1 Introduction
As an essential source of dietary lipids, edible oils not only serve as a major energy source for the body and provide essential fatty acids that cannot be synthesized endogenously, but also play pivotal roles in the transport of fat-soluble vitamins, the construction of cell membranes, and the regulation of intracellular signaling pathways [
1]. The efficiency of edible oil digestion and absorption is closely related to human metabolic health and nutritional balance, and its disorder may lead to a series of metabolic diseases such as obesity, dyslipidemia and non-alcoholic fatty liver disease [
2].
Edible oil digestion and absorption is a complex process coordinated by multiple organs and steps, involving the sequential participation of the oral cavity, stomach, small intestine and other digestive organs, accompanied by a series of physical and chemical changes (such as emulsification, hydrolysis) and precise molecular regulatory mechanisms. Over the past few decades, several landmark discoveries have continuously deepened our understanding of edible oil digestion and intestinal lipid absorption, and the bibliometric data in Fig. 1 illustrates this trend. For instance, bile acids are essential for the emulsification and micellar solubilization of edible oils. Fatty acid transporters are key mediators of oil-derived fatty acid uptake. Importantly, lipid digestion and absorption are no longer regarded as a local enzymatic hydrolysis and intestinal transport event, but a sophisticated process regulated by multiple dimensions, including the gut-brain axis, microbiota-metabolite interactions, intestinal immune responses and intestinal endocrine system [
3–
4]. This shift has brought unprecedented opportunities for food engineering, enabling the development of functional foods targeting lipid metabolism.
In recent years, with the increasing attention to dietary health and the in-depth application of artificial intelligence technology in the field of food science, the research methods of edible oil digestion and absorption have been constantly innovated, which greatly promotes the in-depth exploration of its regulatory mechanisms. This review systematically combs the research history of edible oil digestion and absorption, summarizes the key processes of edible oil digestion and absorption, focuses on discussing the current research methods and regulatory strategies, and looks forward to the future research directions, aiming to provide references and ideas for subsequent related studies.
2 Historical Progress in Edible Oil Digestion and Intestinal Absorption
As shown in Fig. 2, research on lipid digestion and absorption has undergone a gradual evolution from elucidating the physicochemical processes within the intestinal lumen to analyzing the mechanisms of uptake by intestinal epithelial cells, intracellular transport, and systemic regulation methods. Initially, lipid digestion and absorption theory was at the hypothetical stage, with the core questions being whether lipids are first broken down before absorption and how undigested lipids are absorbed. In the early 20th century, Pflüger proposed the “lipolysis hypothesis,” which posited that dietary triacylglycerols (TAGs) must be completely hydrolyzed in the intestinal lumen into free fatty acids (FFAs) and glycerol, subsequently absorbed by the small intestine in a water-soluble form, completely resynthesized into TAGs within the small intestine, and ultimately enter the lymph in the form of TAGs [
5]. By the mid-20th century, Frazer proposed lipid absorption depends on the partitioning between the oil and water phases that TAGs are partially hydrolyzed into FFAs and glycerol, which are then absorbed by the small intestine in a water-soluble form. In addition, undigested TAGs are directly absorbed by the intestinal epithelium in the form of emulsified lipid droplets, without the resynthesis of TAGs in the small intestine, and lipid absorption depends on the partitioning between the oil and water phases [
5].
As research progressed, the early view that “fat particles enter intestinal cells directly” was gradually refuted. Researchers turned their attention to how lipid digestion products become solubilized in the aqueous intestinal lumen and reach the brush border of the small intestine. Subsequently, Verzar and McDougall discovered that fatty acids are soluble in bile salt solutions at pH levels close to the intestinal lumen. This further confirmed that bile salt-mediated mixed microemulsions play a central role in the transport of FFAs and monoglycerides (MAGs) through the undisturbed water layer to the brush border membrane [
6,
7].
Once it was established that FFAs and MAGs are absorbed in molecular form, the focus of research shifted to how they cross the intestinal epithelial cell membrane. In the 1970s, fatty acid-binding protein (FABP) was first discovered in the intestinal mucosa and other tissues, suggesting that the entry of long-chain fatty acids into intestinal epithelial cells does not rely solely on passive diffusion [
8]. Subsequently, the establishment of primary small intestinal epithelial cell culture systems [
9] and the Caco-2 cell model [
10] enabled the study of fatty acid absorption under controlled
in vitro conditions. With advances in molecular biology techniques, key molecules involved in lipid transmembrane uptake and intracellular processing have gradually been identified. For example, cluster of differentiation 36 (CD36) has been shown to participate in the transmembrane uptake of long-chain fatty acids [
11]. However, the relative contributions, functional complementarity, and regulatory mechanisms of CD36 and other candidate fatty acid transporters under different physiological conditions remain important research topics in this field [
12].
Another issue faced at that time was that, following the digestion of dietary TAGs in the intestinal lumen, intestinal epithelial cells primarily absorbed FFAs and MAGs; however, in the chyle entering the lymphatic system from the intestine, lipids were mainly present in the form of TAGs. Consequently, research began to investigate whether TAGs were resynthesized after the lipolysis products entered the intestinal epithelial cells. By gavaging rats with
14C-labeled palmitic acid and isolating small intestinal mucosa, it was demonstrated that intestinal epithelial cells possess the enzymatic capacity to synthesize MAGs, diglycerides (DAGs), and TAGs [
13]. Furthermore, studies have confirmed that 2-MAG can be directly re-esterified into DAGs and TAGs, which subsequently enter the lymph in the form of chylomicrons [
14]. Subsequently, microsomal triglyceride transfer protein (MTTP) was identified as a key molecule essential for the assembly of chylomicrons containing apolipoprotein B, thereby laying the molecular foundation for elucidating the mechanisms of chylomicron assembly and secretion within intestinal epithelial cells [
15–
16]. Subsequently, increasing evidence has revealed that chylomicron formation involves coordinated multicellular interactions among intestinal villus epithelial cells, the extracellular matrix, and the lymphatic vasculature. These dynamic interactions collectively regulate the packaging, trafficking, and transport of chylomicrons, facilitating efficient dietary lipid absorption [
17].
In recent years, lipid absorption has been viewed not merely as a simple transmembrane transport event of nutrients, but rather as a multidimensional regulatory process involving factors such as the intestinal lumen environment, gut microbiota, epithelial cell metabolism, organelle function, and circadian rhythms. For instance, Kuang et al. discovered that gut microbiota can influence the circadian rhythm and absorption efficiency of lipid metabolism by regulating histone deacetylase 3 (HDAC3) in intestinal epithelial cells [
18]. The re-esterification, processing, and export of lipids within intestinal epithelial cells are also highly dependent on the integrity of organelle function, and mitochondrial dysfunction may significantly disrupt the normal processing of dietary lipids in intestinal epithelial cells [
19]. Furthermore, Chan et al. further demonstrated that bile acid composition and bile salt pool characteristics can selectively modulate the solubilization behavior of different fatty acids, thereby affecting the intestinal absorption of FFAs [
20]. Research on lipid digestion and absorption has made significant breakthroughs in terms of experimental model standardization. The establishment of intestinal organoids derived from Lgr5
+ stem cells provided a model closer to the
in vivo environment for studying intestinal epithelial cell differentiation, lipid processing, and cell type-specific responses [
21]. The development of the INFOGEST
in vitro digestion method has improved the comparability and reproducibility of lipid digestion studies across different laboratories [
22–
23]. These methodological advancements have propelled research on lipid digestion and absorption from a relatively isolated analysis of digestion or transport processes towards a comprehensive investigation of multiscale physiological mechanisms.
3 Physicochemical Changes During Edible Oil Digestion
During gastrointestinal digestion, edible oils undergo a series of complex physical and chemical transformations under the combined action of digestive fluids, enzymes and peristalsis, as shown in Fig. 3.
3.1 Oral stage
The main component of edible oil is TAG, which accounts for more than 95% of their composition. A single TAG molecule consists of a glycerol backbone linked to three fatty acid molecules via ester bonds. The digestion of TAGs begins in the mouth. Dietary fats mix with salivary mucoproteins and undergo preliminary emulsification through the mechanical action of chewing and swallowing, forming a coarse emulsion. This emulsion subsequently undergoes bridging and attrition flocculation reactions. Food intake stimulates the secretion of lingual lipase from the tongue; however, this enzyme is present in only small amounts in adults and contributes minimally to lipid digestion in the oral cavity [
24].
Lingual lipase exhibits catalytic specificity at the
sn-1,3 position, demonstrating significantly higher hydrolytic activity toward short-chain and medium-chain triglycerides compared to long-chain TAGs. This enzyme is crucial for nutrient intake and energy supply in infants and young children, whose pancreases are not yet fully developed and whose pancreatic lipase activity is lower than that of adults; lingual lipase can penetrate milk fat globules and initiate lipid digestion [
25]. Short-chain and medium-chain fatty acids in milk fat are predominantly located at the
sn-3 site; lingual lipase can efficiently hydrolyze the ester bond at this site, releasing short-chain and medium-chain fatty acids that are easily absorbed by the body. Furthermore, for adults with insufficient pancreatic lipase secretion due to conditions such as pancreatic insufficiency, cystic fibrosis, and alcoholic pancreatitis, lingual lipase can also assist in fat breakdown.
3.2 Gastric stage
During the gastric digestion phase, the mechanical peristalsis of the gastric wall muscles (approximately 3 times per minute) and the continuous secretion of highly acidic gastric juice have a significant impact on the physicochemical state of dietary lipids [
26]. The stability of oil emulsions in the gastric lumen is highly dependent on the type of emulsifier and droplet size. Emulsions stabilized by nonionic surfactants (particle size < 0.6 μm) exhibit high tolerance to the gastric environment. In contrast, emulsions stabilized by ionizable surfactants or proteins, as well as oil-in-water emulsions with larger droplet sizes (≥ 15 μm), are highly prone to destabilization upon contact with gastric juice [
27]. This instability triggers changes in the composition of the interfacial layer, such as flocculation and coalescence, which in turn lead to an increase in emulsion droplet size. The physical stability of oil emulsions also affects the surface area of lipase adsorption, which in turn affects lipolysis kinetics. Accordingly, recent studies have focused on controlling emulsion structure during product formulation and processing, including droplet size, interfacial composition, and lipid phase composition. These structural modifications can regulate lipid digestion in the gastric phase and Infantes-Garcia et al. have provided a detailed review of this topic [
28].
The chemical digestion of lipids in the stomach primarily relies on human gastric lipase (molecular weight 50 kDa) [
29]. Both this enzyme and pepsin are secreted by the chief cells of the fundic glands, and their secretion rates and activity are regulated by the type and amount of food ingested [
30]. Dynamic changes in gastric pH directly affect enzyme activity: gastric lipase remains stable within a pH range of 2–7 and exhibits maximum lipolytic activity between pH 4.0 and 5.4; when pH drops to 4, its activity plummets to below 30% [
31]. Similar to lingual lipase, human gastric lipase preferentially hydrolyzes the ester bond at the
sn-1 or
sn-3 position. It initiates the hydrolysis of TAGs by binding to the oil-water interface, primarily producing DAGs and non-esterified fatty acids [
32]. In addition, gastric lipase also exhibits certain activity at the
sn-2 position, which can lead to the formation of
sn-1(3)- MAGs and glycerol in the gastric phase [
33].
As lipids are continuously broken down, these digestion products gradually enter the duodenum through gastric emptying [
34]. FFAs are more effective than TAGs in stimulating the release of satiety hormones, such as cholecystokinin (CCK), and slowing gastric emptying [
35]. In the future, more research is needed on the effects of different oils (lipid composition, physical state, etc.) on gastric emptying, as well as the gastric emptying patterns of lipids under different ages and disease states. The longer the fat emulsion remains in the stomach, the longer it is in contact with active enzymes, and the higher the degree of hydrolysis. The accumulation of long-chain fatty acids at the interface to form a strongly adsorbed layer inhibits the activity of gastric lipase [
36]. In healthy adults, the pre-duodenal digestion phase, including digestion in the oral cavity and stomach, accounts for only 10%–30% of total edible oil digestion [
37]. However, although this phase is limited, it is crucial for subsequent small intestinal digestion. The products of pre-duodenal digestion (such as FFAs and DAGs) not only further promote the emulsification of dietary fats and alter the interfacial properties of fat droplets but also facilitate the binding of lipases to fat droplets in the small intestine, thereby laying the foundation for the efficient digestion and absorption of lipids in the small intestine [
38].
3.3 Intestinal stage
As the emulsion passes through the pylorus, the frequent contractions of the pyloric sphincter cause the fat emulsion to be released into the duodenum in a “jet-like” manner, marking the beginning of the digestive phase of dietary fats in the small intestine [
39]. The high shear forces generated during this process further disperse fat droplets and promote emulsification. The small intestine of an adult is 5 to 6 meters long, consisting of the duodenum (20–25 centimeters), which is C-shaped, the jejunum (approximately 2.5 meters), and the ileum (approximately 3.0 meters) [
40]. Compared to oral and gastric digestion, fat emulsion stays in the small intestine for the longest time. Dietary lipids mix with intestinal fluids, which contain substances such as pancreatic lipase, co-lipase, proteases, bile salts, and phospholipids. Bile salts are amphiphilic, water-soluble steroid surfactants synthesized from cholesterol in the liver [
41]. They effectively adsorb at the oil-water interface and promote lipid emulsification by reducing the surface tension of the oil droplets. Recent studies have reported that when the molar ratio of bile salts to phospholipids is 9:4, the interfacial tension (IFT) at the oil–water interface is significantly reduced, thereby enhancing the lipolysis degree significantly [
42]. Pancreatic lipase is the primary lipase responsible for the hydrolysis of dietary lipids and is secreted from pancreatic tissue into the duodenum. Its active pH range is 4.5–7.5, with an optimal pH of 6.5 [
43].
Pancreatic lipase specifically acts on the ester bonds linking glycerol to fatty acid molecules, producing DAG, MAG, and FFA. The specific process is as follows: with the assistance of bile salts and co-lipases, pancreatic lipase competes for adsorption with the interface proteins of fat globules [
44]. Co-lipases keep the “cap” domain of pancreatic lipase in an open state, hydrolyzing the neutral lipids at the center of the fat globules. Pancreatic lipase first acts on the ester bond at the
sn-1 position, then on the ester bond at the
sn-3 position; that is, during the digestion of TAG molecules,
sn-2,3 DAG is first produced, which is then converted into
sn-2 MAG [
45]. Due to thermodynamic instability, the fatty acid molecule at the
sn-2 position undergoes molecular rearrangement (acyl transfer), transferring to the
sn-1 or
sn-3 position, where it is further hydrolyzed, ultimately yielding glycerol and FFA. Previous studies have shown that approximately 20%–25% of
sn-2 MAG is converted to
sn-1 or
sn-3 MAG, or that
sn-1,2 (
sn-2,3) DAG is converted to
sn-1,3 DAG, and is finally completely hydrolyzed [
35,
46,
47]. The affinity of pancreatic lipase for glycerides, ranked from highest to lowest, is as follows: TAGs > 1,2-DAGs > 1,3-DAGs > 1-MAGs > 2-MAGs [
48].
Both FFAs and MAGs are amphiphilic molecules, consisting of a hydrophobic portion (such as a saturated or unsaturated hydrocarbon chain) and a hydrophilic head group (such as a carboxyl group or glycerol functional group) [
49]. Bile salts and phospholipids (to a lesser extent) remove lipid digestion products accumulated at the interface by increasing the solubility of digestion products in the aqueous phase and forming mixed micelles [
50]. This process also promotes the transport of hydrophobic molecules into small intestinal epithelial cells. An increasing number of studies are focusing on the influence of emulsion components on the solubilization of fatty acids by bile salts [
51–
52]. Amphiphilic digestion products can also self-assemble into ordered structures within the intestinal lumen. Combining
in vitro digestion models with advanced techniques such as molecular dynamics small-angle X-ray scattering (SAXS) and small-angle neutron scattering (SANS) allows for the characterization of lipid mesophases [
53–
56]. These mesophases include the disordered inverse micellar (L2), inverse bi-continuous cubic (V2), inverse hexagonal (H2) phase, and inverse micellar cubic (I2, Fd3m space group) phase, as well as the fluid lamellar (Lα) phase [
57]. During the digestion process, solution conditions such as pH and ionic strength undergo significant changes, which in turn affect intermolecular forces and thereby alter the structural characteristics of dynamic self-assembly [
58].
4 Intestinal Uptake and Transport Mechanisms of Oil Digestion Products
There may be two transmembrane transport mechanisms of lipolysis products, one is passive transport, that is, simple diffusion or assisted diffusion depending on concentration. The major difference between these mechanisms is that the free diffusion does not have significant specificity. The free diffusion can be divided into three rapid and spontaneous processes: adsorption, transmembrane motion, and desorption. This mechanism shows that the membrane does not form a barrier for amphiphilic fatty acids, which can quickly pass through the phospholipid bilayer without the help of membrane proteins, and do not need membrane proteins to release fatty acids into the cytoplasm [
59]. It is generally believed that short chain and medium chain fatty acids (≤ 12C) can passively diffuse into small intestinal epithelial cells, due to their relatively higher water solubility than long-chain fatty acids (LCFAs), relies less on the solubilization effect of luminal micelles and can directly diffuse out of the basolateral side, enter the blood through the hepatic portal vein, and form very low-density lipoprotein (VLDL), which do not enter the lymphatic circulation. Kiela and Ghishan summarized that fat-soluble vitamins, including vitamins A, D, E, and K are passively absorbed by intestinal mucosa to form micelles and pre-chylomicron, and finally transferred to lymphatic vessels [
60].
When the extracellular concentration is low, the protein mediated uptake mechanism may become more important in the uptake of MAG and FFA of intestinal epithelial cells. Murota and Storch detected the cellular uptake of oleic acid and 2-oleic MAG taurocholic acid micellar solution in human intestinal Caco-2 cells. They found that the initial uptake rates of oleic acid and 2-MAG showed saturable dependence on their monomer concentrations, and that FFAs and 2-MAG competed for uptake [
61]. These findings suggest that at least part of the FFAs and 2-MAGs derived from dietary TAGs may be transported into intestinal cells through protein-mediated pathways in the postprandial state. The apparent Km of oleate was lower than the value of 2-MAG, indicating that the intestinal cells uptake rate of oleic acid faster than 2-MAG.
Many proteins on the cell membrane are related to fatty acid binding or transport, such as plasma membrane fatty acid binding protein (FABPpm), fatty acid transport proteins (FATPs) and CD36 [
62]. As the receptor of LCFA, FABPpm promotes the diffusion of fatty acid-albumin complex through the unstirred water layer, and then interacts with CD36 to mediate the transmembrane transport of LCFA [
63]. CD36, a highly glycosylated transmembrane protein also known as fatty acid translocase (FAT), which is largely located on the apical surface of proximal intestinal epithelial cells and needs to be dephosphorylated by intestinal alkaline phosphatase (IAP) [
64]. Palmitoylation modification facilitates CD36 localization on the cell membrane to bind FFAs and CD36 depalmitoylation is essential for its endocytosis-mediated FFA uptake [
65]. It appears that CD36 and FABPpm may collaborate to increase the rates of fatty acid transport, as these proteins co-immunoprecipitate [
66]. FATP4 is a member of the FFA transporter protein (FATP) family. It is highly expressed on the apical surface of mature small intestinal epithelial cells and is the only FATP protein expressed in intestinal cells.
After absorption of lipid digestion products, 2-MAG and FFA are mostly converted into TAGs in the endoplasmic reticulum of intestinal epithelial cells by monoacylglycerol acyltransferases (MGATs) and diacylglycerol acyltransferases (DGATs). These re-synthesized TAGs can either be stored as intracellular lipid droplets (LDs) or used for the assembly of intestinal lipoproteins, primarily chylomicrons, together with apoB48 synthesized by enterocytes [
67]. MTTP initiates the assembly of pre-chylomicron, and binds apoB48 co-translation to dense pre-chylomicron, while preventing the degradation of apoB48. Pre-chylomicron is contained in a unique transport vesicle, the pre-chylomicron transport vesicle (PCTV), which is sprouted from the ER membrane and transports to the Golgi apparatus [
68]. A newly discovered lipid binding protein proline-rich acid protein 1 (PRAP1) will directly bind TAG and then be recognized by MTTP to form a ternary complex, and promote MTTP mediated lipid transport [
69].
The final step in fat absorption is to secrete the resynthesized lipid through the basolateral membrane to the blood or lymph. Pre-chylomicron particles are transported from the endoplasmic reticulum to Golgi apparatus through the pre-chylomicron transport vesicles (PCTVs) for maturation, which is a rate-limiting step of lipid absorption from intestinal cells to lymphatic vessels. COPII starts this step and targets PCTV to Golgi apparatus. The transmembrane protein vesicle associated membrane protein 7 (VAMP7) and CD36 will promote the germination of PCTV from the endoplasmic reticulum. Pre-chylomicrons arrive at Golgi apparatus through PCTV docking for modification. Then, mature chylomicron particles are transported across Golgi apparatus to the basolateral membrane, and secreted into the intercellular space through exocytosis, and then enter the lamina propria, which is transported through the lymphatic system [
2].
In the normal lipid absorption process, the MAG pathway is the main pathway for the synthesis of triacylglycerol, because MAG and FFAs are effectively converted into TAG. The second way to form TAG that exists in the mucosa is α- glycerophosphate pathway, which involves the gradual acylation of glycerol-3-phosphate to form phosphatic acid. In the presence of phosphatidic acid phosphohydrolase, phosphatidic acid is hydrolyzed to form DAG, which is then converted to triacylglycerol. When MAG is abundant, the MAG pathway dominates and the glycerophosphate pathway is suppressed. On the contrary, the α-phosphorylation pathway dominates. Some lysophosphatidylcholine absorbed is reacylated to form phospholipids, and others are hydrolyzed to form glycerol-3-phosphate choline, which can be transported to the liver through the portal vein. The released fatty acids are then used for TAG synthesis. Finally, some lysophosphatidylcholine molecules combine to form a phospholipid molecule and a glycerol-3-phosphate choline molecule.
5 Research Models and Analytical Approaches
Research on lipid digestion and absorption is conducted both
in vivo and through
in vitro simulations.
in vitro models allow for an understanding of the lipid digestion process within the complex dynamic environment of the body using a simplified system. Since many causal mechanisms cannot be clearly studied
in vivo,
in vitro models help address this limitation [
70]. Furthermore, these
in vitro models can reduce the number of samples required, making them relatively cost-effective. Additionally, some studies combine
in vitro methods with
in vivo model or computer simulations to better understand and predict the fate of lipid digestion and absorption. Emerging artificial intelligence (AI) and machine learning (ML) are also being utilized as tools in the study of lipid digestion and absorption. Each method has its limitations, and the most appropriate model should be selected based on the specific research objectives [
71].
5.1 Research methods for oil digestion
The limitation of the in vitro digestive system is that it cannot simulate the complex hormonal feedback mechanisms in the human body that affect digestive motility. The comparative analysis between different in vitro models can be found in Table 1.
5.1.1 Static model
The static model is the preferred tool for the initial screening and basic research of lipid digestion mechanisms. In 2014, the International Food Digestive Union established a standardized static
in vitro digestion protocol; subsequently, revisions and enhancements were made in 2019 (INFOGEST 2.0) [
22–
23]. Static digestion models typically consist of three digestion stages (oral, gastric, and intestinal), though they can also be classified as single-chamber models that include either a gastric or intestinal stage. Reactors used in static models include beakers, conical flasks, reactors, or centrifuge tubes, with magnetic stirring or water bath agitation employed to simulate oral chewing and gastrointestinal peristalsis. Each stage has fixed simulation parameters, including temperature, pH, composition of digestive fluids, enzyme composition, and digestion duration.
Static models are usually combined with pH stat methods, using an automatic electric titrator to control the pH of the system. The total amount and kinetics of fatty acid release during digestion can be measured by the volume of alkali solution added dropwise. Static models have been widely used to compare the digestibility and digestion rates of edible oils (animal and vegetable oils), TAGs, DAGs, milk fat, and structured fats [
72–
81]. By adjusting digestive fluid pH, bile salt concentration, and lipase activity, the model can simulate the digestive patterns of different age groups (infants, adults, elderly) and even special disease populations [
82,
83]. Static models also have significant limitations. Because the static digestion process, gastric digestion and intestinal digestion are independent, and the intestine only has one chamber without continuous duodenum, jejunum, and ileum phases, so it cannot simulate the dynamic changes of the biochemical environment or physiological interactions with the host. In summary, static digestion models help explain how lipids are digested under specific conditions.
5.1.2 Semi-dynamic model
Semi-dynamic digestive models serve as an intermediate system between complex dynamic models and simpler static models, and are primarily used to simulate the dynamic characteristics of the gastrointestinal tract [
84]. Current research on semi-dynamic models focuses mainly on simulating the dynamic changes in gastric pH, controlling enzyme release, and studying mechanical aspects such as gastric motility and shear stress. In 2020, Mulet-Cabero et al. established a standardized semi-dynamic
in vitro digestion method suitable for food. The main advantage of this semi-dynamic protocol is the simulation of the transient nature of gastric secretions, gradual acidification and gastric emptying [
85]. This allows the evaluation of the changes occurring in food structure and disintegration. A key advantage of this semi-dynamic
in vitro digestion protocol lies in its capacity to mimic dynamic gastric secretion fluctuations, gradual pH decline and gastric emptying kinetics, which facilitates the investigation of changes occurring in lipid structure and disintegration. The recently developed digestion-chip, based on an incubation chamber integrated on a polymethyl methacrylate device, not only incorporates key features of semi-dynamic digestion, but also uses a smaller amount of samples and reagents [
86]. Currently, there is a lack of research on oil digestion using semi dynamic models. Lipolysis proceeded rapidly in the static model before reaching a stable plateau. In contrast, a delayed start of the hydrolysis process was showed in the semi-dynamic model [
87–
88].
5.1.3 Dynamic model
In vitro dynamic digestion models are designed to simulate the physiological and morphological characteristics of the gastrointestinal tract, including the continuous secretion of digestive juices, dynamic pH regulation, gastrointestinal motility, and gastric emptying [
89]. Compared to static and semi-dynamic methods, dynamic digestion models can provide data that closely resemble actual human physiological digestion; however, these models are more complex, more expensive, and require large amounts of enzymes and samples. Dupont et al. classified common dynamic models into single-compartment systems, such as DGM, HGS, and ARCOL, and multi-compartment systems, such as DIDGI, TIM, SHIME, ESIN, NERDT, and SHIME [
90]. Singh summarized the design features of dynamic gastric digestion models and the physical mechanisms of food decomposition [
91]. These dynamic gastric digestion models include DGM, HGS, DGIDI, GSM, ESIN, DIVHS and IMGS. The evolution of typical dynamic digestion model is illustrated in Fig. 4.
TIM-1 covers the stages of the stomach, duodenum, jejunum and ileum and it enables precise computer-controlled dynamic changes in gastrointestinal pH, chyme transit, and secretion rates of digestive fluids [
70]. Besides, TIM-1 was widely applied in the
in vitro digestion simulation of lipids, including oil and TAGs [
92–
93]. A semipermeable capillary membrane (0.05 µm pore size) connects the jejunal and ileal compartments in TIM-1, allowing micellized lipids to pass through passively. In static models, digestive products such as free fatty acids and monoglycerides accumulate at the interface, limiting the action of lipases; however, TIM-1 is able to remove them by simulating
in vivo absorption. The proportion of fatty acids that pass through is defined as the lipid bioavailability of TIM-1. Rogers and Wright summarized the research on the influence of different food structures on the accessibility of FFAs in oils by TIM-1 in the past ten years [
94]. It includes the emulsifier type, lipid crystallinity, TAG composition, infant formula milk powder and human milk, and the lipids contained in natural foods—eggs, steaks and hamburgers.
5.1.4 In vivo digestion
The endocrine changes caused by lipid in the human body can alter gastric emptying rate, while
in vitro dynamic digestion models typically use fixed emptying parameters. Rats serve as an effective model for studying how humans process dietary fat. Following oral administration of a lipid emulsion, gastric emptying was assessed using a paracetamol absorption test, and the levels of gastrointestinal hormones were measured in plasma [
102]. Digestion and absorption occur simultaneously in the body, therefore, the level of lipids in the small intestine content not only reflect the rate of lipid hydrolysis, but also the rate of lipid absorption into the bloodstream [
103]. Ren et al. [
104] investigated the lipolytic behaviors of butterfat and its fractions (30L and 30S) procured by dry fractionation at 30 °C using rat model. They found that the initial hydrolysis of TAGs to
sn-1,2-DAGs proceeded more slowly in the high-melting-point solid fat (30S) fraction rich in long-chain fatty acids compared with the low-melting-point liquid oil (30L) fraction rich in short-chain unsaturated fatty acids; moreover, after 30 minutes of digestion in the gastric phase, the hydrolysis rates were 39.22% and 60.11%, respectively. In addition,
in vivo experiments can also capture the dynamic spatiotemporal evolution of lipid digestion. Our laboratory used rat model to compare gastrointestinal digestive characteristics of three types of saturated oil (coconut oil, CO; lard fat, LO; palm oil, PO) and four types of unsaturated oils (beef tallow, BT; high-oleic sunflower oil, HOSO; sunflower oil, SO and linseed oil, LINO) [
105–
106]. The results suggested that the lipase and satiety-signaling hormones played important regulatory roles in the rate of oil digestion.
5.2 Research methods for oil absorption
A range of experimental models has been established to study edible oil absorption at cellular, tissue, whole-animal, and human physiological levels (Fig. 5). Besides, the comparative analysis between different absorption models can be found in Table 2.
5.2.1 Caco-2-based models and Caco-2/HT29-MTX co-culture systems
A monolayer model based on Caco-2 cells has been widely used to study the cellular stage of lipid absorption, particularly the absorption of FFAs, MAGs cholesterol, and fat-soluble micronutrients, as well as the assembly and secretion of chylomicron-like particles. Early studies have shown that Caco-2 monolayer cells can take up micellar lipid digestion products several FFAs and 2-MAGs, were formed a mixed micelle by bile salts and lysophospholipids and subsequently metabolized to resynthesize TAGs. This supports the Caco-2 monolayer cell model as an effective model to study the involvement of lipids in human intestinal absorption [
107]. Subsequent studies further demonstrated that the fatty acid composition of the apical lipid microenvironment can modulate TAG synthesis, apoB secretion, cholesterol trafficking, and the export of chylomicron-like lipoproteins. These findings indicate that Caco-2 cells function not merely as a passive permeability barrier, but retain key biochemical features of intestinal lipid processing [
108–
110]. The Caco-2/HT29-MTX co-culture introduces a mucus layer compared to a single Caco-2 monolayer model, and therefore can better mimic the physiological state of dietary lipids and mixed micelles entering the intestinal barrier in humans. Notably, the Caco-2/HT29-MTX co-culture model has been used to study oleic acid uptake and transport and has shown significantly better function than the Caco-2 monocultural model alone. This suggests that mucin-producing co-culture models may provide a more physiologically relevant interface to study lipid uptake, processing, and downstream lipid metabolism [
111]. However, although these models are relatively close to the theory of human intestinal absorption, they lack bile circulation, lymphatic drainage, immune-microbial interactions, and systemic lipid metabolism, so they need to be integrated with
ex vivo intestinal tissues, animal models, and human postprandial studies.
5.2.2 Intestinal organoids
Intestinal organoids have emerged as advanced
in vitro models for the study of nutrient absorption because they retain key structural and functional properties of native intestinal epithelial tissue, including stem cell self-renewal, epithelial cell polarity, and region-specific intestinal phenotypes [
112]. Compared with traditional two-dimensional cells, organoids can provide an experimental model that more closely resembles human physiology for studying how intestinal epithelial cells sense, absorb, metabolize, and secrete dietary lipid digestion products. In lipid absorption studies, primary mouse intestinal organoids have been used to simulate the processing of dietary TAG, lipoprotein synthesis, and gut-specific regulation of apolipoprotein C-III, indicating that this model can effectively characterize dietary lipid absorption and chylomicron-associated lipid transport. Subsequent studies further showed that basolateral lipid substrate transport is functionally linked to chylomicron secretion and can be regulated by apolipoprotein C-III-dependent mechanisms, which supports the use of intestinal organoids to unravel intestinal epithelial regulation of postprandial lipid transport [
113]. In addition to these lipid studies, intestinal organoids have been increasingly used in the fields of nutrition studies, transporter analysis, intestinal epithelial metabolism, and drug absorption, highlighting their practical value as platforms for the study of intestinal absorption and metabolism with high physiological relevance [
114–
115]. Recently, apical-out intestinal organoids partially overcome the technical limitations of traditional 3D organoids, with their apical surface facing the closed intestinal lumen, by directly exposing the absorptive epithelial surface to the culture medium, enabling the study of nutrient absorption, lipid-related transport processes, and intestinal metabolism without microinjection. However, intestinal organoids are still epithelial cell-centered systems and do not fully exhibit complex processes such as intestinal lipid digestion, hepato-intestinal circulation of bile acids, intestinal peristalsis, lymphatic chylomicron transport, immune-microbial interactions, and systemic lipid homeostasis [
116]. Therefore, organoids are more suitable as mechanistic models of intestinal epithelial lipid uptake, intracellular lipid processing, and lipoprotein secretion and should be used in integration with other model systems.
5.2.3 Everted gut sac model
The everted gut sac model is a classic method for preparing the intestinal tract
ex vivo. It can evaluate the transport process of substances from the mucosa to the serosal layer while retaining the natural structure of the intestinal tissue, including villus structure, epithelial polarity, mucus composition, and the specificity of each intestinal segment. In lipid digestion and absorption studies, its major value lies in its ability to capture tissue-level processes that are difficult to reproduce in two-dimensional epithelial cells, particularly the interactions between bile acid micelles, lipid digestion products, mucus barriers, and intestinal epithelial transport. Early studies based on flipped jejunal sac in rats showed that conjugated bile acids play a key role in fatty acid uptake and esterification to TAGs, and their reduction inhibits fatty acidS absorption and TAGS formation, suggesting that bile acid-dependent micellar solubilization is an important basis for lipid absorption [
117]. Subsequent studies further demonstrated that bile salts, micellar media, and luminal lipid composition could modulate oleic acid uptake, intracellular esterification, and transepithelial transport, supporting the utility of the everted gut sac model for investigating early events in intestinal fatty acid absorption [
118]. Recently, flipped intestinal sacs have also been applied in lipid preparation studies to evaluate intestinal permeability, mucosal absorption, and absorption efficiency [
4]. However, due to its limited duration of tissue activity and lack of blood flow and lymph circulation, it cannot fully simulate chylomicron mediated lipid transport
in vivo, and is more suitable for studying the early transepithelial transport process of lipid absorption. This model provides an
in vitro tissue-level approximate model of the intestinal tract.
5.2.4 Mice/rat model
Rodent models (particularly mice and rats) are widely used to study intestinal lipid absorption, triglyceride re-esterification, chylomicron assembly, and lymphatic lipid transport. Mouse models are suitable for mechanistic studies that combine gene editing, gut-specific signaling analysis, oral lipid challenge tests, and mesenteric lymph collection to analyze regulators of dietary fat absorption and chylomicron secretion, such as GLP-2/nNOS signaling, apoA-V, and KLHL12 [
119]. In contrast, the rat model, especially the lymphatic fistula rat model, remains the classical system for intestinal lymphatic flow, lipid export, and chylomicron transport after direct quantitative dietary administration of lipids [
120]. Compared with postprandial plasma TAG determination, lymph collection more closely approximates intestinal lipid output because it is prior to hepatic and peripheral metabolism [
121]. Therefore, mice are more suitable for gene-oriented mechanistic studies, whereas rats are more suitable for dynamic assessment of lymphatic lipid transport and dietary regulation of fat absorption. However, both models differ from humans in the physiological state of the gastrointestinal tract, lipoprotein metabolism, and dietary pattern. Therefore, the results of rodent studies need to be further validated in large animal or human postprandial models.
5.2.5 Pig model
The gastrointestinal digestive function, feeding behavior, and postprandial metabolic response of pig models are closer to those of humans than those of small rodents, which plays an important role in the research of lipid digestion and absorption. Earlier studies have shown that the type and content of dietary fat can regulate postprandial lipoprotein composition in pigs, providing a basis for analyzing diet-induced changes in lipid transport and lipoprotein profile. A growing number of recent studies have demonstrated the use of growing pigs to quantify the apparent ileal digestibility of fat and fatty acids, suggesting that fat saturation, fat source, dietary fiber have significant effects on fatty acid digestibility and intestinal lipid utilization [
122]. In nutritional physiology, pigs have also been widely used to investigate how dietary fatty acids regulate intestinal barrier function, mucosal immunity, oxidative stress, the gut microbiota, and lipid metabolism, thereby linking lipid absorption to broader intestinal health [
123]. In weaned piglets, insufficient fat absorption is particularly important because the transition from highly digestible milk fat to solid feed can impair fat utilization and cause diarrhea, making this model useful for studying emulsifiers, bile acid-related digestion, pancreatic lipase activity, and nutritional strategies to improve fat absorption [
124]. Compared with mice and rats, pig models provide greater physiological relevance for human nutrition and food structure research, but they are more expensive and less suitable for high-throughput mechanistic screening. Nevertheless, pigs represent an optimal translational large-animal model for validating oil digestibility, fatty acid absorption, postprandial lipoprotein responses, and the effects of lipid nutrition on intestinal health.
5.2.6 Human model
Human studies are essential for validating the physiological relevance of dietary fat digestion and absorption. Oral fat tolerance tests have shown that the amount and composition of dietary fat significantly influence postprandial TAG-rich lipoproteins and chylomicron-related responses [
125]. Stable isotope-labeled fatty acid tracers further allow direct tracking of exogenous dietary fatty acids in plasma TAGs, non-esterified fatty acids, oxidation products, and storage pools [
126–
127]. In addition, sequential-meal studies have shown that a fraction of ingested fat can be transiently stored in the intestine and subsequently released after meals, indicating that lipid absorption in humans is a dynamic process extending beyond the immediate postprandial phase [
128].
5.3 AI and ML applications in lipid digestion and absorption research
AI and ML are increasingly used in food colloid engineering, lipid formulation, bioaccessibility assessment, and nutritional response prediction. In edible oil research, most applications have focused on emulsion design and processing optimization rather than directly linking oil molecular structure with gastrointestinal digestion and intestinal absorption. Vats and Kumar applied regression-based ML to evaluate the effects of oil concentration, surfactant concentration, ultrasonication conditions, and flow parameters on nanoemulsion droplet size and stability [
129], while Damiati et al. predicted droplet size in microfluidic emulsification systems using formulation and operating parameters [
130]. These properties are relevant to digestion because droplet size and interfacial area influence lipase accessibility and fatty acid release. Yildiz et al. further used TreeBoost, neural networks, and support vector machines to predict the
in vitro bioaccessibility of β-carotene, identifying emulsion type, phase ratio, oil type, and emulsifier-related factors as major predictors [
131]. However, model performance may be limited by variability in digestion protocols and by the complex effects of interfacial restructuring, bile salts, enzymes, calcium, and food-matrix components. Mechanistic descriptors may improve model interpretability; for example, Jacobsen et al. proposed an intrinsic lipolysis rate normalized to available lipid surface area [
132]. Parameters such as lipolysis rate, lag time, fatty acid release, and micellization efficiency could therefore complement conventional digestibility endpoints. At the physiological level, Berry et al. integrated dietary and individual characteristics to predict postprandial triglyceride responses, but edible oil type, TAG structure, micellar composition, epithelial uptake, and chylomicron secretion were not separately considered [
133]. Thus, integrated AI/ML models connecting oil structure, processing, digestion, absorption, and postprandial responses remain an important research direction.
6 Regulatory Strategies for Modulating Edible Oil Digestion and Absorption
The digestion and absorption of edible oil is dynamically regulated by a variety of factors, including lipid structure, digestive enzyme activity, bile acid metabolism, the intestinal microenvironment, host genetics, and the gut microbiota. Changes in any of these factors can significantly affect postprandial lipid absorption. As shown in Fig. 6, this section provides a systematic review of various regulatory pathways and intervention strategies, offering a theoretical foundation for the precise regulation of lipid digestion and absorption and the development of targeted nutritional intervention strategies.
6.1 Oil structure/composition
In foods, oils exist in various molecular structures, such as oil bodies, emulsion droplets or fat crystal networks. Oils in modern processed food products, such as emulsified meat products, cheese, yogurt, dressing, ice cream, and sauces, generally exist in emulsion forms (oil-in-water, water-in-oil, or a combination of both) [
134]. The chemical composition and microscopic physical structure of oils are key factors determining their digestive kinetics in the gastrointestinal tract and subsequent physiological feedback. The chain length and saturation of fatty acids in TAGs as well as their spatial distribution on the glycerol backbone, significantly influence the catalytic affinity and hydrolytic efficiency of lipases [
82]. From microstructural perspective, oils undergo complex emulsion evolution within the gastrointestinal tract. The initial droplet size and interfacial layer properties (such as the type and charge of the emulsifier) not only determine the adsorption and steric hindrance of enzyme–coenzyme complexes at the oil–water interface but also profoundly influence the mass transfer process by which digestive products migrate from the oil phase to the water phase and self-assemble into micelles [
26,
135]. By constructing complex structural systems such as multilayer interface films, pickering emulsions, or lipid gel networks, the digestion and release of lipids can be delayed at the spatial and physical levels, thereby altering the permeability of micelles through the intestinal mucosal layer and the uptake rate by intestinal epithelial cells. Furthermore, the physical state of the oil itself (particularly the crystallinity of TAGs) is also a key factor in regulating absorption kinetics. The crystalline phase transition of triglycerides directly alters the colloidal behavior of the emulsion (e.g., by inducing changes in interfacial properties and droplet aggregation) and interferes with gastric emptying, thereby further impeding the release and absorption of lipids in the intestine at the physical level [
136]. Human clinical trials have also confirmed this mechanism: compared to supercooled liquid emulsions, the ingestion of solid lipid emulsions containing partially crystallized particles significantly delays the absorption of fatty acids in humans, effectively reducing postprandial plasma triglyceride levels during the early stages of absorption [
137].
6.2 Inhibitors of enzymes related to oil absorption
Targeted inhibition of pancreatic lipase is a classic strategy for regulating intestinal fat absorption and intervening in obesity. The Food and Drug Administration (FDA)-approved clinical drug, orlistat, can reduce TAG digestion by inhibiting gastric and pancreatic lipase, thereby approximately blocking the absorption of one-third of the fatty acids obtained from food and can be used to treat obesity [
138]. However, due to the adverse gastrointestinal effects of synthetic drugs, natural products remain a key source for discovering novel inhibitors. As the researchers successively identified bioactive compounds with significant pancreatic lipase inhibitory activity—such as theaflavins, curcumin, and specific peptides—from medicinal and edible plants, traditional Chinese medicines and microbial products, the corresponding review articles are also constantly being updated [
45,
139–
140]. These inhibitors not only directly block the catalytic function of pancreatic lipase by occupying hydrophobic hotspot residues on its surface, but some active compounds can also further downregulate the expression of adipogenesis-related genes such as SREBP-1c and PPAR-γ at the cellular level, thereby exerting synergistic lipid absorption-lowering effects through both enzyme inhibition and gene regulation [
141–
142].
Beyond pancreatic lipase, targeting the intracellular re-esterification of lipids via MGAT and DGAT presents another critical avenue for modulating intestinal fat absorption. Zambre et al. highlighted that synthetic fused heterocycles with aromatic and aliphatic substituents could act as potent DGAT and MGAT inhibitors [
143]. However, because synthetic MGAT and DGAT inhibitors often present low gastrointestinal tolerability and safety concerns, recent research has increasingly shifted toward identifying natural, food-derived alternatives. Modulating MGAT2 activity using plant-based aqueous extracts or polyphenol-rich food matrices is now considered a safer, diet-based intervention strategy with fewer adverse gastrointestinal effects [
144].
6.3 Bile acid
The efficient emulsification of dietary lipids by bile acids is an indispensable prerequisite for oil digestion. In the aqueous environment of the small intestine, bile salts aggregate with phospholipids and cholesterol to spontaneously self-assemble into mixed micelles, which markedly reduce interfacial tension [
145]. Increasing bile acid levels can significantly enhance the degree of lipolysis and may further promote absorption [
146]. Emerging evidence demonstrates that the composition of the bile acid pool does not solubilize lipids indiscriminately; instead, polyunsaturated fatty acids (PUFAs) are preferentially micellinated for intestinal uptake [
20]. Furthermore, bile acids dynamically regulate the viscoelasticity and permeability of the intestinal mucus barrier, thereby selectively facilitating the permeation and absorption of specific lipophilic digestive products without impairing mucosal integrity [
147].
To intervene in the bile acid-mediated micellar absorption process, research has gradually shifted from pharmaceutical bile acid sequestering agents toward natural plant-derived bioactive substances. Specific dietary fibers and complex plant polyphenols can interact closely with bile acids during intestinal digestion. On the one hand, they increase intestinal luminal viscosity to restrict micellar migration; on the other hand, they directly form supramolecular complexes with bile acids, effectively blocking the function of this "selective transport channel" and inhibiting lipid assimilation via a safer dietary approach [
148].
Knockout bile acid synthesis enzymes (Cyp27a1, Cyp8b1) alter the bile acid profile, hinders the transport of lipid digestive products, and remodels intestinal lipid sensing signaling [
149–
150]. Meanwhile, upstream regulatory pathways represented by the activation of farnesoid X receptor (FXR) can modulate the relative abundance of cholic acid and taurocholic acid, providing a molecular regulatory pathway for targeted inhibition of intestinal lipid uptake [
151]. In addition to FXR, TGR5 participates in the regulation of bile acid metabolism by modulating the expression of cholesterol 12α-hydroxylase (CYP8B1), a key enzyme involved in bile acid synthesis [
152].
6.4 Enterocyte membrane structure
As a key enzyme in endoplasmic reticulum-localized phospholipid remodeling, LPCAT3 directly determines the efficiency of dietary lipid uptake, intracellular transport, and chylomicron assembly by precisely regulating the composition and physical properties of biological membrane phospholipids. LPCAT3 preferentially catalyzes the incorporation of dietary PUFAs, such as arachidonic acid, into the
sn-2 position of lysophosphatidylcholine (LPC), generating polyunsaturated phospholipids. These phospholipids enhance cell membrane fluidity and curvature, providing a suitable microenvironment for the transmembrane diffusion of fatty acids and cholesterol as well as vesicular transport, thereby facilitating the entry of dietary lipids into intestinal cells and their subsequent assembly into chylomicrons [
153].
In vivo studies have shown that mice with intestinal-specific
Lpcat3 deficiency exhibit severe growth retardation and massive lipid accumulation in intestinal epithelial cells on a high-fat diet, accompanied by significantly reduced plasma TAG, cholesterol, and phospholipid levels [
154]. Furthermore,
Lpcat3 deficiency upregulates the secretion of intestinal hormones such as glucagon-like peptide-1 (GLP-1), leading to appetite suppression and further exacerbating metabolic imbalance. Concurrently, LPCAT3 is transcriptionally regulated by the liver X receptor (LXR), forming the LXR-LPCAT3 signaling axis [
155]. During lipid overload, this axis alleviates lipid toxicity and endoplasmic reticulum stress by increasing the proportion of polyunsaturated phospholipids in the cell membrane, thereby maintaining intestinal lipid homeostasis. It is worth noting that LPCAT3 promotes efficient absorption and incorporation of PUFAs into membrane phospholipids, while objectively increasing the substrate for cell membrane lipid peroxidation. Targeted inhibition of LPCAT3 can reshape the abundance of polyunsaturated phospholipids in cells, effectively protecting them from ferroptosis driven by lipid peroxidation [
156]. This discovery provides a new perspective on the regulation of lipid absorption. In future dietary interventions and food engineering strategies, precisely regulating LPCAT3 activity to balance the absorption efficiency of essential fatty acids with the risk of oxidative damage in intestinal epithelial cells may become a promising research direction.
6.5 Lipid absorption related genes/protein
After lipid hydrolysis, the lipid transport and subsequent chylomicron production in intestinal epithelial cells are strictly regulated by a large number of genes and enzymes. Defects or alterations in genes such as
CD36,
FATP4,
I-FABP (
FABP2),
L-FABP,
SR-BI,
NPC1L1,
MTTP,
APOB,
MGAT1/2,
DGAT1/2,
SAR1B,
ABCG5/G8 and
ACAT2 may severely hamper the lipid uptake, intra-enterocyte lipid trafficking and chylomicron formation [
157]. Xia et al. reviewed the VEGFC-VEGFR3, Hippo, Notch, angiopoietin-TIE, and VEGF-A/VEGFR2 signaling pathways, along with specific genes including
Prox1, CD36, and Calcrl, that regulate lacteal development, integrity maintenance, and the dynamic transformation between permeable button-like and restrictive zipper-like junctions, which collectively modulate chylomicron entry and dietary lipid absorption [
158]. They concluded that promoting the transformation from button-like to zipper-like junctions—thereby enhancing lacteal junctional tightness and impeding chylomicron transport—represents a promising therapeutic target for inhibiting lipid absorption and resisting high-fat diet-induced obesity and related metabolic disorders. In addition, chylomicron release from intestinal epithelial cells regulated by a transmembrane protein, especially DENND5B. The fusion between chylomicron secretory vesicles and basolateral plasma membrane in
DENND5B-deficient mice is defective, which interferes with their ability to reach the lamina propria and reduces intestinal absorption of TAG [
159].
The clock gene, which controls the circadian rhythm pattern of behavior and physiological activities, is also involved in the time control of lipid absorption, and may act as a lipid absorption accelerator [
160] Systemic knockout of KLF15 impaired the diurnal expression of key bile acid synthase and reduced bile acid synthesis, leading to decreased triglyceride/cholesterol absorption [
161]. In addition, F. Yu et al. examined the intestinal expression of clock gene and fat absorption-related genes in high-fat diet (HFD)-fed mice and proposed that targeted inhibition of intestinal
Bmal1 could protect mice from HFD-induced obesity [
162]. They proved that the intestinal core clock gene
Bmal1 promotes dietary fat absorption by regulating the transcription and expression of
Dgat2 (TAG synthase). And the deficiency of BMAL1 repressor Rev-erbα in intestinal can enhance the absorption of dietary fat, and aggravate HFD induced obesity.
6.6 Intestinal hormone
In addition to being an absorptive organ, the intestinal epithelium also functions as a sensory and endocrine organ, with intestinal endocrine cells (EECs) coordinating a complex neuroendocrine network to regulate lipid absorption. Luminal lipids are precisely detected by apical sensors on EECs—most notably the FFA translocase CD36 and FFA receptors (e.g., GPR40/FFAR1 and GPR120/FFAR4) [
163–
164]. This nutrient-sensing process triggers the secretion of a range of peptide hormones, including CCK from I-cells, glucose-dependent insulinotropic polypeptide (GIP) from K-cells, and the proglucagon-derived peptides GLP-1 and GLP-2 from L-cells.
Interestingly, although GLP-1 and GLP-2 are co-secreted by L cells, they have an antagonistic effect on intestinal lipid transport. GLP-1 plays a crucial role as a brake; intravenous injection of GLP-1 amide has been shown to significantly restrict intestinal lymphatic flow, inhibit TAG absorption, and suppress the production of apolipoprotein apoB48 and apoA-IV [
165]. On the contrary, GLP-2 is a potent promoter of chylomicron secretion. GLP-2 not only enhances dietary fatty acid uptake by promoting glycosylation of CD36, but may also stimulate postprandial lipid absorption through the GLP-2-VEGF-NO pathway [
166]. Similarly, CCK actively facilitates lipid processing by enhancing duodenal fatty acid uptake via the CCK-1 receptor (CCK-RA) and increasing enterocyte CD36 expression in response to a high-fat diet [
167].
6.7 Gut microbiota
The diversity of dietary oil components affects the structure of the gut microbiota, and unhealthy dietary lipid patterns such as HFD or saturated fat rich diets may lead to dysbiosis of the gut microbiota [
168]. On the contrary, it has been demonstrated that presence of a regular gut microbiota is a necessary condition for effective absorption of dietary oils [
169–
170]. With the iterative advancement of modern microbiology research technologies, an increasing number of gut bacterial strains that regulate lipid digestion and absorption have been continuously identified and functionally validated. For example, Tazi et al. reported that under normal diet,
Lactobacillus paracasei (
L. paracasei) inhibited fatty acid absorption and promoted lipid droplet accumulation in enterocytes, whereas
Escherichia coli (
E. coli) enhanced fatty acid uptake and β-oxidation, thereby lowering circulating chylomicron levels [
171]. Under HFD, this chylomicron-lowering effect disappeared in
E. coli-colonized hosts but was strengthened in
L. paracasei-colonized animals, which protected against excessive weight gain and hypercholesterolemia. Chang and Martinez-Guryn further found that
Clostridium bifermentans elevated oleic acid uptake and upregulated duodenal Dgat2, while jejunal
Lactobacillus rhamnosus GG induced jejunal Dgat1 expression [
172].
As the main site for lipid digestion and absorption, the small intestine harbors a complex microbial community (≈ 10
3–10
7 microbial cells/g), although its diversity and abundance is much lower than that of the colon (approximately 10
12 cells/g) [
173]. So far, the microbiota from the colon has been extensively studied, the impact of small intestinal microbiota on lipid digestion and absorption has attracted attention in recent years, especially jejunal microbiota [
174]. The small intestinal microbiota participates in lipid digestion through at least four independent ways: (a) the microbiota participates in the oil emulsification process and regulate the colloidal structures and interfacial dynamics, (b) the microbial metabolites (short chain fatty acids, bile acids) stimulate the pancreas to secrete lipase by affecting hormone signals and (c) microbial lipase helps hydrolysis of fat into fatty acids, (d) microbiota regulates intestinal peristalsis rate and subsequently affects oil digestion rate [
175–
176].
Dietary oil absorption may involve complex integration of multiple microbial groups and microbial signals. Yin et al. summarized six pathways through which intestinal microbiota participate in lipid absorption, including: (a) microbiota-derived short-chain fatty acids and microbial degradation of myoinositol tend to inhibit intestinal lipid uptake by down-regulating fatty acid transport proteins, including CD36, FABP2 and NPC1L1; (b) gut microbiota influences the distribution and abundance of bile acids through FXR and/or TGR5 signals; (c) microbiota-derived metabolites, such as 3-oxocholic acid and isocholic acid, can inhibit the differentiation of immune cells (Th17 cells), which function to downregulate the expression of CD36; (d) healthy microbiota impede long noncoding RNA Snhg9, which function to downregulate the expression of CD36 and FABP4; (e) microbiota interact with toll-like receptors and subsequently affect CD36 expression and lipase secretion; (f) intestinal microbiota dysbiosis increases intestinal permeability, expands intercellular spaces and promotes chylomicron translocation [
177].
In addition, certain intestinal bacteria (such as
Lactobacillus and
Bifidobacterium) can utilize isomerases and reductases to convert unsaturated fatty acids (UFAs) into conjugated linoleic acid (CLA), and even fully hydrogenate them into saturated fatty acids (SFAs) [
178–
179]. This further reduces the micellization efficiency of fatty acids and their subsequent absorption rate at the substrate level. The gut microbiota is not merely a passive recipient of circadian signals, but an active orchestrator of host metabolic rhythms. Intrinsic rhythmic metabolite signals derived from the gut microbiota, such as short-chain fatty acids and bile acids, profoundly modulate the expression of host core clock genes (e.g., the Clock/Bmal1 network), lipid sensing, and overall lipid absorption [
180]. Consequently, microbial dysbiosis can induce a state of “intestinal jet lag” triggering the inappropriate temporal gating of lipid absorption channels.
7 Conclusions and Future Perspectives
Future research on edible oil digestion and absorption should move beyond conventional digestibility evaluation. Differences in digestion models, bile salt concentrations, enzyme activities, sampling time points, and endpoint definitions often limit cross-study comparison. Future studies should further clarify the dynamic physicochemical changes of edible oils during gastrointestinal digestion, particularly the relationships among interfacial structure, micelle formation, bile acid-binding capacity, fatty acid release kinetics, and subsequent lipid transport. The integration of in vitro digestion models with lipidomics, particle size analysis, interfacial characterization, bile acid profiling, and intestinal transport assays will help reveal the material basis underlying differences in the digestion and absorption of different edible oils.
Experimental model systems should also be further optimized, but their development should serve mechanistic interpretation and translational validation rather than becoming an isolated research focus. Caco-2 cells, Caco-2/HT29-MTX co-cultures, intestinal organoids, and everted gut sacs can be used to investigate epithelial uptake, mucus barrier effects, intracellular lipid processing, and tissue-level transport, respectively. Animal models and human postprandial studies are necessary to validate absorption efficiency, lipoprotein responses, and metabolic outcomes under physiological conditions. Thus, future research should establish a continuous framework integrating in vitro digestion, epithelial absorption, tissue transport, animal validation, and human postprandial responses, rather than relying on a single model to explain the complex process of lipid digestion and absorption.
More importantly, future studies should strengthen research on strategies for regulating edible oil digestion and absorption. The digestion rate and absorption behavior of oils can be modulated by adjusting emulsification state, droplet size, interfacial protein, structured lipid configuration, microencapsulation method, and food matrix properties. For example, emulsion interface design can influence lipid droplet stability and hydrolysis rate in the gastrointestinal tract, while structured lipids can alter fatty acid distribution on the glycerol backbone and thereby affect digestion, absorption, and metabolic fate. Dietary fiber, proteins, polyphenols, and other food components may also regulate lipid absorption by affecting bile acid binding, micelle formation, and epithelial lipid transport. Therefore, future studies should not only compare absorption differences among oils, but also explore how food processing and structural design can precisely regulate lipid digestion rate, fatty acid release patterns, absorption efficiency, and metabolic effects.
Artificial intelligence and machine learning can provide new tools for predicting and optimizing edible oil digestion and absorption. Multidimensional data, including fatty acid composition, triacylglycerol structure, droplet size, interfacial properties, digestion kinetics, bile acid-binding capacity, lipidomics, epithelial transport, and human postprandial metabolic responses, can be integrated to construct predictive models of lipid digestion and absorption behavior. Machine learning approaches may help identify the key structural features that determine fatty acid release, micellization efficiency, epithelial uptake, and postprandial lipid responses, thereby supporting oil formulation screening, emulsion optimization, and prediction of digestion performance under different processing conditions. Compared with single experimental indicators, AI-assisted models can establish quantitative links among oil structure, digestive behavior, absorption efficiency, and health effects, providing a basis for the design of functional edible oils, low-burden lipid foods, and precision nutrition products.
In addition, the regulation of oil digestion and absorption should be connected with intestinal and metabolic health. Lipid digestion products not only supply energy and participate in lipid transport, but also affect intestinal barrier function, inflammation, oxidative stress, bile acid signaling, gut microbiota composition, and host metabolic homeostasis. Future research should clarify how different edible oils and their digestion products regulate FXR/TGR5-mediated bile acid signaling, tight junction proteins, chylomicron metabolism, postprandial lipemia, and the risk of chronic metabolic diseases.
Under the trend of the global rise in metabolic diseases, such as obesity, type 2 diabetes, and metabolic dysfunction-associated fatty liver disease, research on edible oil digestion and absorption should be integrated with the development of functional lipids, AI-assisted formulation optimization, and precision nutrition assessment. Edible oil research should shift from basic nutritional energy supply toward health-oriented lipid design and controllable digestive and metabolic regulation. Future research should therefore provide scientific support for developing edible oil products with improved digestibility, controlled lipid release, reduced metabolic burden, and targeted health benefits.
The Author(s) 2026. This article is published by Higher Education Press.
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