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Spotlight

The gut microbiome, probiotics, bile acids axis, and human health Mitchell Lawrence Jones*, Catherine Tomaro-Duchesneau*, and Satya Prakash Biomedical Technology and Cell Therapy Research Laboratory, Departments of Biomedical Engineering, Physiology and Artificial Cells and Organs Research Center, Faculty of Medicine, McGill University, 3775 University Street, Montreal, Quebec, H3A 2B4, Canada

The human gut microbiome produces potent ligands to bile acid receptors, and probiotics could act as therapeutics of bile acid dysmetabolism. A recent study in Cell Reports demonstrates that probiotic VSL#3 affects bile acid deconjugation and excretion, as well as the gut– liver FXR–FGF15 axis. A growing body of evidence indicates that a pathological imbalance in the gut microbial community can result in altered microbial bile acid (BA) metabolism and act as an environmental factor associated with disease [1,2]. A number of recent BA studies have shown that BA pool size, metabolite composition and compartment concentrations are directly related to the makeup of the intestinal microbiota and microbial metabolism of BAs [3]. Recent work has shown that the gut microbiome alters the expression of genes controlled by the farnesoid X receptor (FXR) through BAs [3], and that this nuclear BA receptor is differentially activated by BAs and their metabolites [chenodeoxycholic acid (CDCA) > deoxycholic acid (DCA) > lithocholic acid (LCA) >> cholic acid (CA)] [4]. Thus, asking how probiotic strains might affect the gut microbial composition, BA metabolism, and the gut–liver FXR–fibroblast growth factor 15 (FGF15) axis is a highly relevant question which is gaining significant momentum from studies demonstrating that dysbiosis and BA dysmetabolism are associated with disease [1,2]. In a recent study by Degirolamo et al., the authors provide evidence that modulation of the gut microbiota, by administration of the probiotic cocktail formulation VSL#3, increases fecal BA deconjugation and excretion, as well as hepatic BA neo-synthesis in mice [5]. VSL#3 is a probiotic formulation comprised of Lactobacillus acidophilus, Lactobacillus paracasei, Lactobacillus delbrueckii subsp. bulgaricus, Lactobacillus plantarum, Bifidobacterium breve, Bifidobacterium infantis, Bifidobacterium longum, and Streptococcus thermophilus and was administered orally at a dose of 50  109 CFU/day to mice over a period of 21 days. The authors provide evidence that VSL#3 significantly changed the composition of mouse fecal microbiota, increasing counts of Firmicutes and Actinobacteria, while decreasing Bacteroidetes and Proteobacteria Corresponding author: Prakash, S. ([email protected]). * These authors contributed equally to this work. 0966-842X/ ß 2014 Elsevier Ltd. All rights reserved. http://dx.doi.org/10.1016/j.tim.2014.04.010

[5]. The authors show that VSL#3 administration increases fecal BA excretion which was correlated with increased bile salt hydrolase (BSH) transcription and enzymatic activity in feces [5]. VSL#3 administration was shown not to impact the CA:DCA ratio, and did not reduce the conjugated:deconjugated BA ratio levels in mouse fecal samples [5]. The authors demonstrate that the VSL#3-mediated BA fecal excretion occurs independently of the apical sodium dependent bile acid transporter (ASBT), as there was no increase in the transporter’s mRNA and protein levels upon probiotic administration [5]. VSL#3-treated mice, however, demonstrated increased intraluminal retention of taurocholic acid (TCA), as well as lower intracellular BA absorption and serum disposal, associated with decreases in the mRNA expression of BA transporters responsible for ileal intracellular binding and basolateral secretion into the portal circulation [5]. Interestingly, several studies have shown that BSHactive probiotic strains delivered orally to humans [6] and pigs [7] result in a significant increase in the unconjugated BA pool. In addition, human clinical studies evaluating the metabolic and gastrointestinal benefits of BSHactive strains have led to commercial strains with claimed efficacy, but without evidence of a significant increase in fecal excretion of BA [8,9]. Several clinical studies have evaluated orally delivered BSH-active strains, including Lactobacillus reuteri NCIMB 30242 that was shown to lower cholesterol and increase circulating 25-OH vitamin D [6,8,10] and Bifidobacterium animalis DN-173010 that was shown to shorten colonic transit time in healthy females [9]. Certainly, future work should evaluate whether the VSL#3 formulation significantly increases the fecal excretion of BAs in humans, as there may be important differences in murine and human BA physiology that may account for the observed differences and have important consequences on the gut–liver FXR–FGF15 axis. Further investigations by Degirolamo et al., provide substantial evidence that VSL#3 administration impacts the enterohepatic circulation and neo-synthesis of BA [5]. Probiotic treatment increased fecal BA excretion, gallbladder BA, the TCA:tauro-b-muricholic acid (TbMCA) ratio and small intestine luminal BA content with no differences in hepatic BA content, BA pool size and serum levels [5]. Regarding BA neo-synthesis, VSL#3 administration led to increased gene expression of the BA synthesis ratelimiting enzymes cholesterol-7a-hydroxylase (CYP7A1) and sterol-12a-hydroxylase (CYP8B1), both tightly regulated by FXR which induces small heterodimer partner Trends in Microbiology xx (2014) 1–3

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(SHP) and FGF15/19 to suppress CYP7A1 and CYP8B1 [5]. Finally, Degirolamo et al. successfully demonstrated that VSL#3 treatment led to reduced levels of ileal FGF15, with no changes in SHP and liver receptor homolog-1 (Lrh-1) levels, suggesting that VSL#3 CYP7A1 and CYP8B1 upregulation is mediated by FGF15 repression and downregulation of FXR activity [5]. One should note that Degirolamo et al. did not observe any changes in ileal FXR transcript levels following VSL#3 administration [5].

Further, studies evaluating VSL#3 using FXR- and FGF15-deficient mice demonstrated that VSL#3-mediated BA fecal excretion requires a functional FXR–FGF15 axis [5]. Fecal BA loss, as well as biliary and fecal BA composition, were similar in both VSL#3 treated and control animals. Furthermore, no changes in any of the FXR target genes were detected in hepatic and intestinal tissues [5]. Taken together, the data demonstrate that functional FXR activity is necessary for the probiotic VSL#3 to exert its activity on BA excretion and neo-synthesis in mice.

Oral administraon of BSHacve probioc bacteria

CYP7A1

7α-hydroxylase BA & metabolites

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Figure 1. Pathways influenced by orally delivered bile salt hydrolase (BSH) active probiotic bacteria. BSH activity leads to the hydrolysis of conjugated bile acids (CBA) to deconjugated bile acids (BA), with a decrease in BA absorption and increase in BA exretion. BSH enzymatic activity can modulate a number of physiological markers, both in the gastrointestinal tract as well as in the liver. These markers include farnesoid X receptor (FXR), fibroblast growth factor 15 (FGF15), intestinal bile acid-binding protein (Ibabp), organic soluble transporter beta (Ostb), organic soluble transporter alpha (Osta), liver X receptor (LXR), small heterodimer partner (SHP), and cholesterol 7 alphahydroxylase (CYP7A1).

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Spotlight The work by Degirolamo et al. provides much needed evidence of the relationships between the gut microbiome, BA metabolism and the gut–liver FXR–FGF15 axis. Much needed future studies evaluating individual probiotic strains with known BSH enzymatic activity will be able to build upon this mechanistic understanding (Figure 1). Indeed, the identification of microbial BA dysmetabolism as a potential environmental cause of disease warrants further investigation into the potential use of BSH-active probiotic strains for the management of a number of gastrointestinal, inflammatory and metabolic disorders including hyperlipidemia, gut dysbiosis, diarrhea, pouchitis, and ulcerative colitis, inflammatory bowel diseases, irritable bowel syndrome and other diseases. References 1 Duboc, H. et al. (2013) Connecting dysbiosis, bile-acid dysmetabolism and gut inflammation in inflammatory bowel diseases. Gut 62, 531–539 2 Theriot, C.M. et al. (2014) Antibiotic-induced shifts in the mouse gut microbiome and metabolome increase susceptibility to Clostridium difficile infection. Nat. Commun. 5, 3114

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3 Sayin, S.I. et al. (2013) Gut microbiota regulates bile acid metabolism by reducing the levels of tauro-beta-muricholic acid, a naturally occurring FXR antagonist. Cell Metab. 17, 225–235 4 de Aguiar Vallim, T.Q. et al. (2013) Pleiotropic roles of bile acids in metabolism. Cell Metab. 17, 657–669 5 Degirolamo, C. et al. (2014) Microbiota modification with probiotics induces hepatic bile acid synthesis via downregulation of the Fxr-Fgf15 axis in mice. Cell Rep. 7, 12–18 6 Jones, M.L. et al. (2012) Cholesterol lowering and inhibition of sterol absorption by Lactobacillus reuteri NCIMB 30242: a randomized controlled trial. Eur. J. Clin. Nutr. 66, 1234–1241 7 Lepercq, P. et al. (2004) Bifidobacterium animalis strain DN-173 010 hydrolyses bile salts in the gastrointestinal tract of pigs. Scand. J. Gastroenterol. 39, 1266–1271 8 Jones, M.L. et al. (2012) Cholesterol-lowering efficacy of a microencapsulated bile salt hydrolase-active Lactobacillus reuteri NCIMB 30242 yoghurt formulation in hypercholesterolaemic adults. Br. J. Nutr. 107, 1505–1513 9 Marteau, P. et al. (2002) Bifidobacterium animalis strain DN-173 010 shortens the colonic transit time in healthy women: a double-blind, randomized, controlled study. Aliment. Pharmacol. Ther. 16, 587–593 10 Jones, M.L. et al. (2013) Cholesterol lowering with bile salt hydrolaseactive probiotic bacteria, mechanism of action, clinical evidence, and future direction for heart health applications. Expert Opin. Biol. Ther. 13, 631–642

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The gut microbiome, probiotics, bile acids axis, and human health.

The human gut microbiome produces potent ligands to bile acid receptors, and probiotics could act as therapeutics of bile acid dysmetabolism. A recent...
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