Gut microbiota, immunity, and bile acid metabolism: decoding metabolic disease interactions

Abstract

In recent decades, the global prevalence of metabolic syndrome has surged, posing a significant public health challenge. Metabolic disorders, encompassing diabetes, obesity, nonalcoholic fatty liver disease, and polycystic ovarian syndrome, have been linked to alterations in the gut microbiota. Nonetheless, the connection between gut microbiota and host metabolic diseases warrants further investigation. In this review, we delve into the associations between various metabolic disorders and the gut microbiota, focusing on immune responses and bile acid (BA) metabolism. Notably, T helper cells, innate lymphoid cells, macrophages, and dendritic cells have been shown to modulate host metabolism through interactions with intestinal microorganisms and the release of cytokines. Furthermore, secondary BA metabolites, derived from the microbiota, are involved in the pathogenesis of metabolic diseases via the farnesoid X receptor and Takeda G protein-coupled receptor 5. By covering both aspects of this immune system-microorganism axis, we present a comprehensive overview of the roles played by the gut microbiota, microbiota-derived BA metabolites, and immune responses in metabolic diseases, as well as the interplay between these systems.

Graphical abstract

Keywords

intestinal microbiota / metabolic disease / immunity / bile acids

Introduction

Over the past few decades, with the improvement of living conditions and free access to high-caloric diets, a striking increase in the number of people with metabolic syndrome (MetS) worldwide has occurred, which has placed a great burden on human health and the global healthcare system [1]. The gut microbiota plays a critical role in host immune training, digestion of food, regulation of intestinal endocrine function and nerve signaling, alteration of drug action and metabolism, elimination of toxins, and the production of many compounds that affect the host [2]. Although common metabolic diseases, including type 2 diabetes (T2D) [3], obesity [4], non-alcoholic fatty liver disease (NAFLD) [5], and polycystic ovarian syndrome (PCOS) [6], differ greatly in pathology, they are associated with common and disease-­specific abnormalities in the composition and function of the gut microbiota.

Bile acid (BA)-modifying enzymes expressed by intestinal microbiota, including bile salt hydrolases (BSHs), metabolize primary BAs secreted by the liver and stored in the gallbladder into various secondary BAs [7]. Hydrophobic BAs at high concentrations reshape the gut microbiota composition mainly through membrane damage [8]. In addition to regulating the gut microbiota, these primary and secondary BAs influence the pathogenesis of metabolic diseases including NAFLD, T2D, and obesity by regulating receptors, including farnesoid X receptor (FXR) and Takeda G protein-coupled receptor 5 (TGR5) [9–12].

Chronic low-grade inflammation is a hallmark of metabolic diseases, suggesting that immune regulation, including adaptive immunity and innate immunity, plays an important role in affecting the course of metabolic diseases. Host immunity regulated by gut microbes has been reported to influence a variety of metabolic diseases. Bacteroides vulgatus aggravates PCOS by modulating BA profile and reducing type 3 innate lymphoid cell (ILC3)-produced interleukin (IL)-22 level [6]. Gut microbes, including segmented filamentous bacteria (SFB), prevent the development of obesity, MetS, and prediabetic phenotypes by inducing symbiotic-specific T helper 17 (Th17) cells [13].

In this review, we start with a description of the relationship between metabolic diseases and intestinal microbiota, and then highlight how this alters host immunity and BA metabolism. We then conclude with an overview of the crosstalk among BA metabolism, host immunity, and intestinal microbiota, as well as discussing the mechanisms by which these interactions involve intestinal microorganisms in various metabolic diseases.

Intestinal microbiota and metabolic diseases

Observations over the past two decades have suggested that the intestinal microbiome may contribute in important ways to the metabolic health of the human host. Hence, we summarize the changes in the composition of gut microbes in metabolic diseases and their role in these diseases (Fig. 1 and Table 1).

T2D

Increasing evidence has shown the difference in intestinal microbiota composition and metabolic characteristics between patients with T2D and healthy individuals, as well as the relationship between the intestinal microbiota and whole-body metabolism [14, 15]. Two metagenome analyses in China and Europe have demonstrated the structural characteristics of the intestinal microbiota in patients with T2D and healthy individuals. These studies showed that the conditioned pathogens, such as some Clostridium species, Escherichia coli, Eggerthella lenta, and Bacteroides caccae, were increased, while butyrate-producing bacteria, including Clostridiales sp. SS3/4, Roseburia intestinalis, Eubacterium rectale, and Faecalibacterium prausnitzii, were decreased in Chinese patients with T2D [3]. In European patients with T2D, the abundance of Lactobacillus gasseri, some Clostridiales species, Lactobacillus, and Streptococcus mutans was increased. Like the Chinese patients with T2D, a decrease in the abundance of butyrate-producing bacteria, including Eubacterium eligens, Bacteroides intestinalis, and Roseburia, was found [16]. The abundance of Akkermansia muciniphila, an emerging potential probiotic, was inversely correlated with the presence of overweight and diabetes in human and murine studies [17–19]. In addition, oral administration of A. muciniphila improved insulin resistance (IR) in diabetic mice, while decreasing body weight and the levels of blood markers related to liver dysfunction in humans with overweight and obesity [20, 21]. However, it is important to note that the clinical trial mentioned has limitations due to its small sample size, with a total of only 32 participants divided into three groups [21]. As a result, drawing definitive conclusions from such a study can be challenging. It is worth mentioning that a significant portion of the existing researches on A. muciniphila and its potential effects on obesity and T2D are derived from animal or preclinical studies [20, 22, 23]. While these studies provide valuable insights, the translation of findings from animal models to human subjects may not always be straightforward. To establish a more comprehensive understanding of the potential ameliorative effects of A. muciniphila on obesity and diabetes, further large-scale clinical trials with robust methodologies are necessary. These trials will provide more substantial evidence and help determine the true therapeutic potential of A. muciniphila in the context of obesity and diabetes. Like A. muciniphila, another short-chain fatty acids (SCFAs)-producing bacterium, Bifidobacterium animalis, has also been reported to be negatively associated with T2D [24].

Obesity

A poor lifestyle and dietary habits increase the probability of obesity, while evidence has shown that widespread use of antibiotics aggravates obesity, suggesting an important role of the intestinal microbiota in maintaining a proper body weight [25, 26]. Alyssa et al. concluded that antibiotic use can disrupt the gut microbiota, leading to changes in energy metabolism, increased adiposity, and obesity [27]. Nonetheless, a clinical study showed that the use of narrow-spectrum antibiotics (including penicillin and amoxicillin) was not associated with the development of obesity in infants while the use of broad-spectrum antibiotics was associated with early childhood obesity [28]. These studies suggest that not all intestinal microbes are related to obesity. Earlier studies have shown that a transferrable obesity-associated microbiota induces weight gain in lean mice [29]. Furthermore, twin studies have demonstrated that the abundance of bacterial producers of SCFAs, such as Eubacterium ventriosum, is associated with obesity, whereas butyrate producers, such as the methanogenic archaeon Methanobrevibacter smithii and Oscillospira spp., may be associated with leanness [30–33]. Meanwhile, other evidence has shown that SCFAs and SCFA producers contribute to the amelioration of obesity [34]. Administration of A. muciniphila and B. animalis, two SCFA-producing bacteria, improves metabolic indices in patients with obesity [21, 24]. Moreover, several studies have focused on dynamically linking changes in the levels of the major bacteria Bacteroides and Firmicutes to obesity and weight loss [35]. Compared with lean individuals, individuals with obesity presented a reduced proportion of Bacteroidetes and higher levels of Firmicutes. Interestingly, the relative abundance of Bacteroidetes increased while that of Firmicutes decreased after a dietary intervention to treat obesity [36]. Zuo et al. showed that the amount of Bacteroidetes and Clostridium perfringens was significantly lower in patients with obesity than in normal-weight individuals [37]. However, another study reported that the median proportion of Bacteroidetes was higher in individuals with overweight and obesity than lean participants, while Ruminococcus flavefaciens, a bacterial division of Firmicutes, was lower in patients with overweight and obesity, indicating that analysis for intestinal microbiota should be refined to the species classification [38].

NAFLD/non-alcoholic steatohepatitis (NASH)

NAFLD, which encompasses various forms of liver pathology, from simple hepatic steatosis to NASH, the inflammatory and aggressive form of NAFLD [39], has been frequently regarded as the hepatic manifestation of MetS. In many countries, the incidence of NAFLD or NASH is up to 20%–40% of adults, thus representing a very large unmet clinical need [40]. Increasing evidence has shown that the liver and gut are interdependent at multiple levels, and disturbance of the gut–liver axis has been implicated in a number of conditions linked to obesity, including NAFLD [41]. Patients with NAFLD have an increased abundance of Streptococcus, Clostridium, Escherichia, Lactobacillus, and Anaerobacter, while they have a decreased abundance of Flavonifaractor, Odoribacter, Alistipes spp., and Oscillibacter [42]. The abundance of Enterobacteriaceae, Proteobacteria, and Escherichia spp. is elevated in individuals with NASH [43]. To better understand the relationship between NASH/hepatic fibrosis and intestinal microbiota, researchers explored the intestinal microbiome as a biomarker to distinguish simple steatosis from NASH and NAFLD to cirrhosis. Based on a random forest machine learning algorithm, authors identified intestinal microbes that changed during different stages of NALFD, including the increased Veillonella parvula and decreased E. eligens during aggravation of fibrosis [44]. Besides, another study demonstrated that Clostridium spiroforme, Eubacterium dolichum, Streptococcus anginosus, and Veillonella dispar were significantly correlated with NAFLD progression, whereas Annona senegalensis, Lactobacillus crispatus, Limosilactobacillus vaginalis, and Weissella cibaria were significantly negatively associated with NAFLD progression (NAFLD, NASH, fibrosis, and cirrhosis) [45]. We previously showed that Bacteroides xylanisolvens degraded gut nicotine and alleviated smoking-related NASH [46]. In addition, the abundance of Veillonellaceae and Ruminococcaceae was correlated with fibrosis in lean individuals accompanied by enhanced fecal BAs and propionate, and administration of Veillonellaceae and Ruminococcaceae alleviated liver damage in NAFLD mouse models [47]. Given that the microbiota associated with NALFD is enriched in ethanol-producing bacteria, such as E. coli, it has been hypothesized that the aberrant gut microbiomes of individuals with NAFLD produce more ethanol than microbiomes of healthy individuals, as evidenced by increased concentrations of intrinsically generated ethanol in the circulation and breath [43, 48, 49].

PCOS

The relationship between PCOS and changes in intestinal microbiota has been the subject of numerous studies in recent years, which have shown significant differences in gut microbiota composition between patients with PCOS and healthy controls [50–52]. In addition to an alteration in α and β diversity in the gut microbiome, the studies showed that there is also an alteration in the balance of some species of bacteria, including Bacteroidetes and Firmicutes, in patients with PCOS [53]. At the genus level, Bacteroides, Escherichia/Shigella, and Lactobacillus were higher in patients with PCOS [54]. Furthermore, the relative abundance of Bacteroides coprophilus, Porphyromonas spp., and Blautia spp. was consistently higher in patients with PCOS, while Roseburia spp., Odoribacter spp., Anaerococcus spp., and Ruminococcus bromii were significantly lower [50]. Our research demonstrated that the abundance of B. vulgatus was markedly greater in patients with PCOS compared with healthy controls, and administration of B. vulgatus aggravated PCOS in mice [6]. In addition, beneficial bacteria, such as Lactobacilli and Bifidobacteria which enhance immunity and nutrient absorption, were instead significantly lower in patients with PCOS, while level of Prevotella, a proinflammatory gut microorganism, was greater in patients with PCOS, which may induce an adverse inflammatory effect in the host [55–60].

BA metabolism in metabolic diseases

Primary BAs are converted from cholesterol in the liver to taurine and glycine conjugates, which are secreted into the intestines, where they are transformed into secondary BAs [61]. These transformations form a BA pool with extensive diversity. Bacterial-transformed secondary BAs activate different BA receptors to regulate signaling pathways with broad coverage of complex symbiotic metabolism networks, including glucose metabolism, lipid metabolism, energy homeostasis, and inflammation [62]. These BA receptors include the liver X receptor, FXR, pregnane X receptor, and G protein-coupled receptors (GPCRs), such as TGR5. Here, we highlight the role of BAs in regulating metabolic diseases through these BA-binding receptors.

FXR

The major regulator of BA homeostasis is FXR, a ligand-activated member of the nuclear receptor superfamily [63], which can be bound by a number of endogenous BAs, including taurocholic acid (TCA), lithocholic acid (LCA), deoxycholic acid (DCA), chenodeoxycholic acid (CDCA), cholic acid (CA), and muricholic acid (MCA), at various affinities [64, 65]. In a previous paper, we explored the role of the FXR-BA axis in regulating metabolic disease [11], and here we summarize the role of BAs in metabolic disease. Notably, early studies revealed that Fxr-null mice had elevated triglyceride and serum cholesterol levels, and increased liver mass and peripheral IR when fed a standard low-fat diet [66, 67]. However, these mice had reduced adipocyte size and were protected from high-fat diet (HFD)-induced obesity and genetically induced obesity, as well as associated IR, suggesting an important role of FXR signaling in obesity and diabetes [68]. In a BA-FXR-ceramide axis, hepatic BA synthesis and intestinal microbiota-mediated BA deconjugation were upregulated upon HFD feeding, which resulted in increased levels of the endogenous FXR agonists CA, CDCA, DCA, and LCA. Intestinal FXR activation-induced genes (Smpd3/4, Sptlc2, and Cers4) involved in ceramide synthesis, which contributes to increased circulating ceramide levels that in turn promote metabolic disorders [69]. Dietary and drug interventions can regulate the abundance of BSH-secreting gut microbiota and these strategies can modulate BA deconjugation and levels of the endogenous FXR antagonists glycoursodeoxycholic acid (GUDCA), tauroursodeoxycholic acid (TUDCA), and tauro-β-muricholic acid (TβMCA), which contributes to an improvement in metabolic diseases. One study showed that glycine-β-muricholic acid (Gly-MCA) ameliorates NASH in mice by inhibiting intestinal FXR and reducing the production of ceramides [70]. Several of our studies have also illustrated the role of an intestinal FXR-ceramide axis in NASH. Mice treated with tempol or antibiotics exhibited altered BA composition, including the increased abundance of TβMCA, leading to fewer circulating ceramides and reduction of hepatic triglyceride accumulation. The administration of ceramides attenuated the effects of antibiotic treatment on the development of HFD-induced, intestinal FXR-dependent NAFLD [10]. In addition to regulating the production of ceramides by FXR, BAs can also regulate FXR by the production of fibroblast growth factor 15 (FGF15, FGF19 in humans) and TGR5, thus regulating metabolic disorders [69]. Different from the promotional effects of ceramide toward metabolic disorders, activation of intestinal FXR with an intestine-restricted agonist, fexaramine, results in decreased HFD-induced metabolic phenotypes in mice by increasing FGF15 synthesis, which is delivered to the liver where it decreases the expression of the hepatic BA synthesis enzyme cytochrome P450 family 7 subfamily A member 1 (CYP7A1) [71]. Later work found the potential mechanism. Notably, fexaramine alters the intestinal microbiota composition, including increasing the levels of Acetatifactor and Bacteroides, which are the predominant bacteria that convert CDCA and ursodeoxycholic acid (UDCA) to LCA, a secondary BA that acts as a TGR5 agonist [72]. However, a study showed that treatment with fexaramine failed to raise the concentrations of TGR5 ligands, modulate TGR5 signaling, or improve dysmetabolic status [73].

FXR, as an important receptor regulating metabolism, has attracted significant attention in drug development. Several licensed drugs targeting FXR have been reported. Obeticholic acid (OCA), a semisynthetic analog of CDCA, has shown potency ~100-fold higher than CDCA. It inhibits BA synthesis and reduces BA levels in hepatocytes. OCA has been approved for the treatment of primary biliary cholangitis, demonstrating efficacy in improving liver function and reducing alkaline phosphatase levels [74, 75]. In addition, based on the beneficial effects on hepatic inflammation and also on glucose and lipid metabolism, OCA has been shown to improve the histological features of NASH in a Phase 3 trial, including fibrosis [76]. 24-nor-ursodeoxycholic acid (norUDCA) (renamed as norucholic acid) is also a therapeutic modified BA that has shown promising results in Phase II clinical trials for the treatment of primary sclerosing cholangitis (PSC) [77]. Zhu et al. demonstrated that norUDCA ameliorates intestinal inflammation by regulating the intestinal Th17/regulatory T (Treg) cells balance and restricting glutaminolysis during Th17 cell differentiation [78]. As an oral ileal BA transporter inhibitor, elobixibat improves symptoms in patients with functional constipation by increasing BA levels in the colon [79].

TGR5

Gut microbiota-derived LCA activates TGR5 (which is expressed in enteroendocrine L cells) and induces the expression of the gene encoding TGR5, resulting in increased secretion of glucagon-like peptide 1 (GLP-1), thereby improving insulin sensitivity and reducing obesity through white adipose browning [72, 80, 81]. 6a-ethyl-23(S)-methyl-cholic acid (INT-777), a TGR5 agonist, increases energy expenditure and reduces hepatic steatosis and adiposity in diet-induced obesity (DIO) mice [82]. In addition, 6α-hydroxylated BAs, produced from primary BAs by intestinal bacteria when fed a Western-style diet, improve glucose metabolism via TGR5 signaling [83]. In a previous study, we identified hyocholic acid as an agonist of TGR5 and an inhibitor of FXR, improving glucose homeostasis [9]. In addition, we revealed a positive correlation between elevated TCA and DCA levels and activation of TGR5. This activation upregulated the expression of mitochondrial creatine kinase 2 and uncoupling protein 1, leading to an elevation of white adipose tissue thermogenesis [84]. Furthermore, glycodeoxycholic acid (GDCA) treatment improves IR, ovarian dysfunction, and infertility in mice with PCOS, while prevention of TGR5 signaling in Tgr5^−/− mice significantly reduced the enhanced IL-22 secretion by ILC3s [6]. An interesting study showed that genetic downregulation of hypothalamic TGR5 expression in the mediobasal hypothalamus promoted the development of obesity and aggravated established obesity by blunting sympathetic activity [85].

Furthermore, in addition to their binding to receptors such as FXR and TGR5, BAs have the capability to directly interact with mitochondria and regulate metabolic processes associated with the MetS. Specifically, DCA and taurodeoxycholic acid have been shown to induce mitochondrial reactive oxygen species (ROS) production and promote the activation of mitochondria-dependent receptor tyrosine kinases [86]. UDCA has demonstrated positive effects on glycemic parameters, insulin sensitivity, and surrogate markers of IR in patients with NASH [87, 88]. Researchers found that UDCA decreased lipid droplets (LDs), free fatty acids (FFAs), and triglycerides (TG) by improving mitochondrial function, including reduced ROS production and improved mitochondrial swelling [89]. Besides, CDCA was reported to suppress the progression of acute myeloid leukemia through synergistically promoting LD accumulation and lipid peroxidation via ROS/p38 mitogen-activated protein kinase/diacylglycerol O-acyltransferase 1 pathway, which is caused by mitochondrial dysfunction [90].

Intestinal and peripheral immunity in metabolic diseases

Aberrations in the communication between the adaptive and innate immune systems and the intestinal microbiota might contribute to complex diseases [91, 92]. The important relationship between metabolic diseases and host immunity has been widely reported. Given that point, we summarize here the changes in immune cells and related cytokines that occur in metabolic diseases along with the contributions of their regulations toward metabolic diseases (Fig. 2).

Peripheral immunity in metabolic diseases

Macrophages

Among immune cells infiltrating obese adipose tissue, macrophages dominate both in function and number [93]. In the adipose tissue of mice, the ratio of F4/80⁺ cells in obese mice is significantly higher than that in lean mice [94]. In addition to the number, adipose tissue macrophages (ATMs) exhibit significant cellular localization and inflammatory potential [95]. In lean animals, ATMs predominately display an alternatively activated (M2) phenotype, including the secretion of IL-10, and are less inflammatory than classically activated macrophages and uniformly dispersed throughout the adipose tissue. ATMs have a proinflammatory, classical (M1) phenotype, as characterized by the secretion of proinflammatory cytokines, and are primarily found in “crown-like” structures around dying adipocytes in obese mice [96–99]. Regarding the mechanism by which macrophages regulate obesity, cyclooxygenase 2, the rate-limiting enzyme in the biosynthesis of prostaglandin E2 (PGE2), limits adipose tissue dysfunction in obese mice dependent on PGE2 receptor subtype, E-type prostanoid receptor 4 [100].

The contributions of macrophages to the pathogenesis of NASH have been characterized most extensively in the liver. Pathways driven by macrophages include not only fibrosis and inflammation but also steatosis via secretion of tumor necrosis factor alpha (TNF-α), IL-1β, CC-chemokine ligand 2, and monocyte chemoattractant protein-1 (MCP-1) [101]. During NASH, inflammatory signals drive the hepatic recruitment of blood monocytes, which differentiate into monocyte-derived macrophages, thereby increasing the size of the macrophage pool in the liver. Recent studies have shown the diversity of hepatic macrophages in mouse models of NASH. During NASH, embryonically derived Kupffer cells (KCs), a class of resident macrophages present in the sinusoidal sinuses of the healthy liver, are gradually lost. Instead, circulating Ly6C⁺ monocytes are recruited to the liver, where they differentiate into monocyte-derived KCs to maintain the size of the KC pool. Compared with embryonically derived KCs, monocyte-derived KCs are more proinflammatory and affect the liver response to NASH by limiting liver lipid storage and promoting liver injury [102]. With lipid-associated macrophages identified to regulate metabolic homeostasis in a myeloid cell-2 (TREM2)-dependent manner [103]. TREM2 was reported to maintain macrophage-hepatocyte metabolic coordination in NAFLD and prolonged hyper nutrition leads to the production of proinflammatory cytokines, which induces TREM2 shedding through A disintegrin and metallopeptidase domain 17 (ADAM17)-dependent proteolytic cleavage and thus exacerbates the progression of NASH [104, 105]. In our research, we demonstrated that macrophage hypoxia-inducible factor 2-alpha (HIF-2α) alleviates IR by inhibiting NLRP3 [nucleotide-binding domain leucine-rich repeat (NLR) and pyrin domain containing receptor 3] inflammasome activation in a carnitine palmitoyltransferase 1a (CPT1A)-mediated, fatty acid oxidation (FAO)-enhanced manner [106]. Furthermore, macrophage HIF-1α activation triggers vascular inflammation and aggravates aortic dissection by increasing the expression and activity of ADAM17 [107].

T cells

Conventional T cells, expressing the αβT-cell receptor, represent more than 50% of the whole lymphocyte population. They recognize antigen peptides bound to their major histocompatibility complex protein on antigen-presenting cells and are mainly classified into CD8⁺ and CD4⁺ T cells. CD8⁺ cells are involved in macrophage activation, differentiation, and migration, thereby initiating inflammatory cascades in adipose tissue, thus leading to IR. Nevertheless, regarding adaptive immunity, CD4⁺ T cells seem to play a more important role in obesity and IR [108]. Interferon-γ (IFN-γ)–expressing CD4⁺ cells increase in obesity, and IFN-γ deletion improves obesity-induced IR and lowers macrophage infiltration in adipose tissue [109, 110]. A study demonstrated that DIO is predisposed to an increased Th17 bias [111]. Similarly, an increased number of Th17 cells and levels of IL-17 were also observed in adipose tissue and liver tissue in mice with DIO [112–114]. However, interesting findings were observed in the gut of obese mice fed an HFD, which demonstrated that the number of Th17 cells and levels of IL-17 were decreased [115, 116], suggesting different functions of Th17 cells in intestines, which will be discussed in the intestinal immune section below. A number of studies have shown that a dramatic reduction of visceral adipose tissue (VAT) Tregs occurs during DIO in mice [109, 117–119]. Like the findings in mice models, the number of CD4⁺Foxp3⁺ Treg is decreased in adipose tissue and peripheral blood from adult individuals with obesity and diabetes [120–122]. Rag1^−/− mice, lacking lymphocyte immune populations, showed a reversal of the NASH phenotype, suggesting the important role of lymphocytes in the pathogenesis of NASH [123]. Similarly, the depletion of CD8⁺ T cells also prevented liver damage and inflammation without altercating the systemic metabolic phenotype, providing clear evidence for the role of CD8⁺ T cells and their secreted cytokines in NASH development. These findings were reproduced in different nutritional and genetic NASH models associated with obesity; however, CD8⁺ cells seem not to play a central role in models of lean NASH [124, 125]. Th1 cells have been reported to be increased in individuals diagnosed with NASH and in obese mice fed high-caloric diet; however, their role in NASH has been poorly explored, and controversial evidence in experimental murine models exists [126, 127]. Like Th1, published data about Th2 cells and NASH are scarce. In mesenteric lymph nodes, the ratio of Th1/Th2 was shown to be altered in murine models of NAFLD [128]. In humans, the transition from simple fatty liver to NASH was shown to be determined by increased hepatic Th17 cells, expression of IL-17, and reduced frequency of Tregs [129]. IL-17 directly induces type I collagen production in hepatic stellate cells (HSCs) through the signal transducer and activator of transcription 3 pathway, and IL-17 receptor knockout inhibits the formation of hepatic fibrosis [130]. Single-cell metabolomics revealed that the regulation of IL-17A on the metabolic status of liver cells toward steatosis subsets depends on nuclear factor kappaB (NF-κB) [131], and a distinct pathogenic subgroup of liver inflammatory hepatic CXCR3⁺ Th17 (ihTh17) cells in NALFD mice and human patients was identified. Increased numbers of ihTh17 cells were observed in patients and mice with NALFD, and they accelerated the progression of NAFLD through a PKM2-dependent metabolic skewing [132]. In addition to αβT cells, a study focused on γδT cells showed that exogenous commensal lipid antigens augment the hepatic γδT-17 cell number and the microbiota accelerated NAFLD through hepatic γδT-17 cells [133]. At present, few studies on T cells and PCOS have been reported. According to a clinical study, researchers found that the percentage of Treg cells was significantly lower while the percentage of the Th17 cells of the PCOS group was significantly higher than that of the control group. In addition, the ratio of Treg/Th17 was significantly lower in the PCOS group [134].

ILCs

The ILC family consists of cytotoxic cells (natural killer (NK) cell) and non-cytotoxic subsets (ILC1, ILC2, and ILC3). Here we mainly discuss the role of NK cells and ILC3s in metabolic diseases. In humans, several studies have shown that the NK cell number is reduced in the peripheral blood in patients with obesity [135, 136]. However, murine models of obesity demonstrated NK cell accumulation in adipose tissue [137, 138]. One explanation for this disparity is that adipocytes in obesity secrete more MCP-1 and infiltrating NK cells in adipose tissue express higher levels of MCP-1 receptors, such as NKG2D, CD158, and NKp46, which are recruited into the adipose tissue to promote inflammation [139–141]. It is generally agreed that the activation and proliferation of NK cells in the VAT in the context of obesity also play important roles in IR and T2D through interaction with ATMs, triggering and amplifying the secretion of inflammatory cytokines, such as TNF-α and IL-6, by macrophages [142, 143]. The activity and frequency of NK cells in the adipose tissue were comparable in healthy individuals and those with NAFLD or NASH [144]. However, studies in mice have shown an increased accumulation of NK cells in adipose tissue after feeding with an HFD that presents a transcriptional profile different from control diet-fed mice, including increased IL6Ra and the myeloid marker Csf1 [145]. Emerging evidence suggests that ILC3s may regulate obesity or metabolic homeostasis through the secretion of IL-17A or IL-22 [146]. CCR6⁺ ILC3-derived IL-17A promotes the pathogenesis of obesity-associated airway hyperreactivity in Rag1^−/− mice that are dependent on HFD-induced, macrophage-derived IL-1β [147]. IL-22 is required for the prevention of obesity and IR through the regulation of triglyceride lipolysis and FAO in adipocytes. Mice lacking the IL-22 receptor are more susceptible to HFD-induced obesity and IR, and treatment of obese mice with IL-22 suppresses TNF expression in adipose tissue, as well as improving IR [148]. However, ILC3-derived IL-22 can also contribute to metabolic disease [149, 150]. A recent paper reconciled these seemingly contradicting reports and suggested that the role of ILC3s is context dependent [13]. The authors pointed out that ILC3s provide protection from metabolic disease in the absence of Th17 cells and when Th17 cells and Th17-inducing gut microbes are present, ILC3s counteract the protective effects of Th17 cells and promote the pathogenic effects of an HFD [13]. Similar to the protective effect of ILC3s in obesity, ILC3-derived IL-22 protects against obesity-associated NAFLD through the improvement of hepatic lipid metabolism and inhibition of palmitate-induced primary hepatocyte apoptosis [151]. Some published studies have shown a decreased level of RORγt⁺ IL-22⁺ ILC3s in blood and intestinal samples of patients with PCOS and animal models [51].

Dendritic cells (DCs)

Dendritic cells are part of a large and complex group of cells that comprise two major classes, notably, plasmacytoid DCs (pDCs) and conventional or classical DCs (cDCs) [152]. Upon local activation, DCs migrate to tissue-draining lymph nodes (DLNs) where they interact with naive T cells [153]. The presence of cDCs in the VAT has been reported in numerous studies. In patients, the presence of CD11c⁺ CD1c⁺ DCs correlates with the body-mass index (BMI) and an elevation in Th17 cells [154]. In addition, the depletion of CD11c⁺ cells (including CD11c⁺ monocytes/macrophages) results in the normalization of insulin sensitivity and the decrease of proinflammatory cytokines in obese mice [155, 156]. However, mice lacking conventional type 1 DCs (cDC1s) gained weight and were obese during aging, and another study showed that cDC1s promote an anti-inflammatory environment in the body that delays the development of obesity-associated chronic inflammation and IR via an IL-10-dependent activation of the Wnt/β-catenin pathway [157, 158]. Both subsets of cDCs (CD103⁺ cDC1s and CD11b⁺ cDC2s) are present in the liver of mice and accumulate during NASH [159, 160]. In addition, the number of liver cDC1s is higher in patients with NASH compared with the controls, and the increased number of cDC1s is associated with a greater degree of disease hallmarks of NASH [160]. However, their impact on NASH pathogenesis remains elusive. A recent study showed that the knockout of Atg5 in CD11c⁺ cells promotes the pathogenesis of NAFLD through the production of IL-23 in mice fed an HFD, suggesting a key role of liver DCs in accelerating NASH [161].

Intestinal immunity in metabolic diseases

In this section, we highlight the roles of intestinal immunity in obesity and diabetes, NASH/NAFLD, and PCOS in terms of mucosal immunity and its effects on the intestinal barrier and other aspects of gut immunity.

Obesity and diabetes

The intestines display altered immune composition during obesity and function as a crosstalk focus between the intestinal microbiota and intestinal barrier function [162]. In addition to the role of the intestinal physical barrier against gut microbiota, intestinal mucosal immunity is also involved in the regulation of intestinal microbiota. IgA is secreted across the intestinal epithelium in its dimeric form as secretory IgA, which binds to intestinal bacteria and their products to regulate microbiota composition and reduce microbial penetration across the intestinal barrier [163]. Reduced levels of secretory IgA in the stool during DIO in mice lead to dysbiosis, characterized by increased abundance of Proteobacteria and decreased abundance of Clostridia, accompanied by increased intestinal inflammation and reduced intestinal barrier integrity. In addition, HFD feeding induces a dysfunctional glucose metabolism in IgA-deficient mice [164]. As can be seen, a major consequence of the altered intestinal microbial composition in obesity is increased intestinal permeability, which increases leakage of bacteria or bacterial products, such as lipopolysaccharide (LPS), across the intestinal barrier [165–167]. Bacterial products trigger innate immunity, leading to chronic inflammation and metabolic diseases. LPS infusion for four consecutive weeks recapitulates many of the metabolic abnormalities that occur during ­high-caloric dietary consumption, such as elevated fasting blood sugar and insulin, increased adipose tissue, liver and body weight gain, and increased adipose tissue inflammation [167]. Loss of Clostridia and expansion of Desulfovibrio were key features associated with obesity, and administration of Clostridia rescued obesity by downregulating the expression of genes controlling lipid absorption and reducing adiposity. In addition, it was shown that IgA targeting of Clostridia and increased Desulfovibrio antagonize the colonization of beneficial Clostridia, while T follicular helper cell-dependent events are required to prevent the loss of Clostridia and expansion of Desulfovibrio [168].

In addition to the regulation of intestinal microbiota toward the metabolic diseases mediated by host intestinal immunity, host immunity can also affect the process of obesity and T2D through direct and indirect regulation of intestinal microbes. Mice fed an HFD show a reduction in the proportion of intestinal Th17 cells. In addition, gut-tropic Th17 cells promote the expansion of intestinal microbiota, including increasing the abundance of A. muciniphila, as well as controlling obesity and metabolic disorders via the secretion of IL-17 [169]. A. muciniphila has been shown to act as a probiotic that improves abnormal lipid metabolism and IR in mice and individuals with obesity and diabetes [21, 170, 171]. Studies have reported a variety of mechanisms by which A. muciniphila affects host metabolism. Administration of A. muciniphila reverses HFD-induced metabolic disorders by increasing the intestinal levels of endocannabinoids that control inflammation, improving the intestinal barrier, and promoting the secretion of a gut peptide, such as GLP-1 [20]. This improvement in the intestinal barrier is consistent with the treatment of A. muciniphila in mouse models of progeroid and atherosclerosis [172, 173]. In addition, Amuc_1100, a specific protein isolated from the outer membrane of A. muciniphila, has been reported to interact with Toll-like receptor 2 (TLR2) to improve the gut barrier, and its administration partly recapitulates the beneficial effects of the bacterium [22]. Recently, studies have shown that by interacting with TLR2, Amuc_1100 promotes the expression of 5-hydroxytryptamine (5-HT) in the intestine, which was negatively correlated with obesity in college students [174, 175]. SFB was identified as a Th17-induced bacteria that promotes the differentiation of Th17 cells by stimulating the secretion of serum amyloid A [176, 177]. Kawano et al. showed that HFD feeding eliminates the Th17 cell-inducing microbiota, including SFB, which disrupts Th17 cell-mediated intestinal immunity. Th17 cells were subsequently shown by the authors to protect mice from DIO and metabolic disease by regulating epithelial lipid absorption [13].

NAFLD and NASH

Like the disruption of the intestinal barrier exacerbated by obesity and diabetes, intestinal microbiota-induced intestinal barrier ­alteration also regulates the pathogenesis of NASH and NAFLD [178]. We have previously mentioned that HFD feeding damages the intestinal barrier in mice [179]. Using a dextran sulfate sodium (DSS)-induced colitis model, a model of intestinal barrier disruption, it was shown that exacerbation of diet-induced NASH in mice follows a breakdown of the intestinal barrier that is accompanied by an elevation of LPS in the serum [180]. A clinical study implied that fecal microbiota transplantation from healthy patients improves abnormal small intestinal permeability in patients with NAFLD, suggesting the important role of gut microbes in regulating the intestinal barrier in NAFLD and NASH [181]. Interestingly, enhanced mitochondrial activity was reported to reshape the intestinal microbiota composition, thereby delaying the progression of NASH, which is associated with a recovery of the intestinal barrier [182]. Importantly, disruption of the gut vascular barrier (GVB) and intestinal epithelial barrier is an early event in NASH pathogenesis, which was shown to be a prerequisite for the development of NASH [183]. By restoring the intestinal barrier, A. muciniphila was shown to ameliorate NAFLD [184, 185].

In addition to improving the intestinal barrier, A. muciniphila suppresses NASH-associated tumorigenesis through CXCR6⁺ natural killer T cells (NKT) [186]. Although Th17 cells in the liver exacerbate NASH progression, they are decreased in numbers in the small intestine of mice in a methionine choline-deficient (MCD) diet-induced NASH model, suggesting a different function for the cells in this tissue. Indeed, it has been shown that intestinal Th17 cells and IL-17 slow the progression of NAFLD/NASH, which is associated with the restoration of the intestinal barrier that is dependent on the gut microbiota [187]. Disruption of the intestinal barrier is thought to be a risk factor for NASH [179, 180]. As Th17 cell and IL-17 have been reported to improve the intestinal barrier and host MetS, we speculate that intestinal Th17 cells and IL-17 may play a protective role in the progression of NASH and NAFLD [13, 188, 189]. In addition to its role in the gut, Th17 has also been reported to migrate to the liver to aggravate hepatitis [190]. Candida albicans-specific Th17 cells migrate from the intestine to the liver where they activate the KCs through IL-17RA and aggravate ­alcohol-associated liver disease [190]. CX3CR1, a marker of NK cells, cytotoxic T lymphocytes, and macrophages, protects mice from excessive hepatic steatosis and inflammation that is accompanied by the regulation of the intestinal barrier. Depletion of intestinal microbiota by antibiotics promotes macrophage polarization in the liver, as well as improving steatohepatitis in mice [191].

PCOS

Clinical research has shown that zonulin and fatty acid-binding protein 2, two intestinal permeability markers, are not altered in women with PCOS compared with BMI-matched controls [192]. However, Lindheim et al. showed that serum diamine oxidase, a marker of intestinal epithelial damage, is significantly higher in patients with PCOS compared with controls [193]. More studies are expected to explore the relationship between PCOS and intestinal barrier.

Crosstalk between BA metabolism, immune, and intestinal microbiota in different metabolic diseases

By exploring the crosstalk between immunity and BA metabolism, we summarize the mechanisms of intestinal microbial regulation of metabolic diseases (Fig. 3 and Table 2).

Obesity and diabetes

Eggerthella lenta DSM2243, Bacteroides fragilis NCTC9343, and Ruminococcus gnavus ATCC29149 convert LCA to 3-oxolithocholic acid and isolithocholic acid (isoLCA) by bacterial hydroxysteroid dehydrogenases [194]. IsoLCA inhibits Th17 cell differentiation by directly binding to the key transcription factor RORγt and increases the differentiation of Treg cells through the production of mitochondrial ROS [195]. Myeloid differentiation ­primary-response gene 88 (MyD88) is the key adaptor for most TLRs, IL-1 receptor (IL-1R), and IL-18 receptor, which have been shown to play a role in obesity and diabetes [196–198]. Hepatocyte-specific deletion of MyD88 predisposes to inflammation, hepatic IR, and glucose intolerance through modulation of BA metabolism and regulation of FXR [199]. These studies suggest that the effect of BA metabolism on metabolic diseases through the regulation of host immunity also needs further study.

Our previous study showed that tempol, a member of a family of nitroxide compounds, reduces the BSH enzymatic activity in the feces by affecting gut microbiota, including decreased abundance of Lactobacillus caecum. This intervention increases the level of TβMCA, and thus decreases obesity and improves IR in mice downstream of inhibition of intestinal FXR [4]. In addition, we demonstrated that administration of metformin decreases the abundance of B. fragilis, as well as increasing the levels of GUDCA and TUDCA, in the gut, which is accompanied by the inhibition of intestinal FXR signaling. These results may offer at least one mechanism by which metformin improves glucose metabolism. Furthermore, we showed that treatment with B. fragilis reverses the metabolic improvement induced by metformin by reducing the TUDCA levels accompanied by a reduction of BSH activity. Finally, we showed that GUDCA is a novel FXR antagonist that shows therapeutic effects on IR and glucose intolerance [200].

NAFLD and NASH

Recent research has elaborated on the mechanism by which A. muciniphila regulates the pathogenesis of NASH. Treatment with A. muciniphila increases mitochondrial oxidation and regulates BA metabolism in the gut–liver axis, ameliorating oxidative stress-induced cell apoptosis in the intestine and thus leading to the reshaping of the intestinal microbiota. These metabolic improvements occurred with increased L-aspartate levels in the liver, which was transported from the gut. Meanwhile, administration of L-aspartate displayed beneficial metabolic effects and efficiently ameliorated metabolic dysfunction-associated fatty liver disease (MAFLD) in mice [201]. Five F. prausnitzii strains ameliorate NAFLD in mice, which is associated with the regulation of the gut microbiota and metabolic improvement, including enhanced production of SCFAs and regulation of amino acid metabolism [202]. In addition, the gut microbiota also regulates the development of NASH and NAFLD by affecting BA metabolism. Administration of a combination of A. muciniphila and quercetin ameliorated early obesity and NAFLD via remodeling of the intestinal microbiota and elevation of plasma levels of unconjugated hydrophilic BAs, as well as increased hepatic expression of BA synthesis and transport genes [203]. The BA analog and FXR agonist, OCA, has been shown to improve the histological features of NASH in a Phase 3 trial, including fibrosis [204]. Pharmacologic intervention with OCA protected against GVB disruption as a preventive and therapeutic agent [183]. Compared with FXR-induced reductions in TAG levels via an FXR-SHP-SREBP1c de novo lipogenesis pathway, it has been shown that FXR activation protects against NAFLD via BA-dependent reductions in lipid absorption [205]. In addition, apart from the regulation of FXR, TUDCA administration attenuates HFD-induced hepatic steatosis, inflammatory responses, obesity, and IR in mice by promoting the reconstitution of the intestinal microbiota and improving the intestinal barrier [206].

Our team has long been engaged in studies on the relationship between the intestinal microbiota, BA metabolism, FXR signaling, and the pathogenesis of NAFLD and NASH. In a previous review, we discussed the promotional effects of FXR signaling in NAFLD [10]. We further demonstrated that ablation of the intestinal microbiota alleviates obesity-induced hepatic steatosis in hamsters. This alleviation relied on the upregulation of cytochrome P450 family 7 subfamily B member 1 (CYP7B1) in the alternative BA synthesis pathway, leading to an increase in TβMCA levels that in turn inhibits FXR signaling [207]. Importantly, in a recent study, we elaborated on the mechanism by which the gut bacteria alleviate smoking-related NASH by degrading gut nicotine. Tobacco smoking is positively correlated with NAFLD [208, 209]. Nicotine accumulation in the gut activates AMPKα1 phosphorylation, which is bound to sphingomyelin phosphodiesterase 3 (SMPD3), a key enzyme in the ceramide biosynthesis pathway, and exacerbates NASH progression. Furthermore, we identified the gut bacterium B. xylanisolvens as a nicotine degrader, which reduces intestinal nicotine concentrations in nicotine-exposed mice and improves nicotine-exacerbated NAFLD progression [46].

PCOS

Though the relationship between the alteration of intestinal microbiota and PCOS has been established, only a few studies have reported the possible mechanisms by which the gut microbiome regulates PCOS. Intestinal microbiota-derived SCFA production may be only one of the mechanisms by which intestinal microorganisms regulate PCOS [210]. Zhang et al. identified an imbalance in the gut microbiota of patients with PCOS, showing that Bifidobacterium, Blautia, and Faecalibacterium were significantly more abundant in healthy individuals, whereas Clostridium and Parabacteroides were enriched in the PCOS group. They treated 14 patients with PCOS with the probiotic Bifidobacterium lactis V9 and found that this intervention significantly decreased the levels of luteinizing hormone (LH) and the ratio of LH/follicle-stimulating hormone (LH/FSH) in 9 volunteers. The abundance of B. lactis V9 was positively associated with the levels of SCFAs. In addition, the administration of B. lactis V9 changed the intestinal microbiota composition of patients with PCOS, including increasing the colonization of Akkermansia, Faecalibacterium, Butyricimonas, and Bifidobacterium [211]. F. prausnitzii and Akkermansia were reported to produce SCFAs and improve inflammation and host metabolism [212, 213]. The study by Zhang et al. showed a possible mechanism by which the microbiome affects PCOS. Namely, SCFAs bound to their receptors expressed on enteroendocrine cell membranes directly stimulate the release of gut–brain mediators, such as peptide YY (PYY) and ghrelin. The increased PYY and ghrelin influence the secretion of sex hormones by the hypophysis and hypothalamus through the gut–brain axis, thus exerting an impact on PCOS symptoms. Androgen-induced gut dysbiosis has been reported to disrupt glucolipid metabolism and endocrinal functions in PCOS [214]. A rat study showed that compared with letrozole-induced PCOS rats, the abundance of Clostridium, Lactobacillus, and Ruminococcus was decreased, while Prevotella increased compared with the control group. Transplantation of Lactobacillus or fecal microbiota from normal rats improved the PCOS phenotypes, and administration of Lactobacillus reduced androgen biosynthesis [56]. In addition, the abundance of Prevotella was positively associated with androgen levels, especially androstenedione and testosterone.

A study has shown that tempol ameliorates PCOS by modulating the compositions of the gut microbiota and its serum metabolites, including the reduction of serum stachyose and BA levels in PCOS rats [215]. However, the study lacked a mechanism to explain these effects. In our study, we elucidated the mechanism by which the intestinal microbiome regulates PCOS from the perspective of innate immunity and BA metabolism. First, the abundance of B. vulgatus was markedly increased in patients with PCOS compared with the healthy controls. In addition, B. vulgatus in individuals with PCOS showed an increase in the abundance of BSH genes, both of which lead to a reduction of GDCA and TUDCA in the stool and serum. Administration of B. vulgatus disrupted insulin sensitivity and ovarian function, resulting in a decreased level of TUDCA and infiltration of RORγT⁺ IL-22⁺ ILC3s in small intestine lamina propria (siLP). We then identified the preventive effect of IL-22 and GDCA in a prenatal anti-Müllerian hormone-induced PCOS model. By activating the GATA binding protein 3 (GATA3) signaling pathway, GDCA promotes the production of IL-22 dependent on the TGR5 receptor of ILC3s, as well as improving IR and ovarian dysfunction, in PCOS-like mice [6].

Conclusions and perspective

Mammals have trillions of microbes colonizing their intestines. These mutually beneficial microbes can affect many physiological functions of the host, such as regulating the host’s metabolism, enhancing the intestinal barrier function, and regulating the host’s immune function. In addition to understanding the relevant mechanisms, elucidation of microbial regulation of host immunity and metabolism provides new ideas and targets for the clinical treatment of metabolic diseases. A. muciniphila has been reported to improve the metabolism of mice and humans with obesity and diabetes [21, 22]. Although there is no direct clinical evidence that probiotics can treat NASH/NAFLD, several studies have demonstrated the enormous potential of gut microbes in the therapy of NASH. Duan et al. designed a bacteriophage to target Enterococcus faecalis, a cytolysin-positive bacterium that increases hepatitis, and this intervention attenuated alcoholic liver disease [216].

Regulations of probiotics on diseases by BA metabolism are also noteworthy. VSL#3 (a patented probiotic preparation consisting of eight different strains of probiotics) was reported to improve irritable bowel syndrome in patients probably by increasing the deconjugation and absorption of BAs, which resulted in a reduced bile salt load to the colon [217]. Importantly, VSL#3 demonstrated an improved effect on NASH in mice by improving the intestinal barrier and normalizing the dysregulation of BA synthesis and dysbiosis of intestinal microbiota [218, 219]. In a clinical trial, VSL#3 showed beneficial effects on alanine transaminase (ALT) and BMI in obese children with biopsy-proven NAFLD with the increase of GLP-1 [220]. Besides, Lactobacillus acidophilus KLDS1.0901 protected mice against HFD-induced NAFLD by improving liver characteristics through the improvement of intestinal barrier and reduced LPS level [221]. In a randomized controlled trial, combination of L. acidophilus and B. lactis decreased aspartate transaminase (AST) to platelet ratio index score and AST level in NASH patients.

Many human microbiota studies have confirmed the associations between the gut microbiome and their metabolites, BAs, and the development of metabolic diseases. However, the mechanism by which changes in gut microbiota abundance and/or function regulate the occurrence and development of metabolic diseases has not been fully elucidated. With further study on the function of microbiota, researchers have come to realize that gut microbiome can regulate the metabolic homeostasis by interacting with the host immune system through its metabolites and related receptors. Therefore, in recent years, engineered bacteria have been developed to act on the host metabolism by secreting bacterial immune factors. Hendrikx et al. engineered Lactobacillus reuteri to produce IL-22 in the intestine to induce expression of regenerating islet-derived 3 gamma (REG3G) and thus reduce ethanol-induced liver disease in mice [222]. In addition, the study of microbial metabolites also provides hints for the clinical treatment of metabolic diseases. As a kind of key endogenous metabolites, BAs have a wide range of effects on various physiological and pathological processes. For example, artificial BA analogs OCA and norUDCA have shown efficacy in clinical trials for NASH [204, 223]. However, OCA may not be approved for the NASH resolution as endpoint was not met. In addition, BAs may have potential off-target effects (such as pruritus, which can be triggered by multiple BAs, and is also a prominent side effect of the major potential clinical BA drug OCA in the field of hepatobiliary diseases) and thus it is difficult to specifically target a disease through modulation of BAs [204, 224]. As a proven drug for the treatment of PSC, UDCA showed controversial efficacy in the clinical therapy of NAFLD [225, 226]. While both UDCA and norUDCA improve NASH, norUDCA, unlike UDCA, offers protection against the development of steatosis and fibrosis, possibly through mechanisms independent of GPBAR1 (TGR5) and FXR [227]. The distinct mechanism of action of norUDCA has shown promising clinical results for NASH [228]. Another potential therapeutic option for NASH is INT-767, a semisynthetic BA that improves histopathological features in NASH mice by activating both FXR and TGR5 [229]. Tropifexor, on the other hand, is a selective, non-BA FXR agonist that has demonstrated high potency in target engagement and efficacy in animal models of NASH [230, 231]. In a Phase 2a/b clinical trial, tropifexor decreased ALT and hepatic fat fraction. However, like FXR agonists, tropifexor can cause pruritus in a dose-dependent manner [232]. In an in vitro study, both OCA and INT-767 reversed FFA-induced collagen deposition and metalloproteinase (MMP) reduction in HSCs. Tropifexor, although it reduced collagen deposition, did not show modulation of MMP levels [233]. As can be seen, the therapy strategy of metabolic diseases regarding intestinal microorganisms and microbiota-derived BA metabolites as drugs or targets is promising, but also tortuous. Meanwhile, encouragingly, immune targets for NASH/NAFLD are also undergoing clinical trials and preclinical trials, including an anti-IL-17 antibody and an anti-TNF-α drug (Pentoxyfylline) [130, 234, 235].

As a chronic disease, one of the future research directions of targeting intestinal microbes to treat metabolic disease is editing and modification of bacteria after thorough research on bacterial metabolism and host interactions. In this manner, edited intestinal microbes can be colonized once and work for a long time until they are no longer needed and can be cleaned out using the suicide system [236, 237]. Notably, engineered bacteria are currently safe and effective in the clinical treatment of phenylketonuria [238, 239]. However, E. coli Nissle 1917, as an easy-to-manipulate chassis, has a synthetic gene for colibactin which promotes the formation of DNA double-stranded breaks in mammalian DNA [240]. In the future, synthetic biology technology should be considered to target the elimination of harmful genes to ensure the safety of the host.

Historically, researchers have primarily relied on feces and colon contents to assess the composition of gut microbes and gut metabolites. However, it is important to note that pH, nutrient availability, and oxygen partial pressure can vary among regions of the intestine. Consequently, specific intestinal microbes occupying distinct functional and immune niches can be found in specific intestinal regions [241, 242]. Therefore, it became crucial for researchers to develop a method that allows for the collection of intestinal contents from different regions without causing disturbance. In response to this need, Shalon et al. developed a capsule device with a built-in collector, enabling the collection of contents from various regions of the intestine based on pH and intestinal retention time. Through their evaluation of this device, they demonstrated that the composition of intestinal microbiota and BA metabolites differed significantly across different intestinal regions [243].

In general, in this review, we discussed the relationship between intestinal microbiota, host immunity, BA metabolism, and metabolic diseases. By expounding on the crosstalk between intestinal microbiota, the immune system, and BA metabolism, we highlighted the mechanisms by which intestinal microbiota contribute to or ameliorate metabolic diseases, as well as providing a new perspective for the understanding of the pathogenesis of metabolic diseases and their clinical treatment.

References

[1] Eckel RH, Grundy SM, Zimmet PZ. The metabolic syndrome. Lancet 2005;365:1415–28.

[2] Lynch SV, Pedersen O. The human intestinal microbiome in health and disease. N Engl J Med 2016;375:2369–79.

[3] Qin J, Li Y, Cai Z et al. A metagenome-wide association study of gut microbiota in type 2 diabetes. Nature 2012;490:55–60.

[4] Li F, Jiang C, Krausz KW et al. Microbiome remodelling leads to inhibition of intestinal farnesoid X receptor signalling and decreased obesity. Nat Commun 2013;4:2384.

[5] Demir M, Lang S, Hartmann P et al. The fecal mycobiome in non-alcoholic fatty liver disease. J Hepatol 2022;76:788–99.

[6] Qi X, Yun C, Sun L et al. Gut microbiota-bile acid-interleukin-22 axis orchestrates polycystic ovary syndrome. Nat Med 2019;25:1225–33.

[7] Collins SL, Stine JG, Bisanz JE et al. Bile acids and the gut microbiota: metabolic interactions and impacts on disease. Nat Rev Microbiol 2022;21:236–47.

[8] Cai J, Sun L, Gonzalez FJ. Gut microbiota-derived bile acids in intestinal immunity, inflammation, and tumorigenesis. Cell Host Microbe 2022;30:289–300.

[9] Zheng X, Chen T, Jiang R et al. Hyocholic acid species improve glucose homeostasis through a distinct TGR5 and FXR signaling mechanism. Cell Metab 2021;33:791–803.e7.

[10] Jiang C, Xie C, Li F et al. Intestinal farnesoid X receptor signaling promotes nonalcoholic fatty liver disease. J Clin Invest 2015;125:386–402.

[11] Gonzalez FJ, Jiang C, Patterson AD. An intestinal microbiota-farnesoid X receptor axis modulates metabolic disease. Gastroenterology 2016;151:845–59.

[12] Jiang C, Xie C, Lv Y et al. Intestine-selective farnesoid X receptor inhibition improves obesity-related metabolic dysfunction. Nat Commun 2015;6:10166.

[13] Kawano Y, Edwards M, Huang Y et al. Microbiota imbalance induced by dietary sugar disrupts immune-mediated protection from metabolic syndrome. Cell 2022;185:3501–19.e20.

[14] Thingholm LB, Rühlemann MC, Koch M et al. Obese individuals with and without type 2 diabetes show different gut microbial functional capacity and composition. Cell Host Microbe 2019;26:252–64.e10.

[15] Yang G, Wei J, Liu P et al. Role of the gut microbiota in type 2 diabetes and related diseases. Metabolism 2021;117:154712.

[16] Karlsson FH, Tremaroli V, Nookaew I et al. Gut metagenome in European women with normal, impaired and diabetic glucose control. Nature 2013;498:99–103.

[17] Everard A, Lazarevic V, Derrien M et al. Responses of gut microbiota and glucose and lipid metabolism to prebiotics in genetic obese and diet-induced leptin-resistant mice. Diabetes 2011;60:2775–86.

[18] Santacruz A, Collado MC, García-Valdés L et al. Gut microbiota composition is associated with body weight, weight gain and biochemical parameters in pregnant women. Br J Nutr 2010;104:83–92.

[19] Karlsson CL, Onnerfält J, Xu J et al. The microbiota of the gut in preschool children with normal and excessive body weight. Obesity (Silver Spring) 2012;20:2257–61.

[20] Everard A, Belzer C, Geurts L et al. Cross-talk between Akkermansia muciniphila and intestinal epithelium controls diet-induced obesity. Proc Natl Acad Sci U S A 2013;110:9066–71.

[21] Depommier C, Everard A, Druart C et al. Supplementation with Akkermansia muciniphila in overweight and obese human volunteers: a proof-of-concept exploratory study. Nat Med 2019;25:1096–103.

[22] Plovier H, Everard A, Druart C et al. A purified membrane protein from Akkermansia muciniphila or the pasteurized bacterium improves metabolism in obese and diabetic mice. Nat Med 2017;23:107–13.

[23] Zhang J, Ni Y, Qian L et al. Decreased abundance of Akkermansia muciniphila leads to the impairment of insulin secretion and glucose homeostasis in lean type 2 diabetes. Adv Sci (Weinh) 2021;8:e2100536.

[24] Pedret A, Valls RM, Calderón-Pérez L et al. Effects of daily consumption of the probiotic Bifidobacterium animalis subsp. lactis CECT 8145 on anthropometric adiposity biomarkers in abdominally obese subjects: a randomized controlled trial. Int J Obes (Lond) 2019;43:1863–8.

[25] Mcallister EJ, Dhurandhar NV, Keith SW et al. Ten putative contributors to the obesity epidemic. Crit Rev Food Sci Nutr 2009;49:868–913.

[26] Cox LM, Blaser MJ. Antibiotics in early life and obesity. Nat Rev Endocrinol 2015;11:182–90.

[27] Wilkins AT, Reimer RA. Obesity, early life gut microbiota, and antibiotics. Microorganisms 2021;9:413.

[28] Bailey LC, Forrest CB, Zhang P et al. Association of antibiotics in infancy with early childhood obesity. JAMA Pediatr 2014;168:1063–9.

[29] Turnbaugh PJ, Ley RE, Mahowald MA et al. An obesity-associated gut microbiome with increased capacity for energy harvest. Nature 2006;444:1027–31.

[30] Fan Y, Pedersen O. Gut microbiota in human metabolic health and disease. Nat Rev Microbiol 2021;19:55–71.

[31] Gophna U, Konikoff T, Nielsen HB. Oscillospira and related bacteria - from metagenomic species to metabolic features. Environ Microbiol 2017;19:835–41.

[32] Miller TL, Wolin MJ, Conway de Macario E et al. Isolation of Methanobrevibacter smithii from human feces. Appl Environ Microbiol 1982;43:227–32.

[33] Tims S, Derom C, Jonkers DM et al. Microbiota conservation and BMI signatures in adult monozygotic twins. ISME J 2013;7:707–17.

[34] Canfora EE, Jocken JW, Blaak EE. Short-chain fatty acids in control of body weight and insulin sensitivity. Nat Rev Endocrinol 2015;11:577–91.

[35] Abenavoli L, Scarpellini E, Colica C et al. Gut microbiota and obesity: a role for probiotics. Nutrients 2019;11:2690.

[36] Ley RE, Bäckhed F, Turnbaugh P et al. Obesity alters gut microbial ecology. Proc Natl Acad Sci U S A 2005;102:11070–5.

[37] Zuo HJ, Xie ZM, Zhang WW et al. Gut bacteria alteration in obese people and its relationship with gene polymorphism. World J Gastroenterol 2011;17:1076–81.

[38] Schwiertz A, Taras D, Schäfer K et al. Microbiota and SCFA in lean and overweight healthy subjects. Obesity (Silver Spring) 2010;18:190–5.

[39] Brunt EM, Kleiner DE, Wilson LA et al. Nonalcoholic fatty liver disease (NAFLD) activity score and the histopathologic diagnosis in NAFLD: distinct clinicopathologic meanings. Hepatology 2011;53:810–20.

[40] Younossi ZM, Koenig AB, Abdelatif D et al. Global epidemiology of nonalcoholic fatty liver disease-meta-analytic assessment of prevalence, incidence, and outcomes. Hepatology 2016;64:73–84.

[41] Compare D, Coccoli P, Rocco A et al. Gut–liver axis: the impact of gut microbiota on non alcoholic fatty liver disease. Nutr Metab Cardiovasc Dis 2012;22:471–6.

[42] Jiang W, Wu N, Wang X et al. Dysbiosis gut microbiota associated with inflammation and impaired mucosal immune function in intestine of humans with non-alcoholic fatty liver disease. Sci Rep 2015;5:8096.

[43] Zhu L, Baker SS, Gill C et al. Characterization of gut microbiomes in nonalcoholic steatohepatitis (NASH) patients: a connection between endogenous alcohol and NASH. Hepatology 2013;57:601–9.

[44] Oh TG, Kim SM, Caussy C et al. A universal gut-microbiome-derived signature predicts cirrhosis. Cell Metab 2020;32:901.

[45] Wang T, Guo XK, Xu H. Disentangling the progression of non-alcoholic fatty liver disease in the human gut microbiota. Front Microbiol 2021;12:728823.

[46] Chen B, Sun L, Zeng G et al. Gut bacteria alleviate smoking-related NASH by degrading gut nicotine. Nature 2022;610:562–8.

[47] Lee G, You HJ, Bajaj JS et al. Distinct signatures of gut microbiome and metabolites associated with significant fibrosis in non-obese NAFLD. Nat Commun 2020;11:4982.

[48] Nair S, Cope K, Risby TH et al. Obesity and female gender increase breath ethanol concentration: potential implications for the pathogenesis of nonalcoholic steatohepatitis. Am J Gastroenterol 2001;96:1200–4.

[49] Dawes EA, Foster SM. The formation of ethanol in Escherichia coli. Biochim Biophys Acta 1956;22:253–65.

[50] Torres PJ, Siakowska M, Banaszewska B et al. Gut microbial diversity in women with polycystic ovary syndrome correlates with hyperandrogenism. J Clin Endocrinol Metab 2018;103:1502–11.

[51] Insenser M, Murri M, Del Campo R et al. Gut microbiota and the polycystic ovary syndrome: influence of sex, sex hormones, and obesity. J Clin Endocrinol Metab 2018;103:2552–62.

[52] Liu R, Zhang C, Shi Y et al. Dysbiosis of gut microbiota associated with clinical parameters in polycystic ovary syndrome. Front Microbiol 2017;8:324.

[53] Zhou L, Ni Z, Cheng W et al. Characteristic gut microbiota and predicted metabolic functions in women with PCOS. Endocr Connect 2020;9:63–73.

[54] Guo J, Shao J, Yang Y et al. Gut microbiota in patients with polycystic ovary syndrome: a systematic review. Reprod Sci 2022;29:69–83.

[55] Ley RE. Gut microbiota in 2015: Prevotella in the gut: choose carefully. Nat Rev Gastroenterol Hepatol 2016;13:69–70.

[56] Guo Y, Qi Y, Yang X et al. Association between polycystic ovary syndrome and gut microbiota. PLoS One 2016;11:e0153196.

[57] Sherman SB, Sarsour N, Salehi M et al. Prenatal androgen exposure causes hypertension and gut microbiota dysbiosis. Gut Microbes 2018;9:400–21.

[58] Hofer U. Microbiome: pro-inflammatory Prevotella? Nat Rev Microbiol 2014;12:5.

[59] Jiang L, Shang M, Yu S et al. A high-fiber diet synergizes with Prevotella copri and exacerbates rheumatoid arthritis. Cell Mol Immunol 2022;19:1414–24.

[60] Zhao Q, Yu J, Zhou H et al. Intestinal dysbiosis exacerbates the pathogenesis of psoriasis-like phenotype through changes in fatty acid metabolism. Signal Transduct Target Ther 2023;8:40.

[61] Matsubara T, Li F, Gonzalez FJ. FXR signaling in the enterohepatic system. Mol Cell Endocrinol 2013;368:17–29.

[62] Cai J, Rimal B, Jiang C et al. Bile acid metabolism and signaling, the microbiota, and metabolic disease. Pharmacol Ther 2022;237:108238.

[63] Forman BM, Goode E, Chen J et al. Identification of a nuclear receptor that is activated by farnesol metabolites. Cell 1995;81:687–93.

[64] Makishima M, Okamoto AY, Repa JJ et al. Identification of a nuclear receptor for bile acids. Science 1999;284:1362–5.

[65] Parks DJ, Blanchard SG, Bledsoe RK et al. Bile acids: natural ligands for an orphan nuclear receptor. Science 1999;284:1365–8.

[66] Sinal CJ, Tohkin M, Miyata M et al. Targeted disruption of the nuclear receptor FXR/BAR impairs bile acid and lipid homeostasis. Cell 2000;102:731–44.

[67] Cariou B, van Harmelen K, Duran-Sandoval D et al. The farnesoid X receptor modulates adiposity and peripheral insulin sensitivity in mice. J Biol Chem 2006;281:11039–49.

[68] Prawitt J, Abdelkarim M, Stroeve JHM et al. Farnesoid X receptor deficiency improves glucose homeostasis in mouse models of obesity. Diabetes 2011;60:1861–71.

[69] Sun L, Cai J, Gonzalez FJ. The role of farnesoid X receptor in metabolic diseases, and gastrointestinal and liver cancer. Nat Rev Gastroenterol Hepatol 2021;18:335–47.

[70] Jiang J, Ma Y, Liu Y et al. Glycine-β-muricholic acid antagonizes the intestinal farnesoid X receptor-ceramide axis and ameliorates NASH in mice. Hepatol Commun 2022;6:3363–78.

[71] Fang S, Suh JM, Reilly SM et al. Intestinal FXR agonism promotes adipose tissue browning and reduces obesity and insulin resistance. Nat Med 2015;21:159–65.

[72] Pathak P, Xie C, Nichols RG et al. Intestine farnesoid X receptor agonist and the gut microbiota activate G-protein bile acid receptor-1 signaling to improve metabolism. Hepatology 2018;68:1574–88.

[73] Gillard J, Picalausa C, Ullmer C et al. Enterohepatic Takeda G-protein coupled receptor 5 agonism in metabolic dysfunction-associated fatty liver disease and related glucose dysmetabolism. Nutrients 2022;14:2707.

[74] Zhang Y, Jackson JP, St. Claire RL et al. Obeticholic acid, a selective farnesoid X receptor agonist, regulates bile acid homeostasis in sandwich-cultured human hepatocytes. Pharmacol Res Perspect 2017;5:e00329.

[75] Nevens F, Andreone P, Mazzella G et al. A placebo-controlled trial of obeticholic acid in primary biliary cholangitis. N Engl J Med 2016;375:631–43.

[76] Chapman RW, Lynch KD. Obeticholic acid-a new therapy in PBC and NASH. Br Med Bull 2020;133:95–104.

[77] Fickert P, Hirschfield GM, Denk G et al. norUrsodeoxycholic acid improves cholestasis in primary sclerosing cholangitis. J Hepatol 2017;67:549–58.

[78] Zhu C, Boucheron N, Rica R et al. 24-Nor-ursodeoxycholic acid counteracts TH17/Treg imbalance and ameliorates intestinal inflammation by restricting glutaminolysis in differentiating TH17 cells. bioRxiv, 2022.

[79] Nakajima A, Seki M, Taniguchi S et al. Safety and efficacy of elobixibat for chronic constipation: results from a randomised, double-blind, placebo-controlled, phase 3 trial and an open-label, single-arm, phase 3 trial. Lancet Gastroenterol Hepatol 2018;3:537–47.

[80] Pathak P, Liu H, Boehme S et al. Farnesoid X receptor induces Takeda G-protein receptor 5 cross-talk to regulate bile acid synthesis and hepatic metabolism. J Biol Chem 2017;292:11055–69.

[81] Chiang JYL, Ferrell JM. Bile acid receptors FXR and TGR5 signaling in fatty liver diseases and therapy. Am J Physiol Gastrointest Liver Physiol 2020;318:G554–73.

[82] Thomas C, Gioiello A, Noriega L et al. TGR5-mediated bile acid sensing controls glucose homeostasis. Cell Metab 2009;10:167–77.

[83] Makki K, Brolin H, Petersen N et al. 6α-hydroxylated bile acids mediate TGR5 signalling to improve glucose metabolism upon dietary fiber supplementation in mice. Gut 2023;72:314–24.

[84] Wu Q, Liang X, Wang K et al. Intestinal hypoxia-inducible factor 2α regulates lactate levels to shape the gut microbiome and alter thermogenesis. Cell Metab 2021;33:1988–2003.e7.

[85] Castellanos-Jankiewicz A, Guzmán-Quevedo O, Fénelon VS et al. Hypothalamic bile acid-TGR5 signaling protects from obesity. Cell Metab 2021;33:1483–92.e10.

[86] Fang Y, Han SI, Mitchell C et al. Bile acids induce mitochondrial ROS, which promote activation of receptor tyrosine kinases and signaling pathways in rat hepatocytes. Hepatology 2004;40:961–71.

[87] Ratziu V, de Ledinghen V, Oberti F et al. A randomized controlled trial of high-dose ursodesoxycholic acid for nonalcoholic steatohepatitis. J Hepatol 2011;54:1011–9.

[88] Tsuchida T, Shiraishi M, Ohta T et al. Ursodeoxycholic acid improves insulin sensitivity and hepatic steatosis by inducing the excretion of hepatic lipids in high-fat diet-fed KK-Ay mice. Metabolism 2012;61:944–53.

[89] Chen YS, Liu HM, Lee TY. Ursodeoxycholic acid regulates hepatic energy homeostasis and white adipose tissue macrophages polarization in leptin-deficiency obese mice. Cells 2019;8:253.

[90] Liu J, Wei Y, Jia W et al. Chenodeoxycholic acid suppresses AML progression through promoting lipid peroxidation via ROS/p38 MAPK/DGAT1 pathway and inhibiting M2 macrophage polarization. Redox Biol 2022;56:102452.

[91] Thaiss CA, Zmora N, Levy M et al. The microbiome and innate immunity. Nature 2016;535:65–74.

[92] Honda K, Littman DR. The microbiota in adaptive immune homeostasis and disease. Nature 2016;535:75–84.

[93] Odegaard JI, Chawla A. Alternative macrophage activation and metabolism. Annu Rev Pathol 2011;6:275–97.

[94] Weisberg SP, McCann D, Desai M et al. Obesity is associated with macrophage accumulation in adipose tissue. J Clin Invest 2003;112:1796–808.

[95] Lumeng CN, DelProposto JB, Westcott DJ et al. Phenotypic switching of adipose tissue macrophages with obesity is generated by spatiotemporal differences in macrophage subtypes. Diabetes 2008;57:3239–46.

[96] Lumeng CN, Bodzin JL, Saltiel AR. Obesity induces a phenotypic switch in adipose tissue macrophage polarization. J Clin Invest 2007;117:175–84.

[97] Lumeng CN, Deyoung SM, Saltiel AR. Macrophages block insulin action in adipocytes by altering expression of signaling and glucose transport proteins. Am J Physiol Endocrinol Metab 2007;292:E166–74.

[98] Odegaard JI, Ricardo-Gonzalez RR, Goforth MH et al. Macrophage-specific PPARγ controls alternative activation and improves insulin resistance. Nature 2007;447:1116–20.

[99] Chawla A, Nguyen KD, Goh YP. Macrophage-mediated inflammation in metabolic disease. Nat Rev Immunol 2011;11:738–49.

[100] Pan Y, Suga A, Kimura I et al. Cyclooxygenase-2 in adipose tissue macrophages limits adipose tissue dysfunction in obese mice. J Clin Invest 2022;132:e153589.

[101] Krenkel O, Tacke F. Liver macrophages in tissue homeostasis and disease. Nat Rev Immunol 2017;17:306–21.

[102] Huby T, Gautier EL. Immune cell-mediated features of non-alcoholic steatohepatitis. Nat Rev Immunol 2022;22:429–43.

[103] Jaitin DA, Adlung L, Thaiss CA et al. Lipid-associated macrophages control metabolic homeostasis in a Trem2-dependent manner. Cell 2019;178:686–98.e14.

[104] Hou J, Zhang J, Cui P et al. TREM2 sustains macrophage-hepatocyte metabolic coordination in nonalcoholic fatty liver disease and sepsis. J Clin Invest 2021;131:e135197.

[105] Wang X, He Q, Zhou C et al. Prolonged hypernutrition impairs TREM2-dependent efferocytosis to license chronic liver inflammation and NASH development. Immunity 2022;56:58–77.e11.

[106] Li X, Zhang X, Xia J et al. Macrophage HIF-2α suppresses NLRP3 inflammasome activation and alleviates insulin resistance. Cell Rep 2021;36:109607.

[107] Lian G, Li X, Zhang L et al. Macrophage metabolic reprogramming aggravates aortic dissection through the HIF1α-ADAM17 pathway^✰. EBioMedicine 2019;49:291–304.

[108] Sell H, Habich C, Eckel J. Adaptive immunity in obesity and insulin resistance. Nat Rev Endocrinol 2012;8:709–16.

[109] Winer S, Chan Y, Paltser G et al. Normalization of obesity-associated insulin resistance through immunotherapy. Nat Med 2009;15:921–9.

[110] Rocha VZ, Folco EJ, Sukhova G et al. Interferon-gamma, a Th1 cytokine, regulates fat inflammation: a role for adaptive immunity in obesity. Circ Res 2008;103:467–76.

[111] Winer S, Paltser G, Chan Y et al. Obesity predisposes to Th17 bias. Eur J Immunol 2009;39:2629–35.

[112] Zuniga LA, Shen WJ, Joyce-Shaikh B, et al. IL-17 regulates adipogenesis, glucose homeostasis, and obesity. J Immunol 2010;185:6947–59.

[113] Chen Y, Tian J, Tian X et al. Adipose tissue dendritic cells enhances inflammation by prompting the generation of Th17 cells. PLoS One 2014;9:e92450.

[114] Cavallari JF, Denou E, Foley KP et al. Different Th17 immunity in gut, liver, and adipose tissues during obesity: the role of diet, genetics, and microbes. Gut Microbes 2016;7:82–9.

[115] Garidou L, Pomié C, Klopp P et al. The gut microbiota regulates intestinal CD4 T cells expressing RORγt and controls metabolic disease. Cell Metab 2015;22:100–12.

[116] Cox LM, Yamanishi S, Sohn J et al. Altering the intestinal microbiota during a critical developmental window has lasting metabolic consequences. Cell 2014;158:705–21.

[117] Feuerer M, Herrero L, Cipolletta D et al. Lean, but not obese, fat is enriched for a unique population of regulatory T cells that affect metabolic parameters. Nat Med 2009;15:930–9.

[118] Deiuliis J, Shah Z, Shah N et al. Visceral adipose inflammation in obesity is associated with critical alterations in tregulatory cell numbers. PLoS One 2011;6:e16376.

[119] Cipolletta D, Kolodin D, Benoist C et al. Tissular T_regs: a unique population of adipose-tissue-resident Foxp3+CD4+ T cells that impacts organismal metabolism. Semin Immunol 2011;23:431–7.

[120] Yuan N, Zhang H-F, Wei Q et al. Expression of CD4+CD25+Foxp3+ regulatory T cells, interleukin 10 and transforming growth factor β in newly diagnosed type 2 diabetic patients. Exp Clin Endocrinol Diabetes 2018;126:96–101.

[121] Wagner NM, Brandhorst G, Czepluch F et al. Circulating regulatory T cells are reduced in obesity and may identify subjects at increased metabolic and cardiovascular risk. Obesity (Silver Spring) 2013;21:461–8.

[122] Gyllenhammer LE, Lam J, Alderete TL et al. Lower omental t-regulatory cell count is associated with higher fasting glucose and lower β-cell function in adults with obesity. Obesity (Silver Spring) 2016;24:1274–82.

[123] Ramadori P, Kam S, Heikenwalder M. T cells: friends and foes in NASH pathogenesis and hepatocarcinogenesis. Hepatology 2022;75:1038–49.

[124] Bhattacharjee J, Kirby M, Softic S et al. Hepatic natural killer T-cell and CD8⁺ T-cell signatures in mice with nonalcoholic steatohepatitis. Hepatol Commun 2017;1:299–310.

[125] Breuer DA, Pacheco MC, Washington MK et al. CD8⁺ T cells regulate liver injury in obesity-related nonalcoholic fatty liver disease. Am J Physiol Gastrointest Liver Physiol 2020;318:G211–24.

[126] Inzaugarat ME, Ferreyra Solari NE, Billordo LA et al. Altered phenotype and functionality of circulating immune cells characterize adult patients with nonalcoholic steatohepatitis. J Clin Immunol 2011;31:1120–30.

[127] Sun G, Jin H, Zhang C et al. OX40 regulates both innate and adaptive immunity and promotes nonalcoholic steatohepatitis. Cell Rep 2018;25:3786–99.e4.

[128] Su L, Wu Z, Chi Y et al. Mesenteric lymph node CD4⁺ T lymphocytes migrate to liver and contribute to non-alcoholic fatty liver disease. Cell Immunol 2019;337:33–41.

[129] Rau M, Schilling AK, Meertens J et al. Progression from nonalcoholic fatty liver to nonalcoholic steatohepatitis is marked by a higher frequency of Th17 cells in the liver and an increased Th17/resting regulatory T cell ratio in peripheral blood and in the liver. J Immunol 2016;196:97–105.

[130] Meng F, Wang K, Aoyama T et al. Interleukin-17 signaling in inflammatory, Kupffer cells, and hepatic stellate cells exacerbates liver fibrosis in mice. Gastroenterology 2012;143:765–776.e3.

[131] Rappez L, Stadler M, Triana S et al. SpaceM reveals metabolic states of single cells. Nat Methods 2021;18:799–805.

[132] Moreno-Fernandez ME, Giles DA, Oates JR et al. PKM2-dependent metabolic skewing of hepatic Th17 cells regulates pathogenesis of non-alcoholic fatty liver disease. Cell Metab 2021;33:1187–204.e9.

[133] Li F, Hao X, Chen Y et al. The microbiota maintain homeostasis of liver-resident γδT-17 cells in a lipid antigen/CD1d-dependent manner. Nat Commun 2017;7:13839.

[134] Yang Y, Xia J, Yang Z et al. The abnormal level of HSP70 is related to Treg/Th17 imbalance in PCOS patients. J Ovarian Res 2021;14:155.

[135] Viel S, Besson L, Charrier E et al. Alteration of natural killer cell phenotype and function in obese individuals. Clin Immunol 2017;177:12–7.

[136] Tobin LM, Mavinkurve M, Carolan E et al. NK cells in childhood obesity are activated, metabolically stressed, and functionally deficient. JCI Insight 2017;2:e94939.

[137] Wensveen FM, Jelenčić V, Valentić S et al. NK cells link obesity-induced adipose stress to inflammation and insulin resistance. Nat Immunol 2015;16:376–85.

[138] Lee BC, Kim M-S, Pae M et al. Adipose natural killer cells regulate adipose tissue macrophages to promote insulin resistance in obesity. Cell Metab 2016;23:685–98.

[139] Kanda H, Tateya S, Tamori Y et al. MCP-1 contributes to macrophage infiltration into adipose tissue, insulin resistance, and hepatic steatosis in obesity. J Clin Invest 2006;116:1494–505.

[140] Bahr I, Spielmann J, Quandt D et al. Obesity-associated alterations of natural killer cells and immunosurveillance of cancer. Front Immunol 2020;11:245.

[141] O’rourke RW, Gaston GD, Meyer KA et al. Adipose tissue NK cells manifest an activated phenotype in human obesity. Metabolism 2013;62:1557–61.

[142] Ferno J, Strand K, Mellgren G et al. Natural killer cells as sensors of adipose tissue stress. Trends Endocrinol Metab 2020;31:3–12.

[143] Bonamichi B, Lee J. Unusual suspects in the development of obesity-induced inflammation and insulin resistance: NK cells, iNKT cells, and ILCs. Diabetes Metab J 2017;41:229–50.

[144] Stiglund N, Strand K, Cornillet M et al. Retained NK cell phenotype and functionality in non-alcoholic fatty liver disease. Front Immunol 2019;10:1255.

[145] Theurich S, Tsaousidou E, Hanssen R et al. IL-6/Stat3-dependent induction of a distinct, obesity-associated NK cell subpopulation deteriorates energy and glucose homeostasis. Cell Metab 2017;26:171–84.e6.

[146] Zhou L, Lin Q, Sonnenberg GF. Metabolic control of innate lymphoid cells in health and disease. Nat Metab 2022;4:1650–9.

[147] Kim HY, Lee HJ, Chang YJ et al. Interleukin-17-producing innate lymphoid cells and the NLRP3 inflammasome facilitate obesity-associated airway hyperreactivity. Nat Med 2014;20:54–61.

[148] Wang X, Ota N, Manzanillo P et al. Interleukin-22 alleviates metabolic disorders and restores mucosal immunity in diabetes. Nature 2014;514:237–41.

[149] Wang Y, Kuang Z, Yu X et al. The intestinal microbiota regulates body composition through NFIL3 and the circadian clock. Science 2017;357:912–6.

[150] Sasaki T, Moro K, Kubota T et al. Innate lymphoid cells in the induction of obesity. Cell Rep 2019;28:202–17.e7.

[151] Hamaguchi M, Okamura T, Fukuda T et al. Group 3 innate lymphoid cells protect steatohepatitis from high-fat diet induced toxicity. Front Immunol 2021;12:648754.

[152] Ganguly D, Haak S, Sisirak V et al. The role of dendritic cells in autoimmunity. Nat Rev Immunol 2013;13:566–77.

[153] Merad M, Sathe P, Helft J et al. The dendritic cell lineage: ontogeny and function of dendritic cells and their subsets in the steady state and the inflamed setting. Annu Rev Immunol 2013;31:563–604.

[154] Bertola A, Ciucci T, Rousseau D et al. Identification of adipose tissue dendritic cells correlated with obesity-associated insulin-resistance and inducing Th17 responses in mice and patients. Diabetes 2012;61:2238–47.

[155] Patsouris D, Li PP, Thapar D et al. Ablation of CD11c-positive cells normalizes insulin sensitivity in obese insulin resistant animals. Cell Metab 2008;8:301–9.

[156] Stefanovic-Racic M, Yang X, Turner MS et al. Dendritic cells promote macrophage infiltration and comprise a substantial proportion of obesity-associated increases in CD11c⁺ cells in adipose tissue and liver. Diabetes 2012;61:2330–9.

[157] Macdougall CE, Wood EG, Loschko J et al. Visceral adipose tissue immune homeostasis is regulated by the crosstalk between adipocytes and dendritic cell subsets. Cell Metab 2018;27:588–601.e4.

[158] Hernandez-Garcia E, Cueto FJ, Cook ECL et al. Conventional type 1 dendritic cells protect against age-related adipose tissue dysfunction and obesity. Cell Mol Immunol 2022;19:260–75.

[159] Haas JT, Vonghia L, Mogilenko DA et al. Transcriptional network analysis implicates altered hepatic immune function in NASH development and resolution. Nat Metab 2019;1:604–14.

[160] Deczkowska A, David E, Ramadori P et al. XCR1⁺ type 1 conventional dendritic cells drive liver pathology in non-alcoholic steatohepatitis. Nat Med 2021;27:1043–54.

[161] Galle-Treger L, Helou DG, Quach C et al. Autophagy impairment in liver CD11c⁺ cells promotes non-alcoholic fatty liver disease through production of IL-23. Nat Commun 2022;13:1440.

[162] Winer DA, Luck H, Tsai S et al. The intestinal immune system in obesity and insulin resistance. Cell Metab 2016;23:413–26.

[163] Bunker JJ, Bendelac A. IgA responses to microbiota. Immunity 2018;49:211–24.

[164] Luck H, Khan S, Kim JH et al. Gut-associated IgA⁺ immune cells regulate obesity-related insulin resistance. Nat Commun 2019;10:3650.

[165] Amar J, Chabo C, Waget A et al. Intestinal mucosal adherence and translocation of commensal bacteria at the early onset of type 2 diabetes: molecular mechanisms and probiotic treatment. EMBO Mol Med 2011;3:559–72.

[166] Cani PD, Bibiloni R, Knauf C et al. Changes in gut microbiota control metabolic endotoxemia-induced inflammation in high-fat diet-induced obesity and diabetes in mice. Diabetes 2008;57:1470–81.

[167] Cani PD, Amar J, Iglesias MA et al. Metabolic endotoxemia initiates obesity and insulin resistance. Diabetes 2007;56:1761–72.

[168] Petersen C, Bell R, Klag KA et al. T cell-mediated regulation of the microbiota protects against obesity. Science 2019;365:eaat9351.

[169] Hong CP, Park A, Yang BG et al. Gut-specific delivery of T-helper 17 cells reduces obesity and insulin resistance in mice. Gastroenterology 2017;152:1998–2010.

[170] Shin NR, Lee JC, Lee HY et al. An increase in the Akkermansia spp. population induced by metformin treatment improves glucose homeostasis in diet-induced obese mice. Gut 2014;63:727–35.

[171] Zhao Q, Yu J, Hao Y et al. Akkermansia muciniphila plays critical roles in host health. Crit Rev Microbiol 2022;49:82–100.

[172] Barcena C, Valdés-Mas R, Mayoral P et al. Healthspan and lifespan extension by fecal microbiota transplantation into progeroid mice. Nat Med 2019;25:1234–42.

[173] Li J, Lin S, Vanhoutte PM et al. Akkermansia muciniphila protects against atherosclerosis by preventing metabolic endotoxemia-induced inflammation in Apoe^-/- mice. Circulation 2016;133:2434–46.

[174] Wang J, Xu W, Wang R et al. The outer membrane protein Amuc_1100 of Akkermansia muciniphila promotes intestinal 5-HT biosynthesis and extracellular availability through TLR2 signalling. Food Funct 2021;12:3597–610.

[175] Si J, Zhang H, Zhu L et al. The relationship between overweight/obesity and executive control in college students: the mediating effect of BDNF and 5-HT. Life (Basel) 2021;11:313.

[176] Goto Y, Panea C, Nakato G et al. Segmented filamentous bacteria antigens presented by intestinal dendritic cells drive mucosal Th17 cell differentiation. Immunity 2014;40:594–607.

[177] Ivanov I, Atarashi K, Manel N et al. Induction of intestinal Th17 cells by segmented filamentous bacteria. Cell 2009;139:485–98.

[178] Schnabl B, Brenner DA. Interactions between the intestinal microbiome and liver diseases. Gastroenterology 2014;146:1513–24.

[179] Rahman K, Desai C, Iyer SS et al. Loss of junctional adhesion molecule a promotes severe steatohepatitis in mice on a diet high in saturated fat, fructose, and cholesterol. Gastroenterology 2016;151:733–46.e12.

[180] Gabele E, Dostert K, Hofmann C et al. DSS induced colitis increases portal LPS levels and enhances hepatic inflammation and fibrogenesis in experimental NASH. J Hepatol 2011;55:1391–9.

[181] Craven L, Rahman A, Nair Parvathy S et al. Allogenic fecal microbiota transplantation in patients with nonalcoholic fatty liver disease improves abnormal small intestinal permeability: a randomized control trial. Am J Gastroenterol 2020;115:1055–65.

[182] Juárez-Fernández M, Goikoetxea-Usandizaga N, Porras D et al. Enhanced mitochondrial activity reshapes a gut microbiota profile that delays NASH progression. Hepatology 2023;77:1654–69.

[183] Mouries J, Brescia P, Silvestri A et al. Microbiota-driven gut vascular barrier disruption is a prerequisite for non-alcoholic steatohepatitis development. J Hepatol 2019;71:1216–28.

[184] Morrison MC, Gart E, Duyvenvoorde WV et al. Heat-inactivated Akkermansia muciniphila improves gut permeability but does not prevent development of non-alcoholic steatohepatitis in diet-induced obese Ldlr-/-Leiden mice. Int J Mol Sci 2022;23:2325.

[185] Shi Z, Lei H, Chen G et al. Impaired intestinal Akkermansia muciniphila and aryl hydrocarbon receptor ligands contribute to nonalcoholic fatty liver disease in mice. mSystems 2021;6:e00985-20.

[186] Li T, Lin X, Shen B et al. Akkermansia muciniphila suppressing nonalcoholic steatohepatitis associated tumorigenesis through CXCR6⁺ natural killer T cells. Front Immunol 2022;13:1047570.

[187] He S, Cui S, Song W et al. Interleukin-17 weakens the NAFLD/NASH process by facilitating intestinal barrier restoration depending on the gut microbiota. mBio 2022;13:e0368821.

[188] Leonardi I, Gao IH, Lin WY et al. Mucosal fungi promote gut barrier function and social behavior via type 17 immunity. Cell 2022;185:831–846.e14.

[189] Lee JS, Tato CM, Joyce-Shaikh B et al. Interleukin-23-independent IL-17 production regulates intestinal epithelial permeability. Immunity 2015;43:727–38.

[190] Zeng S, Rosati E, Saggau C et al. Candida albicans-specific Th17 cell-mediated response contributes to alcohol-associated liver disease. Cell Host Microbe 2023;31:389–404.e7.

[191] Schneider KM, Bieghs V, Heymann F et al. CX3CR1 is a gatekeeper for intestinal barrier integrity in mice: limiting steatohepatitis by maintaining intestinal homeostasis. Hepatology 2015;62:1405–16.

[192] Lingaiah S, Arffman RK, Morin-Papunen L et al. Markers of gastrointestinal permeability and dysbiosis in premenopausal women with PCOS: a case-control study. BMJ Open 2021;11:e045324.

[193] Lindheim L, Bashir M, Münzker J et al. Alterations in gut microbiome composition and barrier function are associated with reproductive and metabolic defects in women with polycystic ovary syndrome (PCOS): a pilot study. PLoS One 2017;12:e0168390.

[194] Paik D, Yao L, Zhang Y et al. Human gut bacteria produce T_H17-modulating bile acid metabolites. Nature 2022;603:907–12.

[195] Hang S, Paik D, Yao L et al. Bile acid metabolites control T_H17 and T_reg cell differentiation. Nature 2019;576:143–8.

[196] Kleinridders A, Schenten D, Könner AC et al. MyD88 signaling in the CNS is required for development of fatty acid-induced leptin resistance and diet-induced obesity. Cell Metab 2009;10:249–59.

[197] Everard A, Geurts L, Caesar R et al. Intestinal epithelial MyD88 is a sensor switching host metabolism towards obesity according to nutritional status. Nat Commun 2014;5:5648.

[198] Wen L, Ley RE, Volchkov PY et al. Innate immunity and intestinal microbiota in the development of type 1 diabetes. Nature 2008;455:1109–13.

[199] Duparc T, Plovier H, Marrachelli VG et al. Hepatocyte MyD88 affects bile acids, gut microbiota and metabolome contributing to regulate glucose and lipid metabolism. Gut 2017;66:620–32.

[200] Sun L, Xie C, Wang G et al. Gut microbiota and intestinal FXR mediate the clinical benefits of metformin. Nat Med 2018;24:1919–29.

[201] Rao Y, Kuang Z, Li C et al. Gut Akkermansia muciniphila ameliorates metabolic dysfunction-associated fatty liver disease by regulating the metabolism of L-aspartate via gut-liver axis. Gut Microbes 2021;13:1–19.

[202] Hu W, Gao W, Liu Z et al. Specific strains of Faecalibacterium prausnitzii ameliorate nonalcoholic fatty liver disease in mice in association with gut microbiota regulation. Nutrients 2022;14:2945.

[203] Juarez-Fernandez M, Porras D, Petrov P et al. The synbiotic combination of Akkermansia muciniphila and quercetin ameliorates early obesity and NAFLD through gut microbiota reshaping and bile acid metabolism modulation. Antioxidants (Basel) 2021;10:2001.

[204] Younossi ZM, Ratziu V, Loomba R et al. Obeticholic acid for the treatment of non-alcoholic steatohepatitis: interim analysis from a multicentre, randomised, placebo-controlled phase 3 trial. Lancet 2019;394:2184–96.

[205] Clifford BL, Sedgeman LR, Williams KJ et al. FXR activation protects against NAFLD via bile-acid-dependent reductions in lipid absorption. Cell Metab 2021;33:1671–1684.e4.

[206] Wang W, Zhao J, Gui W et al. Tauroursodeoxycholic acid inhibits intestinal inflammation and barrier disruption in mice with non-alcoholic fatty liver disease. Br J Pharmacol 2018;175:469–84.

[207] Sun L, Pang Y, Wang X et al. Ablation of gut microbiota alleviates obesity-induced hepatic steatosis and glucose intolerance by modulating bile acid metabolism in hamsters. Acta Pharm Sin B 2019;9:702–10.

[208] Ou H, Fu Y, Liao W et al. Association between smoking and liver fibrosis among patients with nonalcoholic fatty liver disease. Can J Gastroenterol Hepatol 2019;2019:6028952.

[209] Jung HS, Chang Y, Kwon MJ et al. Smoking and the risk of non-alcoholic fatty liver disease: a cohort study. Am J Gastroenterol 2019;114:453–63.

[210] Wang L, Zhou J, Gober HJ et al. Alterations in the intestinal microbiome associated with PCOS affect the clinical phenotype. Biomed Pharmacother 2021;133:110958.

[211] Zhang J, Sun Z, Jiang S et al. Probiotic Bifidobacterium lactis V9 regulates the secretion of sex hormones in polycystic ovary syndrome patients through the gut-brain axis. mSystems 2019;4:00017-19.

[212] Maldonado-Gomez MX, Martínez I, Bottacini F et al. Stable engraftment of Bifidobacterium longum AH1206 in the human gut depends on individualized features of the resident microbiome. Cell Host Microbe 2016;20:515–26.

[213] De La Cuesta-Zuluaga J, Mueller NT, Corrales-Agudelo V et al. Metformin is associated with higher relative abundance of mucin-degrading Akkermansia muciniphila and several short-chain fatty acid-producing microbiota in the gut. Diabetes Care 2017;40:54–62.

[214] Han Q, Wang J, Li W et al. Androgen-induced gut dysbiosis disrupts glucolipid metabolism and endocrinal functions in polycystic ovary syndrome. Microbiome 2021;9:101.

[215] Li T, Zhang T, Gao H et al. Tempol ameliorates polycystic ovary syndrome through attenuating intestinal oxidative stress and modulating of gut microbiota composition-serum metabolites interaction. Redox Biol 2021;41:101886.

[216] Duan Y, Llorente C, Lang S et al. Bacteriophage targeting of gut bacterium attenuates alcoholic liver disease. Nature 2019;575:505–11.

[217] Kim HJ, Vazquez Roque MI, Camilleri M et al. A randomized controlled trial of a probiotic combination VSL# 3 and placebo in irritable bowel syndrome with bloating. Neurogastroenterol Motil 2005;17:687–96.

[218] Mencarelli A, Cipriani S, Renga B et al. VSL#3 resets insulin signaling and protects against NASH and atherosclerosis in a model of genetic dyslipidemia and intestinal inflammation. PLoS One 2012;7:e45425.

[219] Jena PK, Sheng L, Li Y et al. Probiotics VSL#3 are effective in reversing non-alcoholic steatohepatitis in a mouse model. Hepatobiliary Surg Nutr 2020;9:170–82.

[220] Alisi A, Bedogni G, Baviera G et al. Randomised clinical trial: the beneficial effects of VSL#3 in obese children with non-alcoholic steatohepatitis. Aliment Pharmacol Ther 2014;39:1276–85.

[221] Wang Y, Wang Z, Wan Y et al. Assessing the in vivo ameliorative effects of Lactobacillus acidophilus KLDS1.0901 for induced non-alcoholic fatty liver disease treatment. Front Nutr 2023;10:1147423.

[222] Hendrikx T, Duan Y, Wang Y et al. Bacteria engineered to produce IL-22 in intestine induce expression of REG3G to reduce ethanol-induced liver disease in mice. Gut 2019;68:1504–15.

[223] Traussnigg S, Schattenberg JM, Demir M et al. Norursodeoxycholic acid versus placebo in the treatment of non-alcoholic fatty liver disease: a double-blind, randomised, placebo-controlled, phase 2 dose-finding trial. Lancet Gastroenterol Hepatol 2019;4:781–93.

[224] Yu H, Zhao T, Liu S et al. MRGPRX4 is a bile acid receptor for human cholestatic itch. Elife 2019;8:e48431.

[225] Troisi G, Crisciotti F, Gianturco V et al. The treatment with ursodeoxycholic acid in elderly patients affected by NAFLD and metabolic syndrome: a case-control study. Clin Ter 2013;164:203–7.

[226] Lindor KD, Kowdley KV, Heathcote EJ et al. Ursodeoxycholic acid for treatment of nonalcoholic steatohepatitis: results of a randomized trial. Hepatology 2004;39:770–8.

[227] Marchiano S, Biagioli M, Roselli R et al. Beneficial effects of UDCA and norUDCA in a rodent model of steatosis are linked to modulation of GPBAR1/FXR signaling. Biochim Biophys Acta Mol Cell Biol Lipids 2022;1867:159218.

[228] Traussnigg S, Schattenberg JM, Demir M et al. norUrsodeoxycholic acid (norUDCA) improves non-alcoholic fatty liver disease (NAFLD): results from a randomized placebo-controlled, double-blind phase IIa study. Hepatology 2017;66:106A–8.

[229] Roth JD, Feigh M, Veidal SS et al. INT-767 improves histopathological features in a diet-induced ob/ob mouse model of biopsy-confirmed non-alcoholic steatohepatitis. World J Gastroenterol 2018;24:195–210.

[230] Hernandez ED, Zheng L, Kim Y et al. Tropifexor-mediated abrogation of steatohepatitis and fibrosis is associated with the antioxidative gene expression profile in rodents. Hepatol Commun 2019;3:1085–97.

[231] Tully DC, Rucker PV, Chianelli D et al. Discovery of tropifexor (LJN452), a highly potent non-bile acid FXR agonist for the treatment of cholestatic liver diseases and nonalcoholic steatohepatitis (NASH). J Med Chem 2017;60:9960–73.

[232] Sanyal AJ, Lopez P, Lawitz EJ et al. Tropifexor for nonalcoholic steatohepatitis: an adaptive, randomized, placebo-controlled phase 2a/b trial. Nat Med 2023;29:392–400.

[233] Anfuso B, Tiribelli C, Adorini L et al. Obeticholic acid and INT-767 modulate collagen deposition in a NASH in vitro model. Sci Rep 2020;10:1699.

[234] Van Wagner LB, Koppe SWP, Brunt EM et al. Pentoxifylline for the treatment of non-alcoholic steatohepatitis: a randomized controlled trial. Ann Hepatol 2011;10:277–86.

[235] Zein CO, Yerian LM, Gogate P et al. Pentoxifylline improves nonalcoholic steatohepatitis: a randomized placebo-controlled trial. Hepatology 2011;54:1610–9.

[236] Russell BJ, Brown SD, Siguenza N et al. Intestinal transgene delivery with native E. coli chassis allows persistent physiological changes. Cell 2022;185:3263–77.e15.

[237] Jin M, Chen J, Zhao X et al. An engineered lambda phage enables enhanced and strain-specific killing of enterohemorrhagic Escherichia coli. Microbiol Spectr 2022;10:e0127122.

[238] Isabella VM, Ha BN, Castillo MJ et al. Development of a synthetic live bacterial therapeutic for the human metabolic disease phenylketonuria. Nat Biotechnol 2018;36:857–64.

[239] Puurunen MK, Vockley J, Searle SL et al. Safety and pharmacodynamics of an engineered E. coli Nissle for the treatment of phenylketonuria: a first-in-human phase 1/2a study. Nat Metab 2021;3:1125–32.

[240] Lynch JP, Goers L, Lesser CF. Emerging strategies for engineering Escherichia coli Nissle 1917-based therapeutics. Trends Pharmacol Sci 2022;43:772–86.

[241] Kastl AJ, Terry NA, Wu GD et al. The structure and function of the human small intestinal microbiota: current understanding and future directions. Cell Mol Gastroenterol Hepatol 2020;9:33–45.

[242] James KR, Gomes T, Elmentaite R et al. Distinct microbial and immune niches of the human colon. Nat Immunol 2020;21:343–53.

[243] Shalon D, Culver RN, Grembi JA et al. Profiling the human intestinal environment under physiological conditions. Nature 2023;617:581–91.

[244] Le Chatelier E, Nielsen T, Qin J et al. Richness of human gut microbiome correlates with metabolic markers. Nature 2013;500:541–6.

[245] Uusitupa HM, Rasinkangas P, Lehtinen MJ et al. Bifidobacterium animalis subsp. lactis 420 for metabolic health: review of the research. Nutrients 2020;12:892.

[246] Wang J, Tang H, Zhang C et al. Modulation of gut microbiota during probiotic-mediated attenuation of metabolic syndrome in high fat diet-fed mice. ISME J 2015;9:1–15.

[247] Verdam FJ, Fuentes S, de Jonge C et al. Human intestinal microbiota composition is associated with local and systemic inflammation in obesity. Obesity (Silver Spring) 2013;21:E607–15.

[248] Wang K, Liao M, Zhou N et al. Parabacteroides distasonis alleviates obesity and metabolic dysfunctions via production of succinate and secondary bile acids. Cell Rep 2019;26:222–35.e5.

[249] Yang J, Li Y, Wen Z et al. Oscillospira - a candidate for the next-generation probiotics. Gut Microbes 2021;13:1987783.

[250] Konikoff T, Gophna UO. A central, enigmatic component of the human gut microbiota. Trends Microbiol 2016;24:523–4.

[251] Barrow F, Khan S, Fredrickson G et al. Microbiota-driven activation of intrahepatic B cells aggravates NASH through innate and adaptive signaling. Hepatology 2021;74:704–22.

RIGHTS & PERMISSIONS

The Author(s) 2023. Published by Oxford University Press on behalf of Higher Education Press.