Role of Bile Acid Receptors in Non-Infectious Diarrhea: A Narrative Review

Abstract

Non-infectious diarrhea constitutes a prevalent gastrointestinal pathology that severely compromises patient well-being. Its etiology is progressively associated with gut-liver axis dysfunction, although exact molecular pathways remain undefined. This narrative review consolidates the existing research to investigate 5 distinct bile acid-activated receptors: farnesoid X receptor (FXR), Takeda G protein-coupled receptor 5 (TGR5/GPBAR1), pregnane X receptor (PXR), vitamin D receptor (VDR), and retinoid-related orphan receptor gamma t (RORγt). These molecules function as pivotal hubs linking bile acid metabolism, microbial community structure, and intestinal homeostatic balance. Synthesized hepatically and biotransformed by commensal bacteria, bile acids signal through these receptors; specifically, FXR governs bile acid biosynthesis and epithelial barrier strength, TGR5 modulates motility and inflammatory responses, and PXR and VDR attenuate inflammation via nuclear factor-kappa B (NF-κB) suppression, while RORγt regulates immunity through T helper 17 (Th17) cell modulation. Perturbations within this axis—manifesting as defective bile acid reclamation, microbiota dysbiosis, or receptor malfunction—compromise intestinal permeability, provoke electrolyte imbalances, and disrupt immune equilibrium, thereby driving bile acid diarrhea, diarrhea-predominant irritable bowel syndrome, and post-surgical diarrheal conditions. Current data suggest FXR activation is essential for driving bile acid diarrhea management, whereas TGR5 overactivation underlies the hypermotility observed in diarrhea-predominant irritable bowel syndrome. Additionally, rifaximin, acting as a PXR agonist, provides therapeutic benefit. This manuscript evaluates bile acid receptor contributions to non-infectious diarrhea, emphasizing the translational potential of targeting these signaling cascades.

Introduction

The human gastrointestinal tract hosts a sophisticated ecosystem including over 2000 bacterial species and participates in essential biological activities including metabolic processes, immune regulation, and barrier maintenance. Recent studies have increasingly highlighted the critical function of bile acids in maintaining metabolic homeostasis and their involvement in the pathogenesis of various diseases, including non-alcoholic fatty liver disease, ulcerative colitis, Crohn disease, diabetes, and allergic disorders [1]. As bioactive metabolites derived from cholesterol, bile acids play a crucial role within the gut-liver axis by aiding in lipid digestion and absorption, regulating energy metabolism, and serving as signaling molecules that integrate physiological functions across the gut, liver, and immune system [2]. Aberrant bile acid secretion precipitates substantial clinical complications. Regardless of whether an excess or deficiency in bile acid secretion occurs, such imbalance undermines mucosal integrity, elevates intestinal permeability, triggers excessive water and electrolyte secretion, and ultimately culminates in diarrhea.

Non-infectious diarrhea, defined as intestinal dysfunction arising from non-pathogenic etiologies, encompasses several clinical subtypes, including bile acid diarrhea (BAD), diarrhea-predominant irritable bowel syndrome (IBS-D), postoperative diarrhea (eg, following cholecystectomy), drug-induced diarrhea (eg, due to antibiotics), and functional diarrhea [3]. BAD primarily arises from 2 mechanisms: impaired absorption of bile acids in the ileum or excessive production of bile acids by the liver. Both causes lead to bile acid accumulation in the colon. In contrast, IBS-D is strongly linked to heightened visceral sensitivity and an imbalance in the brain-gut communication. Meanwhile, diarrhea following surgery frequently results from irregularities in the enterohepatic circulation. Despite affecting approximately 1% of the global adult population, BAD presents significant therapeutic challenges due to suboptimal treatment efficacy and limited patient tolerability, underscoring the need for deeper mechanistic insights to inform novel therapeutic strategies [4].

Bile acid receptors serve as critical mediators in gut-liver crosstalk, transducing bile acid signals into regulatory effects on metabolism, immune responses, and epithelial barrier function. The unique functions of these receptors in various diarrheal subtypes, their relationships with the gut microbiota, and the potential for their targeted application in clinical settings have not been completely clarified or incorporated into a unified framework. Consequently, this article aims to review the role of bile acid receptors in non-infectious diarrhea.

Biology of Bile Acids

Bile acids are water-soluble derivatives formed from the catabolic breakdown of highly insoluble cholesterol. They exhibit a distinct structure characterized by 4 steroid rings arranged into a hydrocarbon framework, featuring a convex hydrophobic surface along with a concave hydrophilic side bearing hydroxyl groups [5,6]. Additionally, these structures have a short pentanoic acid side chain, which is generally conjugated with either taurine or glycine [7,8]. The amphiphilic nature of bile acids [9] imparts them with detergent-like properties [10], which facilitate the digestion and absorption of dietary lipids, as well as fat-soluble vitamins A, D, E, and K, within the small intestine [1,11].

Hepatic bile acid synthesis occurs via 2 different pathways (Figure 1). Approximately 75% is produced via the classical or alternative pathway, wherein cholesterol is converted into 7α-hydroxyl cholesterol by CYP7A1, and subsequently into cholic acid through the action of CYP8A1, or into chenodeoxycholic acid (CDCA) via CYP27A1 [12,13]. The remaining 25% is synthesized through the alternative or acidic pathway, where CYP27A1 converts cholesterol to 27-hydroxycholesterol [14]. This compound is then further metabolized into CDCA by CYP27A1 [14–16]. Following their synthesis, bile acids are retained in the gallbladder and subsequently released into the duodenum after meals. Around 95% of these acids are reabsorbed in the terminal ileum through enterohepatic circulation, while the remaining 5% is expelled in feces and replenished through de novo synthesis [17–19]. The bile acid pool, which consists of 3 g of bile acids (40% cholic acid, 40% CDCA, 20% deoxycholic acid [DCA], and trace amounts of lithocholic acid [LCA]), circulates between 4 and 12 times daily to maintain bile acid–cholesterol balance [20–22].

Figure 1.

Bile acid synthesis pathways and enterohepatic circulation.

Bile acids (BAs) are synthesized from cholesterol in the liver through oxidation catalyzed by cytochrome P450 (CYP) enzymes and conjugation catalyzed by bile acid-CoA synthetase (BACS) and bile acid-CoA: amino acid N-acyltransferase (BAAT). Following food intake, BAs are secreted into the intestine. Approximately 90% to 95% of BAs are reabsorbed into the liver via the portal circulation, whereas only 5% to 10% are excreted in the feces. Intestinal microbiota biotransform primary bile acids (PBAs) into secondary bile acids (SBAs) and deconjugate conjugated BAs to generate unconjugated BAs. Figure was created by the authors using Figdraw (original, no published source).

The conversion of bile acids by various microorganisms is species-specific, as different members of the gut microbiota, including Bacteroides and Prevotella, demonstrate unique abilities to modify bile acids. Important bacterial enzymes, such as 7α-dehydroxylase, facilitate the reversible transformation of bile acids and sustain the dynamic balance of the bile acid pool through processes such as 7α-dehydroxylation and other related biochemical reactions.

Bile acids significantly affect gut microbial composition, particularly in C. difficile. Primary bile acids, such as cholic acid and CDCA, inhibit C. difficile spore germination and reduce intestinal colonization by regulating tight junction proteins. Secondary bile acids, such as DCA and LCA, promote C. difficile growth, with DCA being a particularly potent growth promoter. At physiological concentrations (1–10 μmol/L), DCA activates Takeda G protein-coupled receptor 5 (TGR5)-mediated anti-inflammatory signaling, whereas at pathological concentrations (> 100 μmol/L), it triggers pro-inflammatory responses through reactive oxygen species accumulation and NLRP3 inflammasome activation, thereby influencing C. difficile colonization and toxin-mediated pathogenicity. These mechanisms highlight the critical role of bile acid conversion in gut health [2,23].

Bile Acid Receptors and Non-Infectious Diarrhea

Disruptions in gut microflora are significantly associated with the development and progression of non-infectious diarrhea. A study conducted by Baumgartner et al [24] showed that as many as 34% of individuals with ulcerative colitis and 22% of those with Crohn disease exhibited yellow-green bacterial biofilms in the ileum and right colon; however, only 6% of participants in the control group demonstrated an adherent layer of these dense biofilms. Analysis of biofilms through metabolomics disclosed that there was an accumulation related to the tricarboxylic acid cycle, which correlated with the excretion of fecal bile acids. Furthermore, a link between mucus production and total bile acids was identified among patients with ulcerative colitis, who showed marked increases in cholic acid levels alongside declines in LCA, DCA, and CDCA levels [25]. For those diagnosed with Crohn disease or unspecified inflammatory bowel disease (IBD), CDCA concentrations were found to be higher in comparison to those in patients without IBD [26,27]. These results deepen our understanding of the pathogenesis of non-infectious diarrhea, suggesting that restoring proper bile acid signaling could form the foundation for treatments aimed at non-infectious diarrhea [13]. Consequently, it is clear that the bile acid–gut microbiota axis is pivotal in the pathogenesis of non-infectious diarrhea [28], and managing this pathway to reinstate normal intestinal function may present a promising new therapeutic avenue for non-infectious diarrhea [29,30].

Bile acid receptors are primarily expressed in hepatic and intestinal tissues, although they are also present in extrahepatic organs. These receptors function as key signaling mediators within the complex gut–liver metabolic network, regulating pathways involved in lipid, glucose, and energy metabolism (Figure 2) [31,32]. Their expression in hepatic and intestinal tissues and immune cells enables regulation of bile acid metabolism, inflammation, and barrier function, which are core processes disrupted in non-infectious diarrhea (Table 1). Below, we provide a detailed introduction to the ligand specificity, signaling pathways, and contributions of each receptor to different diarrhea subtypes, followed by a comparative analysis of their functions.

Figure 2.

Signaling pathways of bile acid receptors in intestinal homeostasis and diarrhea.

Differential activation profiles of bile acids on metabolic nuclear receptors and G protein-coupled receptors. This figure systematically illustrates the agonistic activity of different bile acid subtypes, including free and conjugated forms, toward key metabolic regulatory receptors: farnesoid X receptor (FXR), Takeda G protein-coupled receptor 5 (TGR5), pregnane X receptor (PXR), vitamin D receptor (VDR), and retinoid-related orphan receptor gamma t (RORγt). Figure was created by the authors using Adobe Photoshop (original, no published source).

Table 1.

Comparative summary of bile acid receptors in non-infectious diarrhea.

Receptor	Type	Tissue distribution	Key functions	Role in diarrhea subtype	Agonists/antagonists (clinical/preclinical)
TGR5/GPBAR1	Nuclear	Intestinal epithelium, neurons, macrophages, gallbladder	Motility regulation, anti-inflammation, barrier maintenance	IBS-D (hypermotility), BAD (inflammation)	Agonists: INT-777 (preclinical),MK-0893 (phase 1)
FXR	Nuclear	Intestinal epithelium, hepatocytes, macrophages	Bile acid homeostasis, anti-inflammation, barrier protection	BAD(FGF19 deficiency), IBD-related diarrhea	Agonists: OCA (approved, PBC), cilofexor (phase 2, BAD)
PXR	Nuclear	Intestinal epithelium, liver, lymphocytes	Xenobiotic detoxification, anti-inflammation, microbiota modulation	IBS-D (rifaximin-responsive), drug-related diarrhea	Agonists: Rifaximin (approved, IBS-D), SR12813 (preclinical)
VDR	Nuclear	Intestinal epithelium, immune cells, bone	Calcium metabolism, immune balance, barrier maintenance	IBS-D (vitaminD deficiency), IBD-related diarrhea	Agonists: Calcitriol (approved, vitamin D deficiency), paricalcitol (preclinical)
RORγt	Nuclear	Th17 cells, ILC3s	Th17 cell differentiation	IBD-related diarrhea, severe IBS-D	Reverse agonists: 3-oxo-LCA (preclinical), digoxin derivatives (preclinical)

Abbreviations: 3-oxo-LCA, 3-oxo-lithocholic acid; BAD, bile acid diarrhea; FGF19, fibroblast growth factor 19; FXR, farnesoid X receptor; GPBAR1, G protein-coupled bile acid receptor 1; IBD, inflammatory bowel disease; IBS-D, diarrhea-predominant irritable bowel syndrome; ILC3, group 3 innate lymphoid cell; OCA, obeticholic acid; PBC, primary biliary cholangitis; PXR, pregnane X receptor; RORγt, retinoid-related orphan receptor gamma t; TGR5, Takeda G protein-coupled receptor 5; Th17, T helper 17; VDR, vitamin D receptor.

Intestinal Function Mediated by TGR5 Signaling

TGR5 is a key mediator of motility-related diarrhea, including IBS-D and postoperative diarrhea [33,34]. Its hyperactivation by excess secondary bile acids, such as DCA, accelerates colonic peristalsis, while its anti-inflammatory effects (M1 to M2 macrophage polarization) may counteract intestinal inflammation [35,36]. However, the clinical translation of TGR5-targeted therapies is limited due to the lack of Phase III clinical data.

TGR5, which is also referred to as GPBAR1, functions as a G-protein-coupled receptor located on the surface of cells that interacts with bile acids [24]. While it does not directly influence bile acid homeostasis, its role in the regulation of energy metabolism is significant [19,37]. The discovery of TGR5 occurred in 2002, and its name is attributed to the research conducted by Kawamata et al [38]. This receptor is found abundantly in a variety of tissues across humans and animals, and it shows particularly high expression levels in non-parenchymal liver cells, notably in the epithelial cells of the gallbladder and bile ducts, as well as in intestinal epithelial cells, Kupffer cells, and other immune cells. Furthermore, TGR5 is present in brown adipose tissue, muscle, intestinal endocrine cells, intestinal neurons, and the brain [1]. Its interaction with bile acids activates several intracellular signaling pathways, with activation potency following the rank order LCA > DCA > CDCA > CA [19,39]. Secondary bile acids, particularly LCA and DCA, serve as more potent agonists of TGR5 and are predominantly found in the distal ileum and colon. When these bile acids combine with taurine or glycine, their activating efficacy is further enhanced. The activation of TGR5 [40] can also trigger a series of intracellular signal changes, beginning with receptor internalization, which is succeeded by a marked rise in cyclic adenosine monophosphate (cAMP) levels, ultimately leading to the activation of protein kinase A (PKA). This sequential signaling process culminates in enhanced phosphorylation of downstream target proteins, among which the cAMP response element-binding protein (CREB) transcription factor is a pivotal substrate [41]. The consequences of this activation are diverse and cell-type specific, including the anti-inflammatory effect of macrophages, augmented energy expenditure in brown adipose tissue, enhanced glucose metabolism coupled with improved insulin sensitivity, relaxation of gallbladder smooth muscle, and heightened intestinal motility [42].

Data derived from preclinical studies indicate that TGR5 significantly influences immunomodulation related to inflammatory regulation in rodent models of colitis [43]. Research has demonstrated that bile acids can trigger the TGR5 receptor in immune cells, including macrophages, monocytes, and dendritic cells, via the TGR5-CAMP-PKA signaling pathway [44]. They also suppress the pro-inflammatory nuclear factor-kappa B (NF-κB) signaling pathway through mechanisms dependent on signal transducer and activator of transcription 1 (STAT1) and inhibit the TGR5-CAMP-PKA pathway. Furthermore, the stimulation of TGR5 enhances the expression of tight junction proteins, such as occludin and claudin-1, decreases permeability, and sustains intestinal barrier homeostasis [45]. TGR5 exhibits a high level of expression in neurons and chromaffin cells located in the distal ileum and colon. Its activation enhances colonic peristalsis by stimulating the secretion of GLP-1 and GLP-2. The ability of macrophages to exhibit plasticity allows them to evolve into 2 distinct phenotypes: classically activated macrophages (M1) and alternatively activated macrophages (M2) [15]. The M1 subtype is known for its pro-inflammatory characteristics and its capacity to produce cytokines such as interleukin (IL)-12, IL-6, IL-1β, and tumor necrosis factor α (TNF-α) [37]. Conversely, the M2 subtype is recognized for its anti-inflammatory properties and is distinguished by the secretion of IL-10. The modulation of TGR5 has the potential to facilitate the conversion of macrophages from the M1 phenotype to the M2 phenotype [45,46], a shift that can have a direct impact on the inflammatory response.

Intestinal Function Mediated by Farnesoid X Receptor Signaling

Farnesoid X receptor (FXR) is the most well-validated receptor in BAD [47]. In patients with BAD, colonic mucosa FXR mRNA expression is 2.3-fold higher than in healthy controls, and impaired FXR-FGF19 signaling reduces bile acid reabsorption [48]. FXR agonists, such as obeticholic acid, show a pooled odds ratio (OR = 3.2; 95% CI: 2.1–4.5) for diarrhea remission, making them a promising therapeutic option [49,50].

FXR functions as a nuclear transcription factor that is triggered by primary bile acids and was first identified in 1995 [51]. This factor is mainly found in intestinal epithelial cells, hepatocytes, and specific immune cells, including macrophages and dendritic cells, located in both the gut and liver [52]. While FXR shows the highest expression in the liver, it also has significant roles within the gut. Among intestinal cells, CDCA acts as a strong natural agonist of FXR, with DCA, LCA, and cholic acid following in potency [53,54]. Additionally, muricholic acids form a specific subset of primary bile acids found in mice; both α-muricholic acid and β-muricholic acid are known to act as powerful antagonists of FXR [13]. The influence of gut microbes on FXR primarily occurs via changes in bile acids, which means that both the activation and inhibition of FXR can affect gut microbial populations.

FXR serves as a key regulator of bile acid homeostasis, exerting control over bile acid concentrations through its actions on a variety of target genes within enterohepatic tissues [55]. The FXR-mediated endocrine axis includes ileal fibroblast growth factors (FGF) 19 and 15, along with the hepatic small heterodimer partner (SHP). This axis negatively regulates bile acid synthesis while ensuring bile acid homeostasis in the liver [56,57]. In mice, the absence of FXR can result in significant bile acid disorders, whereas genetic variations in the FXR gene in humans may lead to severe familial intrahepatic cholestasis [58]. As the bile acid pool expands, a feedback mechanism derived from the gut is triggered, which suppresses the de novo synthesis of bile acids in the liver.

The initial pathway that involves the FXR feedback mechanism takes place within hepatic tissue. During instances of cholestasis, this mechanism provides protection to liver cells against harm from elevated levels of bile acids. In hepatocytes, CDCA engages with FXR and subsequently moves into the nucleus, where it assembles heterodimer complexes alongside retinoid X receptors that interact with hormone-responsive DNA elements. This interaction leads to the creation of a small heterodimer companion, which inhibits the trans-activation of hepatic nuclear factor 4α, ultimately decreasing the expression levels of CYP7A1 and CYP8B1 [59], thereby reducing production of cholic acid and CDCA [60]. It also inhibits SHP by suppressing liver receptor homolog-1. Moreover, small heterodimer chaperones impede the transcription of the taurocholate sodium transporter gene, which subsequently lowers the absorption of bile acids from the bloodstream by liver cells.

A second pathway involves the interaction between bile acids and FXR in ileal enterocytes, which triggers the transcriptional activation of the endocrine peptide FGF19 in humans, with its murine ortholog designated as FGF15. Both proteins primarily function to mediate the inhibition of bile acid synthesis via the bile acid-FXR pathway. However, they differ in their metabolic regulatory emphasis: FGF19 more prominently regulates glucose metabolism, whereas FGF15 primarily influences lipid metabolism indirectly through bile acid homeostasis [61]. FGF19 is absorbed into the portal circulation and liver cells, where it engages with the FGF4 receptor complex alongside the beta-Klotho co-receptor [62]. This interaction leads to the downregulation of CYP7A1 gene expression and a decrease in cholic acid production [60,63]. In humans, peak concentrations of serum FGF19 occur 1.5 to 2 hours after the secretion of bile acids in response to eating, with this elevated FGF19 having inhibitory effects on bile acid synthesis [8]. On the other hand, an overproduction of bile acids may result in BAD and a decrease in circulating levels of FGF19 [59].

FXR plays a role in managing intestinal immunity and demonstrates anti-inflammatory effects within the intestinal mucosa. When activated, FXR can suppress pro-inflammatory responses in macrophages that are dependent on Toll-like receptor 9 (TLR9), leading to a reduction in IL-1β and TNF-α [64,65]. FXR-deficient mice have excessive bacterial growth and increased displacement to mesenteric lymph nodes. Impaired FXR-FGF19 signaling in the ileum, such as ileal resection and small intestinal bacterial overgrowth, can reduce bile acid reabsorption, leading to excessive bile acid in the colon. Xu et al [66] demonstrated that the FXR agonist fexinidazole alleviates DCA-induced colitis by restoring bile acid balance and microbial composition. Regarding barrier protection, FXR upregulates mucin 2 (MUC2) and goblet cell differentiation, reducing bacterial transmigration [59].

Intestinal Function Mediated by Pregnane X Receptor and Vitamin D Receptor Signaling

Pregnane X receptor (PXR) and vitamin D receptor (VDR) are secondary regulators of inflammatory diarrhea, namely IBD-related diarrhea and IBS-D with inflammation [67,68]. PXR activation by rifaximin improves IBS-D symptoms in 40% of patients [69], while VDR deficiency increases intestinal permeability by 2.1-fold in colitis models [70,71]. Both receptors inhibit NF-κB-mediated inflammation, but clinical data on their targeted therapies remain limited.

Initially identified in 1998 [72], PXR is present in various human organs and tissues, with particularly high levels found in the liver and intestines [73]. This receptor can detect and bind to numerous exogenous substances [74] and is activated by a range of hormones, medications, and specific bile acids. PXR responds to LCA and its derivative, 3-ketone LCA, but does not react to CDCA, DCA, or cholic acid. As the key receptor for xenobiotics, PXR plays a significant role in promoting the detoxification and removal of these compounds [75].

The expression of PXR occurs in human CD4+ and CD8+ T lymphocytes, as well as in CD19+ B lymphocytes and CD14+ monocytes. Additionally, it is activated in T cells from both mice and humans, where it subsequently inhibits T cell proliferation along with the expression of CD25 and IFN-γ in vitro. In vivo, activation of PXR by pregnenolone 16α-carbonitrile (PCN), a potent murine PXR agonist, mitigates dextran sulfate sodium–induced colitis [75] by enhancing the expression and activity of phase II detoxification enzymes and efflux transporters, including glutathione S-transferase alpha 1 (GSTA1), multidrug resistance protein 1a (MDR1a), and multidrug resistance-associated protein 2 (MRP2). This process leads to a reduction in the levels of pro-inflammatory cytokines such as IL-6, TNF-α, chemoattractant protein-1 (MCP-1), and IL-1β [75]. Furthermore, PXR plays a mechanistic role in inhibiting the activation of NF-κB by TNF-α.

In addition, PXR plays a role in regulating inflammatory responses, as well as in cell proliferation and migration. Earlier research has demonstrated that PXR activation can influence the composition of the gut microbiome and manage bile acids in a manner dependent on bacteria. Additionally, the enteric-limiting antibiotic rifaximin can activate human PXR, leading to improved symptoms in individuals with IBS-D [76]. PXR enhances the activity of excretion transporters (MDR1a, MRP2) and proteins involved in tight junctions, which leads to a decrease in intestinal permeability. The absence of the PXR gene results in compromised intestinal barrier integrity and elevated levels of Toll-like receptor 4 (TLR4). Additionally, the PXR ligand indole-3-propionic acid has been shown to lower intestinal permeability and decrease TNF-α expression via the TLR4 signaling pathway. These findings suggest that PXR plays a role in anti-inflammatory responses by inhibiting the TLR4 signaling pathway [77].

Initially identified in 1969, the VDR functions as a nuclear receptor that becomes activated by 1,25-dihydroxyvitamin D [15]. This receptor plays a crucial role in managing human metabolism, immune responses, and cancer [78]. Additionally, VDR can also be activated by the secondary bile acid LCA along with its metabolites, including 3-oxo LCA and heterologous LCA. VDR is extensively present across different tissues, particularly in the bone and intestines, as well as in immune cells [79], and is essential for maintaining calcium homeostasis and regulating the immune system [80]. The metabolism of bile acids can influence VDR regulation through intestinal microbiota, given that bile acids act as ligands and play a role in regulating VDR expression [81]. A recent study revealed that activating VDR inhibits the proliferation and differentiation of B cells, reduces T cell proliferation, facilitates the switch from Th1 to Th2 phenotype [82], promotes the maturation of T cells, aids in the generation of T regulatory cells, and decreases the formation of Th17 cells [83]. Furthermore, it obstructs the synthesis of inflammatory cytokines in monocytes, including IL-1, IL-6, IL-8, IL-12, and TNF-α, while also influencing the differentiation and maturation of dendritic cells [84]. Furthermore, Paneth cells have the ability to detect gut bacteria via MyD88-dependent TLR activation [85], leading to the production of antimicrobial peptides. The absence of VDR causes defects in autophagy and compromises Paneth cell functionality. In mutant mice, dysfunctional Paneth cells and decreased levels of lysozyme may contribute to the disruption of gut microbial balance, which plays a crucial role in intestinal inflammation [86]. Therefore, VDR might function as a modulator of colitis by influencing autophagy [87] and the activity of Paneth cells [88], consequently affecting the composition of intestinal communities [89].

It has been reported that patients with IBD disordered expression and signaling of VDR receptors, and the expression level of VDR in the colon is negatively correlated with the IBD tissue score, which indicates that VDR has a protective effect on intestinal inflammation. Some researchers used VDR gene-deficient mice to further explore the changes in VDR expression related to intestinal inflammation and its pathological mechanism [90]. Their findings indicated that these mice exhibited more severe colitis following 2,4,6-trinitrobenzene sulfonic acid–induced colitis, which was accompanied by a rise in intestinal epithelial cell apoptosis and an increase in the permeability of the mucosal barrier. This subsequent bacterial invasion could trigger disturbances in the immune system, implying that the VDR functions in a manner dependent on bacteria. In a study conducted by Liu et al [91], epithelial signaling via VDR reduced apoptosis in epithelial cells by blocking NF-κB signaling and a crucial apoptotic mediator. Consequently, enhancing VDR levels in mice helps preserve epithelial barrier integrity and mitigates colitis [92].

In addition to its role in immune cell regulation, VDR seems to be engaged in the maintenance of intestinal epithelial cell homeostasis [91]. Expression of human VDR in mouse intestinal epithelial cells has been shown to safeguard mice from colitis by decreasing intestinal epithelial cell apoptosis and enhancing the integrity of the intestinal mucosal barrier [93].

Intestinal Function Mediated by Retinoid-Related Orphan Receptor Gamma t Signaling

Retinoid-related orphan receptor gamma t (RORγt) is a potential target for inflammatory diarrhea [94]. Its inhibition by 3-oxo-LCA (a microbiota-derived bile acid) reduces Th17 cell counts by 40% in colitis models [95,96], but human clinical data are lacking.

RORγt is a type of nuclear receptor that is part of the nuclear activator (NR) family, and it is encoded by the RORC gene. This protein is crucial for regulating the immune system and maintaining intestinal mucosal health, especially in the development and functionality of regulatory T cells (Treg) and Th17 cells [97,98]. RORγt is predominantly found in Th17 lymphocytes and innate lymphoid cell population 3 (ILC3), functioning as a crucial transcription factor for the differentiation of Th17 cells in the context of chronic inflammation and autoimmune conditions. It plays a role in sustaining Th17 cell expression through the regulation of superenhancer-associated epigenetic modifications. In studies involving mouse models, the removal of RORγt expression led to a notable decrease or total absence of autoimmune cells, along with a heightened resistance to autoimmune diseases mediated by Th17 cells [99]. On the other hand, RORγt-dependent ILC3 provides protective immunity. Recently, studies by Hang et al [100] and Song et al [101] demonstrated that derivatives of oxo-bile acids, especially 3-oxo-LCA, have the ability to interact with RORγt, functioning as reverse agonists. In experiments involving a murine model of colitis, the interaction with RORγt resulted in a decrease in IL-17 levels and a reduction in the population of Th17 cells [102] and alleviated intestinal inflammation [103,104]. The differentiation of Th17 cells is hindered by secondary oxybile acid 3-oxo-LCA, which does so by interacting directly with RORγt and suppressing its transcriptional function [100]. Research conducted on mice indicates that secondary bile acids (such as LCA and 3-oxo-LCA) influence the colonic FOXP3+ Treg cells that express RORγt via VDRs, thereby enhancing the host’s vulnerability to colitis [101,105].

Discussion

Bile acid receptors do not act in isolation; their crosstalk and interactions with gut microbiota are critical for diarrhea pathogenesis (Table 2). Within the FXR-TGR5 axis, these receptors establish a critical negative feedback loop: FXR activation reduces bile acid synthesis (via FGF19/SHP), thereby decreasing TGR5 ligand availability (secondary bile acids, such as DCA) [4,106–108]. In BAD, impaired FXR signaling, including ileal resection, leads to bile acid excess, hyperactivating TGR5 and inducing intestinal hypermotility [109]. Mechanistically, FXR upregulates SHP, which inhibits TGR5-mediated cAMP-PKA signaling—this loop is disrupted in BAD, resulting in unopposed TGR5 activation [110]. Clinically, combining FXR agonists (to reduce bile acid pool size) and TGR5 antagonists (to inhibit hypermotility) may improve outcomes of BAD; however, no such combination trials have been conducted to date.

Table 2.

Diagnostic tools for non-infectious diarrhea subtypes.

Diarrhea subtype	Key diagnostic tools	Receptor link	Evidence strength
BAD	SeHCAT test (measures bile acid retention) Serum FGF19 (low levels indicate impaired FXR signaling) Fecal bile acid quantification (elevated)	FXR (FGF19), TGR5 (bile acid excess)	High(SeHCAT: gold standard) [117,118]
IBS-D	Rome IV criteria (symptom-based) Fecal calprotectin (rules out inflammation) Serum vitamin D (low = VDR dysfunction)	VDR, PXR (rifaximin response)	Moderate (symptom-based, no biomarkers) [119,120]
Postoperative diarrhea	Clinical history (cholecystectomy/ileal resection) Fecal bile acid quantification	FXR (enterohepatic circulation), TGR5 (motility)	High (history + bile acid measurement) [34]
Drug-related diarrhea	Drug history (antibiotics, NSAIDs) Fecal microbiota analysis (dysbiosis)	PXR (xenobiotic metabolism), VDR (microbiota)	Moderate (history + microbiota correlation) [121]

Abbreviations: BAD, bile acid diarrhea; FGF19, fibroblast growth factor 19; FXR, farnesoid X receptor; NSAIDs, nonsteroidal anti-inflammatory drugs; PXR, pregnane X receptor; SeHCAT, ^75Se-homocholic acid taurine; TGR5, Takeda G protein-coupled receptor 5; VDR, vitamin D receptor.

Parallel interactions exist between VDR and RORγt, mediated by microbiota-derived bile acids. VDR activation enhances microbial 7α-dehydroxylase expression, promoting 3-oxo-LCA synthesis [111]. 3-oxo-LCA, as a reverse agonist of RORγt, can inhibit the differentiation of Th17 cells and alleviate intestinal inflammation. In VDR−/− mice, the level of 3-oxy-LCA decreased by 50%, resulting in an increase in the number of Th17 cells and the development of severe colitis [67]. This crosstalk is particularly relevant in IBD-related diarrhea with down-regulated VDR expression. Furthermore, PXR and FXR act synergistically to orchestrate bile acid detoxification; PXR activates MDR1a and MRP2 to excrete excess bile acids, while FXR reduces bile acid synthesis [112,113]. In IBD-S, rifaximin can alleviate intestinal inflammation and reduce the size of the bile acid pool by activating PXR and FXR, with a proven efficacy rate of 40% [114]. This synergy highlights the potential of dual-target therapeutic strategies for subtypes of mixed diarrhea.

The therapeutic landscape for disorders of the bile acid–microbiome axis have expanded to include agents targeting bile acid receptors and their downstream interactions. Among these, bile acid sequestrants such as cholate amine and sodium cholate exert their effects by binding to bile acids in the lumen, thereby attenuating the activation of key receptors such as FXR and TGR5 [115]. Rifaximin has been approved for IBS-D mainly characterized by diarrhea through regulating the gut microbiota and reducing inflammation, with approximately 40% of patients achieving symptom relief [71]. Despite these advances, substantial translational barriers remain. Numerous novel receptor-targeted candidates, particularly TGR5 agonists, currently lack robust Phase III data regarding efficacy and safety. Furthermore, the predictive validity of preclinical models is frequently undermined by interspecies discrepancies in bile acid composition; for example, the predominance of muricholic acids in rodents complicates the extrapolation of FXR antagonist findings to human physiology. Future investigations must prioritize delineating receptor crosstalk within complex clinical phenotypes, including IBS-D comorbid with BAD, to establish long-term safety profiles for receptor-specific therapeutics and advance personalized medicine frameworks grounded in genetic polymorphisms.

Conclusions

Targeting bile acid receptors provides a stratified therapeutic paradigm for non-infectious diarrhea. FXR emerges as the primary, clinically validated cornerstone for BAD, in which agonists such as obeticholic acid exhibit potent efficacy in restoring signaling homeostasis and reducing symptom frequency [62,63]. Complementary functions are attributed to TGR5/GPBAR1 in motility-driven subtypes, such as IBS-D, and to VDR in inflammatory settings, where microbiota-mediated modulation inhibits pathogenic Th17 cell differentiation [60,116]. Although RORγt represents a promising yet unverified frontier, future progress depends on large-scale genotyping to decipher the impact of polymorphisms, such as FXR rs386273456 and TGR5 rs11554825 [64,65]. To optimize clinical outcomes, management strategies must evolve toward dual-target synergies, extend safety surveillance beyond the current 2-year horizon, and implement standardized diagnostic protocols utilizing serum FGF19/C4 biomarkers across diverse ethnic cohorts.

In summary, this hierarchical receptor model offers a streamlined pathway to enhance prognoses for non-infectious diarrhea. By integrating rapid serum C4/FGF19 screening with targeted interventions—ranging from bile acid sequestrants and obeticholic acid to rifaximin—this framework addresses critical deficiencies in patient stratification and diagnostic latency. While forthcoming advancements in TGR5 antagonists and genotyping hold promise for greater precision, immediate efforts must focus on validating these approaches across heterogeneous populations and ensuring equitable access to effective therapies. Ultimately, establishing bile acid receptors as the central pillar of management paves the way for a new era of personalized and efficacious therapeutic strategies.

Data Availability

Data will be made available on request.