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Impact of Probiotics on Human Gut Microbiota and the Relationship with Obesity
Published in Marcela Albuquerque Cavalcanti de Albuquerque, Alejandra de Moreno de LeBlanc, Jean Guy LeBlanc, Raquel Bedani, Lactic Acid Bacteria, 2020
Fernanda Bianchi, Katia Sivieri
The gut microbiota modulates bile acid metabolism by influencing the nuclear bile acid receptor farnesoid X (FXR)/G protein-coupled receptor (TGR5) signalling that indirectly contribute to obesity development (Dahiya et al. 2017). FXR is a receptor that negatively regulates the expression of the gene cholesterol 7α-hydroxylase (CYP7A1), which encodes the enzyme cholesterol 7α-hydroxylase. The enzyme cholesterol 7α-hydroxylase catalyses the initial step of cholesterol catabolism and bile acid synthesis in liver (Chiang 2009). In the intestine, FXR induces fibroblast growth factor 15/19 (FGF15/FGF19), which will indirectly signal to inhibit CYP7A1 gene transcription and, consequently, the initial step of cholesterol catabolism and bile acid synthesis in liver. Decreasing BSH activity in gut microbiota increases tauro-β-muricholic acid (TβMCA), which antagonizes FXR activity, reducing FGF15/19 and stimulating CYP7A1, which will consequently stimulate bile acid synthesis in hepatocytes (Figure 5) (Chiang et al. 2017). The G protein-coupled receptor (TGR5) is a membrane receptor sensitive to the presence of bile acids expressed in the ileum and colon. This receptor promotes an intracellular elevation of cyclic Adenosine MonoPhosphate (cAMP). When cAMP is elevated in the adipose and muscle tissue cells, it triggers mechanisms of energy expenditure and stimulates insulin secretion in pancreatic β cells to improve insulin sensitivity (Figure 5) (de Fabiani et al. 2003, Watanabe et al. 2006, Chiang et al. 2017). Because of these facts, it is possible to state that the gut-liver axis has an important role in metabolic homeostasis regulation and bile acid synthesis (Chiang et al. 2017).
Gut associated metabolites and their roles in Clostridioides difficile pathogenesis
Published in Gut Microbes, 2022
Andrea Martinez Aguirre, Joseph A. Sorg
Mice are one of the most common animal models used in CDI studies and their murine bile acid composition and their effects on CDI are well understood.39,42 In rodents, the presence of alternative hydroxylating enzymes yields other primary bile acids (α/β/ω-muricholic acids) (Figure 1).43 Muricholic acids have a MIC similar to that of CDCA and DCA.39 Similar to CA, muricholic acids are also trihydroxyl bile acids but the hydroxyls are in the 3, 6, and 7 positions instead of the 3, 7, and 12 positions that are found on CA-derived bile acids (Figure 1).39 A study found that in addition to the bile acids described above, isodeoxycholic acid (a 7α, 12α-hydroxy bile acid), lithocholic acid (a 3α-hydroxy bile acid), isolithocholic acid (a 3β-hydroxy bile acid), and hyodeoxycholic acid also inhibit the growth of C. difficile vegetative cells.44 Furthermore, isoallolithocholic acid (isoalloLCA), the isomer of isoLCA had an MIC90 of 2 µM in C. difficile CD630 (a laboratory strain) and in the highly toxigenic C. difficile VPI10463 strain.45
Depletion of gut microbiota induces skeletal muscle atrophy by FXR-FGF15/19 signalling
Published in Annals of Medicine, 2021
Yixuan Qiu, Jiaming Yu, Yi Li, Fan Yang, Huiyuan Yu, Mengjuan Xue, Fan Zhang, Xin Jiang, Xueying Ji, Zhijun Bao
Nevertheless, this study had several limitations of note. Firstly, GF mice were a better animal model to investigate gut microbiota-skeletal muscle axis. However, these mice not only have compensatory mechanisms to balance the absence of microbiota but also have a dramatically different bile acid profile [47]. Secondly, considering that FGF15/19 is a transversal metabolic coordinator at the crossroads of liver, skeletal muscle and intestine [59], we could not exclude the possibility that FGF15/19 exerted influence on the liver or intestine, which in turn regulated skeletal muscle. Therefore, skeletal-muscle-specific FGFR4/KLB knockout mice were better animal models to verify the effects of FGF15/19 on skeletal muscle in future studies. Thirdly, muricholic acids (MCAs), including TβMCA, are generally detected in rodents but not humans [47,60], therefore, whether the results can be generalised to human warrants further examination. Last but not least, several studies have reported that FGF15/19 contributed to hepatocellular carcinoma development [61,62], so the usage of FGF15/19 to ameliorate skeletal muscle atrophy needs more attention because of safety concerns. However, nontumorigenic FGF19 variants have been engineered and used to treat cholestatic liver disease and regulate glucose homeostasis [39,63,64]. Thus, it would be promising to investigate whether the FGF19 variant can treat skeletal muscle atrophy in future works.
In vitro and in vivo characterization of Clostridium scindens bile acid transformations
Published in Gut Microbes, 2019
Solenne Marion, Nicolas Studer, Lyne Desharnais, Laure Menin, Stéphane Escrig, Anders Meibom, Siegfried Hapfelmeier, Rizlan Bernier-Latmani
In contrast, the murine primary bile acids αMCA and βMCA remained unchanged (Figure S1), confirming previous reports that human intestinal bacteria are unable to metabolize muricholic acids.17,45 A possible explanation for this is host specificity as C. scindens may have evolved in the human gut in the absence of murine primary bile acids. However, C. scindens may not be an exclusively human commensal as a new strain (strain G10) was recently isolated from rat feces.25 The 7β-dehydroxylation of UDCA was also tested in vitro. This transformation was previously reported for several 7-dehydroxylating organisms including several C. scindens strains (VPI 12708, 36S, M-18, Y-98, Y-1112, Y-1113) and Eubacterium strain C-25.31,46 The gene baiI is predicted to encode a 7β-dehydratase47 but this remains to be confirmed as this process could also occur via a 7β-epimerization to CDCA followed by 7α-dehydroxylation. Here, we did not observe any conversion of UDCA by C. scindens ATCC 35704 in vitro (Figure S1), consistent with previous reports.48