. Phytotherapy Research. 2017; 31: 1621–1632. https://doi.org/10.1002/ptr.5898.

[141] Cowan SF, Leeming ER, Sinclair A, Dordevic AL, Truby H, Gibson SJ. Effect of whole foods and dietary patterns on markers of subclinical inflammation in weight-stable overweight and obese adults: a systematic review. Nutrition Reviews. 2020; 78: 19–38. https://doi.org/10.1093/nutrit/nuz030.

[142] Chylikova J, Dvorackova J, Tauber Z, Kamarad V. M1/M2 macrophage polarization in human obese adipose tissue. Biomedical Papers of the Medical Faculty of the University Palacky, Olomouc, Czechoslovakia. 2018; 162: 79–82. https://doi.org/10.5507/bp.2018.015.

[143] Dorneles GP, Haddad DO, Fagundes VO, Vargas BK, Kloecker A, Romão PRT, et al. High intensity interval exercise decreases IL-8 and enhances the immunomodulatory cytokine interleukin-10 in lean and overweight-obese individuals. Cytokine. 2016; 77: 1–9. https://doi.org/10.1016/j.cyto.2015.10.003.

[144] Ngamsamer C, Sirivarasai J, Sutjarit N. The Benefits of Anthocyanins against Obesity-Induced Inflammation. Biomolecules. 2022; 12: 852. https://doi.org/10.3390/biom12060852.

[145] Li W, Chen W. Weight cycling based on altered immune microenvironment as a result of metaflammation. Nutrition & Metabolism. 2023; 20: 13. https://doi.org/10.1186/s12986-023-00731-6.

[146] Kang SH, Jeon YD, Moon KH, Lee JH, Kim DG, Kim W, et al. Aronia Berry Extract Ameliorates the Severity of Dextran Sodium Sulfate-Induced Ulcerative Colitis in Mice. Journal of Medicinal Food. 2017; 20: 667–675. https://doi.org/10.1089/jmf.2016.3822.

[147] Nikbakht E, Singh I, Vider J, Williams LT, Vugic L, Gaiz A, et al. Potential of anthocyanin as an anti-inflammatory agent: a human clinical trial on type 2 diabetic, diabetic at-risk and healthy adults. Inflammation Research. 2021; 70: 275–284. https://doi.org/10.1007/s00011-021-01438-1.

[148] Lee S, Keirsey KI, Kirkland R, Grunewald ZI, Fischer JG, de La Serre CB. Blueberry Supplementation Influences the Gut Microbiota, Inflammation, and Insulin Resistance in High-Fat-Diet-Fed Rats. The Journal of Nutrition. 2018; 148: 209–219. https://doi.org/10.1093/jn/nxx027.

[149] Guo H, Punvittayagul C, Vachiraarunwong A, Phannasorn W, Wongpoomchai R. Cancer chemopreventive potential of cooked glutinous purple rice on the early stages of hepatocarcinogenesis in rats. Frontiers in Nutrition. 2022; 9: 1032771. https://doi.org/10.3389/fnut.2022.1032771.

[150] Kiselova-Kaneva Y, Nashar M, Roussev B, Salim A, Hristova M, Olczyk P, et al. Sambucus ebulus (Elderberry) Fruits Modulate Inflammation and Complement System Activity in Humans. International Journal of Molecular Sciences. 2023; 24: 8714. https://doi.org/10.3390/ijms24108714.

[151] Magalhães IDFB, Figueirêdo ALM, da Silva EM, de Miranda AAB, da Rocha CQ, da Silva Calabrese K, et al. Effects of Passovia ovata Mistletoe on Pro-Inflammatory Markers In Vitro and In Vivo. Plants. 2023; 12: 1814. https://doi.org/10.3390/plants12091814.

[152] Nemes A, Homoki JR, Kiss R, Hegedűs C, Kovács D, Peitl B, et al. Effect of Anthocyanin-Rich Tart Cherry Extract on Inflammatory Mediators and Adipokines Involved in Type 2 Diabetes in a High Fat Diet Induced Obesity Mouse Model. Nutrients. 2019; 11: 1966. https://doi.org/10.3390/nu11091966.

[153] Wondmkun YT. Obesity, Insulin Resistance, and Type 2 Diabetes: Associations and Therapeutic Implications. Diabetes, Metabolic Syndrome and Obesity: Targets and Therapy. 2020; 13: 3611–3616. https://doi.org/10.2147/DMSO.S275898.

[154] Różańska D, Regulska-Ilow B. The significance of anthocyanins in the prevention and treatment of type 2 diabetes. Advances in Clinical and Experimental Medicine. 2018; 27: 135–142. https://doi.org/10.17219/acem/64983.

[155] Maxwell ND, Smiley CE, Sadek AT, Loyo-Rosado FZ, Giles DC, Macht VA, et al. Leptin Activation of Dorsal Raphe Neurons Inhibits Feeding Behavior. Diabetes. 2024; 73: 1821–1831. https://doi.org/10.2337/db24-0207.

[156] Obradovic M, Sudar-Milovanovic E, Soskic S, Essack M, Arya S, Stewart AJ, et al. Leptin and Obesity: Role and Clinical Implication. Frontiers in Endocrinology. 2021; 12: 585887. https://doi.org/10.3389/fendo.2021.585887.

[157] Theilade S, Christensen MB, Vilsbøll T, Knop FK. An overview of obesity mechanisms in humans: Endocrine regulation of food intake, eating behaviour and common determinants of body weight. Diabetes, Obesity & Metabolism. 2021; 23 Suppl 1: 17–35. https://doi.org/10.1111/dom.14270.

[158] Singh S, Netticadan T, Ramdath DD. Expression of cardiac insulin signalling genes and proteins in rats fed a high-sucrose diet: effect of bilberry anthocyanin extract. Genes & Nutrition. 2016; 11: 8. https://doi.org/10.1186/s12263-016-0516-4.

[159] Li D, Zhang Y, Liu Y, Sun R, Xia M. Purified anthocyanin supplementation reduces dyslipidemia, enhances antioxidant capacity, and prevents insulin resistance in diabetic patients. The Journal of Nutrition. 2015; 145: 742–748. https://doi.org/10.3945/jn.114.205674.

[160] Yan F, Dai G, Zheng X. Mulberry anthocyanin extract ameliorates insulin resistance by regulating PI3K/AKT pathway in HepG2 cells and db/db mice. The Journal of Nutritional Biochemistry. 2016; 36: 68–80. https://doi.org/10.1016/j.jnutbio.2016.07.004.

[161] Colorado D, Fernandez M, Orozco J, Lopera Y, Muñoz DL, Acín S, et al. Metabolic Activity of Anthocyanin Extracts Loaded into Non-ionic Niosomes in Diet-Induced Obese Mice. Pharmaceutical Research. 2020; 37: 152. https://doi.org/10.1007/s11095-020-02883-z.

[162] Tian L, Ning H, Shao W, Song Z, Badakhshi Y, Ling W, et al. Dietary Cyanidin-3-Glucoside Attenuates High-Fat-Diet-Induced Body-Weight Gain and Impairment of Glucose Tolerance in Mice via Effects on the Hepatic Hormone FGF21. The Journal of Nutrition. 2020; 150: 2101–2111. https://doi.org/10.1093/jn/nxaa140.

[163] Mokhtari Z, Hosseini E, Hekmatdoost A, Haskey N, Gibson DL, Askari G. The effects of fasting diets on nonalcoholic fatty liver disease. Nutrition Reviews. 2023; 81: 857–868. https://doi.org/10.1093/nutrit/nuac092.

[164] Mansouri A, Gattolliat CH, Asselah T. Mitochondrial Dysfunction and Signaling in Chronic Liver Diseases. Gastroenterology. 2018; 155: 629–647. https://doi.org/10.1053/j.gastro.2018.06.083.

[165] Al Mamun A, Wu Y, Jia C, Munir F, Sathy KJ, Sarker T, et al. Role of pyroptosis in liver diseases. International immunopharmacology. 2020; 84: 106489. https://doi.org/10.1016/j.intimp.2020.106489.

[166] Zhang T, Liu Q, Gao W, Sehgal SA, Wu H. The multifaceted regulation of mitophagy by endogenous metabolites. Autophagy. 2022; 18: 1216–1239. https://doi.org/10.1080/15548627.2021.1975914.

[167] Park YS, Choi SE, Koh HC. PGAM5 regulates PINK1/Parkin-mediated mitophagy via DRP1 in CCCP-induced mitochondrial dysfunction. Toxicology Letters. 2018; 284: 120–128. https://doi.org/10.1016/j.toxlet.2017.12.004.

[168] Li X, Shi Z, Zhu Y, Shen T, Wang H, Shui G, et al. Cyanidin-3-O-glucoside improves non-alcoholic fatty liver disease by promoting PINK1-mediated mitophagy in mice. British Journal of Pharmacology. 2020; 177: 3591–3607. https://doi.org/10.1111/bph.15083.

[169] Wang J, Zhao X, Zheng J, Herrera-Balandrano DD, Zhang X, Huang W, et al. In vivo antioxidant activity of rabbiteye blueberry (Vaccinium ashei cv. ‘Brightwell’) anthocyanin extracts. Journal of Zhejiang University. Science. B. 2023; 24: 602–616. https://doi.org/10.1631/jzus.B2200590.

[170] Wang L, Zhao Y, Zhou Q, Luo CL, Deng AP, Zhang ZC, et al. Characterization and hepatoprotective activity of anthocyanins from purple sweet potato (Ipomoea batatas L. cultivar Eshu No. 8). Journal of Food and Drug Analysis. 2017; 25: 607–618. https://doi.org/10.1016/j.jfda.2016.10.009.

[171] Xu Y, Ke H, Li Y, Xie L, Su H, Xie J, et al. Malvidin-3-O-Glucoside from Blueberry Ameliorates Nonalcoholic Fatty Liver Disease by Regulating Transcription Factor EB-Mediated Lysosomal Function and Activating the Nrf2/ARE Signaling Pathway. Journal of Agricultural and Food Chemistry. 2021; 69: 4663–4673. https://doi.org/10.1021/acs.jafc.0c06695.

[172] Wang Y, Zhao L, Wang D, Huo Y, Ji B. Anthocyanin-rich extracts from blackberry, wild blueberry, strawberry, and chokeberry: antioxidant activity and inhibitory effect on oleic acid-induced hepatic steatosis in vitro. Journal of the Science of Food and Agriculture. 2016; 96: 2494–2503. https://doi.org/10.1002/jsfa.7370.

[173] Park S, Cho SM, Jin BR, Yang HJ, Yi QJ. Mixture of blackberry leaf and fruit extracts alleviates non-alcoholic steatosis, enhances intestinal integrity, and increases Lactobacillus and Akkermansia in rats. Experimental Biology and Medicine. 2019; 244: 1629–1641. https://doi.org/10.1177/1535370219889319.

[174] Romualdo GR, de Souza IP, de Souza LV, Prata GB, Fraga-Silva TFDC, Sartori A, et al. Beneficial effects of anthocyanin-rich peels of Myrtaceae fruits on chemically-induced liver fibrosis and carcinogenesis in mice. Food Research International. 2021; 139: 109964. https://doi.org/10.1016/j.foodres.2020.109964.

[175] Song EK, Park H, Kim HS. Additive effect of walnut and chokeberry on regulation of antioxidant enzyme gene expression and attenuation of lipid peroxidation in d-galactose-induced aging-mouse model. Nutrition Research. 2019; 70: 60–69. https://doi.org/10.1016/j.nutres.2018.09.011.

[176] Zhang PW, Chen FX, Li D, Ling WH, Guo HH. A CONSORT-compliant, randomized, double-blind, placebo-controlled pilot trial of purified anthocyanin in patients with nonalcoholic fatty liver disease. Medicine. 2015; 94: e758. https://doi.org/10.1097/MD.0000000000000758.

[177] Glisan SL, Ryan C, Neilson AP, Lambert JD. Cranberry extract attenuates hepatic inflammation in high-fat-fed obese mice. Journal of Nutritional Biochemistry. 2016; 37: 60–66. https://doi.org/10.1016/j.jnutbio.2016.07.009.

[178] Fan M, Choi YJ, Tang Y, Bae SM, Yang HP, Kim EK. Efficacy and Mechanism of Polymerized Anthocyanin from Grape-Skin Extract on High-Fat-Diet-Induced Nonalcoholic Fatty Liver Disease. Nutrients. 2019; 11: 2586. https://doi.org/10.3390/nu11112586.

[179] Ezzat SM, Salama MM, Seif El-Din SH, Saleh S, El-Lakkany NM, Hammam OA, et al. Metabolic profile and hepatoprotective activity of the anthocyanin-rich extract of Hibiscus sabdariffa calyces. Pharmaceutical Biology. 2016; 54: 3172–3181. https://doi.org/10.1080/13880209.2016.1214739.

[180] Park M, Yoo JH, Lee YS, Lee HJ. Lonicera caerulea Extract Attenuates Non-Alcoholic Fatty Liver Disease in Free Fatty Acid-Induced HepG2 Hepatocytes and in High Fat Diet-Fed Mice. Nutrients. 2019; 11: 494. https://doi.org/10.3390/nu11030494.

[181] Madduma Hewage S, Prashar S, O K, Siow YL. Lingonberry Improves Non-Alcoholic Fatty Liver Disease by Reducing Hepatic Lipid Accumulation, Oxidative Stress and Inflammatory Response. Antioxidants. 2021; 10: 565. https://doi.org/10.3390/antiox10040565.

[182] Morrison MC, Liang W, Mulder P, Verschuren L, Pieterman E, Toet K, et al. Mirtoselect, an anthocyanin-rich bilberry extract, attenuates non-alcoholic steatohepatitis and associated fibrosis in ApoE(*)3Leiden mice. Journal of Hepatology. 2015; 62: 1180–1186. https://doi.org/10.1016/j.jhep.2014.12.011.

[183] Li X, Zhang Y, Yuan Y, Sun Y, Qin Y, Deng Z, et al. Protective Effects of Selenium, Vitamin E, and Purple Carrot Anthocyanins on D-Galactose-Induced Oxidative Damage in Blood, Liver, Heart and Kidney Rats. Biological Trace Element Research. 2016; 173: 433–442. https://doi.org/10.1007/s12011-016-0681-8.

[184] Hao R, Shan S, Yang D, Zhang H, Sun Y, Li Z. Peonidin-3-O-Glucoside from Purple Corncob Ameliorates Nonalcoholic Fatty Liver Disease by Regulating Mitochondrial and Lysosome Functions to Reduce Oxidative Stress and Inflammation. Nutrients. 2023; 15: 372. https://doi.org/10.3390/nu15020372.

[185] Tian L, Tan Y, Chen G, Wang G, Sun J, Ou S, et al. Metabolism of anthocyanins and consequent effects on the gut microbiota. Critical Reviews in Food Science and Nutrition. 2019; 59: 982–991. https://doi.org/10.1080/10408398.2018.1533517.

[186] Jayarathne S, Stull AJ, Park OH, Kim JH, Thompson L, Moustaid-Moussa N. Protective Effects of Anthocyanins in Obesity-Associated Inflammation and Changes in Gut Microbiome. Molecular Nutrition & Food Research. 2019; 63: e1900149. https://doi.org/10.1002/mnfr.201900149.

[187] Wang L, Jiang G, Jing N, Liu X, Li Q, Liang W, et al. Bilberry anthocyanin extracts enhance anti-PD-L1 efficiency by modulating gut microbiota. Food & Function. 2020; 11: 3180–3190. https://doi.org/10.1039/d0fo00255k.

[188] Wang H, Liu D, Ji Y, Liu Y, Xu L, Guo Y. Dietary Supplementation of Black Rice Anthocyanin Extract Regulates Cholesterol Metabolism and Improves Gut Microbiota Dysbiosis in C57BL/6J Mice Fed a High-Fat and Cholesterol Diet. Molecular Nutrition & Food Research. 2020; 64: e1900876. https://doi.org/10.1002/mnfr.201900876.

[189] Liu J, Hao W, He Z, Kwek E, Zhu H, Ma N, et al. Blueberry and cranberry anthocyanin extracts reduce bodyweight and modulate gut microbiota in C57BL/6 J mice fed with a high-fat diet. European Journal of Nutrition. 2021; 60: 2735–2746. https://doi.org/10.1007/s00394-020-02446-3.

[190] Zhang Y, Chang H, Shao S, Zhao L, Zhang R, Zhang S. Anthocyanins from Opuntia ficus-indica Modulate Gut Microbiota Composition and Improve Short-Chain Fatty Acid Production. Biology. 2022; 11: 1505. https://doi.org/10.3390/biology11101505.

[191] Mo J, Ni J, Zhang M, Xu Y, Li Y, Karim N, et al. Mulberry Anthocyanins Ameliorate DSS-Induced Ulcerative Colitis by Improving Intestinal Barrier Function and Modulating Gut Microbiota. Antioxidants. 2022; 11: 1674. https://doi.org/10.3390/antiox11091674.

[192] Chen J, Shu Y, Chen Y, Ge Z, Zhang C, Cao J, et al. Evaluation of Antioxidant Capacity and Gut Microbiota Modulatory Effects of Different Kinds of Berries. Antioxidants. 2022; 11: 1020. https://doi.org/10.3390/antiox11051020.

[193] Su H, Xie L, Xu Y, Ke H, Bao T, Li Y, et al. Pelargonidin-3-O-glucoside Derived from Wild Raspberry Exerts Antihyperglycemic Effect by Inducing Autophagy and Modulating Gut Microbiota. Journal of Agricultural and Food Chemistry. 2020; 68: 13025–13037. https://doi.org/10.1021/acs.jafc.9b03338.

[194] Jennings A, Koch M, Jensen MK, Bang C, Kassubek J, Müller HP, et al. The role of the gut microbiome in the association between habitual anthocyanin intake and visceral abdominal fat in population-level analysis. The American Journal of Clinical Nutrition. 2020; 111: 340–350. https://doi.org/10.1093/ajcn/nqz299.

[195] Açar Y, Ağagündüz D, De Cicco P, Capasso R. Flavonoids: Their putative neurologic roles, epigenetic changes, and gut microbiota alterations in Parkinson’s disease. Biomedicine & Pharmacotherapy. 2023; 168: 115788. https://doi.org/10.1016/j.biopha.2023.115788.

[196] Zimmerman M, Morgan TA, Stanton K. The severity of psychiatric disorders. World Psychiatry. 2018; 17: 258–275. https://doi.org/10.1002/wps.20569.

[197] Dreiseitel A, Korte G, Schreier P, Oehme A, Locher S, Domani M, et al. Berry anthocyanins and their aglycons inhibit monoamine oxidases A and B. Pharmacological Research. 2009; 59: 306–311. https://doi.org/10.1016/j.phrs.2009.01.014.

[198] Thukham-Mee W, Wattanathorn J, Paholpak P, Ransikachi P, Piyavhatkul N. The Positive Modulation Effect of a 6-Week Consumption of an Anthocyanin-Rich Mulberry Milk on Working Memory, Cholinergic, and Monoaminergic Functions in Healthy Working-Age Adults. Oxidative Medicine and Cellular Longevity. 2021; 2021: 5520059. https://doi.org/10.1155/2021/5520059.

[199] Cásedas G, Les F, Gómez-Serranillos MP, Smith C, López V. Bioactive and functional properties of sour cherry juice (Prunus cerasus). Food & Function. 2016; 7: 4675–4682. https://doi.org/10.1039/c6fo01295g.

[200] Lu X, Zhou Y, Wu T, Hao L. Ameliorative effect of black rice anthocyanin on senescent mice induced by D-galactose. Food & Function. 2014; 5: 2892–2897. https://doi.org/10.1039/c4fo00391h.

[201] Gapski A, Gomes TM, Bredun MA, Ferreira-Lima NE, Ludka FK, Bordignon-Luiz MT, et al. Digestion behavior and antidepressant-like effect promoted by acute administration of blueberry extract on mice. Food Research International. 2019; 125: 108618. https://doi.org/10.1016/j.foodres.2019.108618.

[202] Shewale PB, Patil RA, Hiray YA. Antidepressant-like activity of anthocyanidins from Hibiscus rosa-sinensis flowers in tail suspension test and forced swim test. Indian Journal of Pharmacology. 2012; 44: 454–457. https://doi.org/10.4103/0253-7613.99303.

[203] Imran I, Javaid S, Waheed A, Rasool MF, Majeed A, Samad N, et al. Grewia asiatica Berry Juice Diminishes Anxiety, Depression, and Scopolamine-Induced Learning and Memory Impairment in Behavioral Experimental Animal Models. Frontiers in Nutrition. 2021; 7: 587367. https://doi.org/10.3389/fnut.2020.587367.

[204] Lopresti AL, Smith SJ, Hood SD, Drummond PD. Efficacy of a standardised saffron extract (affron®) as an add-on to antidepressant medication for the treatment of persistent depressive symptoms in adults: A randomised, double-blind, placebo-controlled study. Journal of Psychopharmacology. 2019; 33: 1415–1427. https://doi.org/10.1177/0269881119867703.

[205] Fisk J, Khalid S, Reynolds SA, Williams CM. Effect of 4 weeks daily wild blueberry supplementation on symptoms of depression in adolescents. The British Journal of Nutrition. 2020; 124: 181–188. https://doi.org/10.1017/S0007114520000926.

[206] Eker ME, Aaby K, Budic-Leto I, Brnčić SR, El SN, Karakaya S, et al. A Review of Factors Affecting Anthocyanin Bioavailability: Possible Implications for the Inter-Individual Variability. Foods. 2019; 9: 2. https://doi.org/10.3390/foods9010002.

[207] Gui H, Sun L, Liu R, Si X, Li D, Wang Y, et al. Current knowledge of anthocyanin metabolism in the digestive tract: absorption, distribution, degradation, and interconversion. Critical Reviews in Food Science and Nutrition. 2023; 63: 5953–5966. https://doi.org/10.1080/10408398.2022.2026291.

[208] Lila MA, Burton-Freeman B, Grace M, Kalt W. Unraveling Anthocyanin Bioavailability for Human Health. Annual Review of Food Science and Technology. 2016; 7: 375–393. https://doi.org/10.1146/annurev-food-041715-033346.

Funding

Ministry of Education, Science and Technology(RS-2025-00562716)

Busan Metropolitan City and Busan Techno Park

Rural Development Administration(RS-2022-RD010228)