Interactions between gut bacteria and bile in health and disease
Introduction
Bile acids are the major functional components of bile. They are synthesized from cholesterol in hepatocytes, stored in the gall bladder and are subsequently released into the small intestine (Joyce and Gahan, 2016). The host enzymes involved in bile acid synthesis have been well characterised, and there is significant information available concerning the pathways that are central to bile acid synthesis (Li and Chiang, 2014). Significantly, bile acids are further modified by unique microbial enzymes that are encoded within the gut microbiome. These enzymes are as important to the host metabolism of bile acids as the liver cytochrome P450 enzymes that are encoded within the host genome. Indeed, the relationship between host and microbe-mediated bile acid metabolism represents an excellent exemplar of the symbiotic reliance upon microbial enzymes to complete functions that are essential to homeostasis in the host. Without a microbial contribution to bile acid metabolism the host bile acid signature is perturbed with resultant impacts upon a range of host physiological processes (Joyce et al., 2014a, Sayin et al., 2013, Swann et al., 2011). The basic microbial enzymes that contribute to bile acid metabolism include bile salt hydrolase (BSH) and bile acid dehydratase enzymes that generate unconjugated and secondary and tertiary bile acids (see Fig. 1).
A major function of bile acids is to facilitate the emulsification of dietary fats and to aid intestinal absorption of lipids and lipophilic vitamins (Begley et al., 2005a). However much recent work has also shown that bile acids represent signalling molecules in the host with the capacity to regulate cellular and metabolic activities through interaction with host bile acid receptors (Li and Chiang, 2014, Vitek and Haluzik, 2016). These receptors include the ligand-activated nuclear receptors such as the farnesoid-X-receptor (FXR) and the vitamin D receptor (VDR) as well as the cell surface-located G protein-coupled bile acid receptor TGR5 (Li and Chiang, 2014). Importantly different receptors have differing affinity for individual bile acids. For instance the most potent agonists of the FXR (in rank order of potency) are CDCA > LCA = DCA > CA with both conjugated and unconjugated moieties capable of activating the FXR (Parks et al., 1999, Zhou and Hylemon, 2014). TGR5 recognises both conjugated and free bile acids with a preference for TLCA followed by TDCA > TCDCA > TCA (Joyce and Gahan, 2016, Li and Chiang, 2014). This implies that subtle variations to the local or systemic bile acid signature may alter the signalling properties of the bile acid pool with a resultant physiological impact upon the host. Given that the gut microbiota has a major influence upon this bile acid signature, perturbations to the gut microbial community structure will have significant consequences for the signalling properties of bile acids in the host. This is most likely to occur in disease states where alterations of the gut microbiota are exaggerated.
In the current review we examine the role of specific microbial enzymes upon bile acid metabolism in the host and outline how perturbations to the microbiota may influence systemic bile acid profiles with an emphasis upon disease states. For in-depth reviews on the biochemical signalling effects of bile acids the reader is referred to excellent reviews by Li and Chiang (2014) and Zhou and Hylemon (2014) (Li and Chiang, 2014, Zhou and Hylemon, 2014).
Section snippets
Host synthesis of bile acids
Bile acids are products of steroid cholesterol and are generated through either the classical or alternative pathway primarily in hepatocytes (see Fig. 1). The host enzymes responsible for bile acid synthesis are cytochrome P450 family enzymes. Over 200 potential cytochrome P450 enzymes are encoded by the human genome, 57 of which have an assigned function either as hydroxylases or as oxidases involved in many cellular processes including cholesterol biosynthesis, steroid hormone biosynthesis,
Microbial modifications of bile acids
Host synthesis of bile acids represents the origin of bile acids in the bile acid pool. However, the chemical composition of bile acids is significantly influenced by the gut microbial community and therefore the microbiota should be considered as an essential factor in bile acid homeostasis in the host (Fig. 1). Here BSH enzymes deconjugate bile acids to unconjugated forms which are then subject to further modifications. The key enzymes involved in these biochemical conversions are outlined
Perturbation of microbial populations and effects upon bile acid metabolism
Changes to the gut microbial community which alter the copy number or expression levels of BSH or BAI enzymes will influence the detergent and signalling properties of the bile acid pool in the host. This is most clearly evidenced by the significant differences in the bile acid pool that exist when germ free or antibiotic treated animals are compared to their conventionally raised counterparts (Sayin et al., 2013, Swann et al., 2011). In healthy subjects subtle changes to the microbial
Conclusions
Whilst bile acids are synthesized within the host liver, the significant diversity of the bile acid pool is ultimately generated by the gut microbiota through microbial conversions of primary bile acids to unconjugated and secondary bile acids. This is an aspect of bile acid metabolism that is missing in germ free animals and is a good example of the interplay between gut microbes and the host that is essential for homeostasis (Joyce et al., 2014a, Sayin et al., 2013, Swann et al., 2011). Given
Acknowledgements
The authors acknowledge the funding of the APC Microbiome Institute by the Science Foundation of Ireland Centres for Science, Engineering and Technology (CSET) programme (Grant Number SFI/12/RC/2273). The authors declare no conflict of interest.
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