Bile acids (BAs) are cholesterol-derived products with amphipathic properties due to several hydrophilic hydroxyl groups, a polar carboxyl group, and a steroid nucleus (Fiorucci and Distrutti 2019). There are two types of BAs: primary and secondary. Cholic acid (CA) and chenodeoxycholic acid (CDCA) are the main primary BAs produced by humans, while in mice, the predominant primary BAs are CA and muricholic acid (MCA) (Chiang and Ferrell 2019). Primary BAs are synthesized in the liver, and after conjugation with taurine or glycine, they are secreted into the biliary tracts. BAs constitute a main component of bile, which is accumulated in the gallbladder and, following the food intake, is secreted into the intestinal lumen (Ridlon et al. 2006). As natural detergents, BAs play a key role in lipid emulsification and absorption of lipids and liposoluble vitamins (Dawson and Karpen 2015).
Besides the participation in digestion, BAs are characterized by many other functions since they act as signaling molecules involved in regulating various metabolic processes (Fiorucci and Distrutti 2019). BAs are well-known ligands of widespread nuclear and membrane receptors. The nuclear receptors activated by BAs include farnesoid X receptor (FXR), pregnane X receptor (PXR), vitamin D receptor, liver X receptor (LXR), and glucocorticoid receptor (GR). Whereas G protein-coupled receptors (GPCR) on cell surface activated by BAs are Takeda G-protein receptor 5 (TGR5), sphingosine-1-phosphate receptor 2 (S1PR2), muscarinic receptors (M2 and M3), and formyl-peptide receptor (FPR) (Ticho et al. 2019).
The FXR activation modulates glucose, lipid, and protein metabolism, and energy expenditure. It also regulates various metabolic pathways in the liver, including hepatic fibrosis (Ferrebee and Dawson 2015). The FXR stimulation via BAs results in fibroblast growth factor 19 (FGF19) production in humans (FGF15 is the mouse ortholog). FGF19 regulates BA synthesis in the negative feedback loop by repressing cholesterol-7α-hydroxylase activity in hepatocytes, consequently leading to decreased hydroxylation of BAs and the reduction of BA synthesis (Babaknejad et al. 2018). Moreover, BA-mediated FXR stimulation regulates microbiota composition due to the enhanced expression of genes, the products of which, like nitric oxide, arrest bacterial overgrowth (Di Gregorio et al. 2021). Furthermore, FXR is involved in modulating intestinal innate inflammatory reactions through nuclear factor-kappa B (NF-κB) signaling. The BA binding to FXR also enhances mucosal integrity contributing to the protection against intestinal infections (Matsubara et al. 2013).
BA-mediated TGR5 activation influences glucose metabolism through enhanced secretion of incretins: glucose like peptide-1 and glucose like peptide-2 into the portal vein (Dawson and Karpen 2015). Moreover, it stimulates intestinal motility (Xie et al. 2021), induces gallbladder relaxation, reduces intrahepatic biliary pressure, and modulates BA pool composition (Bidault-Jourdainne et al. 2021). Additionally, the TGR5 activation restrains hepatic macrophage activity (Xie et al. 2021) and diminishes proinflammatory cytokines in monocytes, hence modulating inflammatory processes (Duboc et al. 2014). A summary of the main BA functions is presented in Fig. 1.
Main functions of bile acids. Bile acids (BAs), as the main bile component, are responsible for lipid emulsification, micelle formation, and participation in the absorption of lipids and liposoluble vitamins. BAs also have an important impact on gut microbiota composition. BAs are farnesoid X receptor (FXR) ligands leading to fibroblast growth factor 19 (FGF19) synthesis. Moreover, FXR stimulation influences gut microbiota composition and intestinal innate immune response. BAs also activate Takeda G-protein receptor 5 (TGR5), stimulating intestinal motility, inducing gallbladder relaxation, reducing intrahepatic biliary pressure, modulating the composition of the BA pool, and affecting glucose metabolism. Additionally, the TGR5 activation regulates inflammatory processes and energy expenditure. Based on Dawson and Karpen (2015).
Due to the direct relationship between BAs and gut microbiota, and the impact of BAs on the regulation of various metabolic processes, especially modulation of the immune response, there is a growing attention directed toward the relationship between BAs and gastrointestinal infections, in particular
Two publication databases have been searched: PubMed and Scopus. Combinations of the following keywords were used (“bile acid” or “bile acids” or “ursodeoxycholic acid” or “ursodiol” or “obeticholic acid”) and (“
In the small intestine, the gut bacteria metabolize BAs. The main transformation processes include deconjugation and oxidation of hydroxyl groups (Marin et al. 2015). Bile salt hydrolases (BSHs), the only enzymes responsible for the pivotal deconjugation reaction, allow BAs to become less toxic to the microbiota. BSHs cleave the conjugated glycine or taurine from BAs. The activity of BSHs serves as a gatekeeper to subsequent BA transformations (Foley et al. 2019). Approximately 95% of BAs are actively reabsorbed in the terminal ileum by the apical sodium-dependent bile acid transporter (ASBAT) to the portal vein from where they reach the liver and return into bile. It is called enterohepatic circulation (Ticho et al. 2019). The remaining 5% of unabsorbed BAs pass to the large intestine, where they undergo further microbial transformation (Marin et al. 2015). Only a narrow group of commensal bacteria can perform 7α-dehydroxylation, which is the crucial reaction in secondary BA origination. The
BA biotransformation results in modifying their properties, allowing for passive absorption of some BAs in the colon. Secondary BAs constitute an essential part of the BA metabolome. Partially BAs are also eliminated in the feces (Marin et al. 2015). Fig. 2 presents an overview of the BA circulation and biotransformation.
Enterohepatic circulation and bile acid biotransformation. Primary bile acids (BAs) are produced in the liver and after conjugation with taurine or glycine are secreted into bile ducts. As a component of bile, they are accumulated in the gallbladder. After every meal, they are secreted into the intestinal lumen. In the small intestine, microbiota biotransformation starts. The deconjugation is performed by bile salt hydrolases (BSH), which constitute the key reaction enabling further transformations. Most BAs are absorbed in the distal ileum by the apical sodium-dependent bile acid transporter (ASBAT) to the portal vein from where they reach the liver and return into bile. The unabsorbed BAs pass to the large intestine, undergoing further microbial transformation. 7α-dehydroxylation is the crucial reaction in secondary BA origination. Some BAs are passively absorbed in the colon, and some are also eliminated in the feces. CA – cholic acid, CDCA – chenodeoxycholic acid, TCA – taurocholic acid, GCA – glycocholic acid, TCDCA – taurochenodeoxycholic acid, GCDCA – glycochenodeoxycholic acid, UDCA – ursodeoxycholic acid. Based on Fiorucci and Distrutti (2019).
CDI is the most common cause of antibiotic-associated diarrhea (Abt et al. 2016). It is related to a significant morbidity, mortality, and a substantial global burden to the healthcare system (Guh et al. 2020).
CDI may be manifested by an asymptomatic carriage, mild to moderate diarrhea, colitis, pseudomembranous colitis, or even fulminant colitis. Antibiotic therapy, abdominal surgery, hospitalization, age over 65, and severe concomitant diseases are the major risk factors of CDI (Napolitano and Edmiston 2017).
The gut microbiota composition has an ability to protect against invasion by pathogenic microorganisms. The mechanism is not fully known; however, it is proposed that microbiota-derived secondary BAs take an important part in this process (Winston and Theriot 2016).
Primary BAs such as CA and taurocholic acid (TCA), which are present in significant concentrations in the small intestine, promote
Impact of bile acids on the life cycle of
The healthy microbiota inhibits
Noteworthy, obesity constitutes CDI risk factor (Mulki et al. 2017). One potential mechanism underlying greater susceptibility of obese subjects to a more severe CDI course might be an obesity-related dysbiosis resulting in BA disturbances. In a study conducted by Jose et al. (2021), mice with diet-induced obesity had a significantly higher ratio of primary to secondary BAs in cecal content compared to mice on a regular chow diet. Primary BA production in the liver was enhanced in these obese mice, and consequently,
In the study conducted by Wei et al. (2020), the number of
BA dysregulation has been reported in patients with CDI. Allegretti et al. (2016) have observed the shift in BA concentration in human stool with the primary BA predominance during CDI. Moreover, higher primary BA content in feces was noted during recurrent CDI compared to the first episode of CDI (Allegretti et al. 2016). On the other hand,
FMT is based on administering bacteria present in donor fecal filtrate to reestablish the resident microbiota. Apart from living bacteria, the products of their metabolism also significantly contribute to the FMT effectiveness. The microbial species with 7α-dehydroxylase activity present in the transplanted microbiota play a pivotal role in restoring resistance to
Buffie et al. (2015) demonstrated that administration of
The study conducted by Winston et al. (2020) demonstrated that no significant difference in microbiome after UDCA application could be seen in a mouse model. However, another study showed that the UDCA administration results in reducing the abundance of
As mentioned above, CDI is associated with decreased secondary BA and increased primary BA levels in the stool. Importantly, UCDA treatment of mice with CDI is associated with the BA pool alteration leading to the enhanced concentration of β-MCA, tauro-β-MCA, TCA, tauroursodeoxycholic acid (TUDCA), and UDCA in feces (Palmieri et al. 2018; Winston et al. 2020). However, differences in BA profiles and metabolism among species may constitute major limitations in BA research, making it challenging to translate animal models into clinic (Winston and Theriot 2020).
Palmieri et al. (2018) revealed that UDCA administration failed in CDI prevention in a rodent model. Similar results were obtained by Winston et al. (2020). They demonstrated in a murine model that UDCA treatment did not prevent CDI; however, it was associated with a retardation of the onset of symptoms. Therefore, UDCA may impact on the early stages of CDI pathogenesis (Winston et al. 2020). The retrospective analysis showed that the UDCA treatment of primary sclerosing cholangitis in patients with inflammatory bowel disease did not protect from CDI development (Palmieri et al. 2018). In another study, UDCA was prescribed off-label to patients with recurrent CDI and risk factors of relapses. In those cases, UDCA treatment was associated with 87.5% effectiveness in CDI prevention at a median follow-up of 264 days (Webb et al. 2019). Weingarden et al. (2016a) presented a single case report on a patient with recurrent
Noteworthy, UDCA can modulate the immune response through NF-κB signaling. In the study by Winston et al. (2020) in a mouse model, UDCA application was associated with decreased expression of genes encoding products mediating the inflammatory response to CDI, including IFN-γ, IL-6, TNF-α, and IL-1β. Therefore, it may be concluded that UDCA treatment could reduce the excessive inflammatory response during CDI, subsequently alleviating severe forms of CDI. Moreover, the immune response modulation was associated with the UDCA-induced activation of TGR5 and FXR. Pretreatment with UDCA resulted in a significantly enhanced expression of TGR5, FXR, and FGF15 during CDI compared to the no-UDCA treatment (Winston et al. 2020). However, this effect of UDCA on the FXR signaling was not confirmed in prior studies. It has been reported that UDCA administration might also lead to the suppression of FGF19 transcription and increment of CYP7A1 expression, thus suggesting that UDCA is an FXR antagonist (Gonzalez et al. 2015).
Moreover, studies performed on primary human hepatocyte cultures have demonstrated that UDCA has no effect on hepatic FXR (Liu et al. 2014; Zhang et al. 2017). However, the administration of UDCA at supratherapeutic concentrations results in the FGF19 enhancement and subsequent CYP7A1 suppression. It has been suggested that the UDCA effect in higher doses is most likely exerted through the PXR signaling pathway and not mediated by FXR mechanisms (Zhang et al. 2017). The PXR activation also downregulates the NF-κB signaling (Mohandas and Vairappan 2017).
Given that obesity is a risk factor for a severe CDI, Jose et al. (2021) conducted a study administering OCA to obese mice after exposition to
It is well known that gut microbiota plays a pivotal role in CDI prevention. The CDI risk factors contribute to dysbiosis leading to dysregulation of the BA metabolome. Since BAs regulate