Systemic gut microbial modulation of bile acid metabolism in host tissue compartments

Abstract

We elucidate the detailed effects of gut microbial depletion on the bile acid sub-metabolome of multiple body compartments (liver, kidney, heart, and blood plasma) in rats. We use a targeted ultraperformance liquid chromatography with time of flight mass-spectrometry assay to characterize the differential primary and secondary bile acid profiles in each tissue and show a major increase in the proportion of taurine-conjugated bile acids in germ-free (GF) and antibiotic (streptomycin/penicillin)-treated rats. Although conjugated bile acids dominate the hepatic profile (97.0 ± 1.5%) of conventional animals, unconjugated bile acids comprise the largest proportion of the total measured bile acid profile in kidney (60.0 ± 10.4%) and heart (53.0 ± 18.5%) tissues. In contrast, in the GF animal, taurine-conjugated bile acids (especially taurocholic acid and tauro-β-muricholic acid) dominated the bile acid profiles (liver: 96.0 ± 14.5%; kidney: 96 ± 1%; heart: 93 ± 1%; plasma: 93.0 ± 2.3%), with unconjugated and glycine-conjugated species representing a small proportion of the profile. Higher free taurine levels were found in GF livers compared with the conventional liver (5.1-fold; P < 0.001). Bile acid diversity was also lower in GF and antibiotic-treated tissues compared with conventional animals. Because bile acids perform important signaling functions, it is clear that these chemical communication networks are strongly influenced by microbial activities or modulation, as evidenced by farnesoid X receptor-regulated pathway transcripts. The presence of specific microbial bile acid co-metabolite patterns in peripheral tissues (including heart and kidney) implies a broader signaling role for these compounds and emphasizes the extent of symbiotic microbial influences in mammalian homeostasis.farnesoid X receptor | gut microbiota | TGR5 | ultra-performance liquid chromatography mass spectrometry | G protein-coupled bile acid receptor 1 T he importance of gut microbiome variation in relation to human health and diverse diseases is now well-recognized (1-4). The microbiome is a virtual organ that performs many digestive and metabolic functions for the host, including enhanced calorific recovery from ingested foods and degradation of complex plant polysaccharides. Microbial communities have coevolved with man and show remarkable diversity dependent on topographical location and interperson variability (5). Co-evolution has refined the microbiome of organisms to a state where metabolic complementarity exists within the microbiota (6), and important biosynthetic/ metabolic pathways are provided for the host that significantly extend host metabolic capacity (3). As such, the mammalian host can be considered a superorganism (7), whose metabolism is the sum of that of both the host and the collective microbial community. The enterohepatic circulation provides a vehicle for this transgenomic metabolism, and bile acids, whose functional role in the global mammalian system is multifaceted, are an important class of metabolites that u...

Distinct signatures of host–microbial meta-metabolome and gut microbiome in two C57BL/6 strains under high-fat diet

“…This effect was also observed in KK-Ay mice, which showed increased levels of CA, DCA, TCA and TDCA in liver and intestine, which were also observed in our study in cecal samples of C57J mice fed with a HFD (Watanabe et al, 2006). The patterns of TBAs can be modulated through diet, absence of bacteria, distinct microbiome community, BAs or farnesoid X receptors agonists (Claus et al, 2008;Li et al, 2010a;Swann et al, 2011;Watanabe et al, 2011). In this study, lower abundance of TBAs in cecum of C57N mice could also be explained through an increase in their deconjugation rate by specific gut bacteria that are using the sulfur-containing taurine as an energy source such as Enterobacteria or Bacteroides spp.…”

“…Most of the metabolomics studies relevant in the research of obesity were performed with body fluids that cover only a small subset of metabolites (Xie et al, 2012). Only few metabolomics studies applied MS based techniques to investigate the metabolite patterns in intestinal/fecal and liver samples following exposure to different diets and disease conditions to discover the role and influence on the metabolome as a readout (Jansson et al, 2009;Antunes et al, 2011;Baur et al, 2011;Swann et al, 2011;Matsumoto et al, 2012). This study is performed by using two C57BL/6 mouse strains (C57BL/6J (C57J) and C57BL/6N (C57N)) exposed to a high-fat diet (HFD) for 3 weeks.…”

Consequences of bile salt biotransformations by intestinal bacteria

“…87 The global physiological significance of these alterations in bile acid profiles is unknown. However, decades of research strongly suggest that secondary bile acids (DCA and LCA), a product of bacterial metabolism of primary bile acids, are involved in disease processes including cancers of the colon, 76 liver, 75 and cholesterol gallstone disease in some patients.…”

Clostridium difficile heterogeneously impacts intestinal community architecture but drives stable metabolome responses

“…They include (i) two fatty acids, 22 lipids (including gluco-, glycero-and glycerophospho-lipids) and 10 bile acid derivatives, low levels of which have been reported to promote cell lipotoxicity and apoptosis and have an overall cathartic effect on the colon (Yoon et al, 2002;Senkal et al, 2011;Swann et al, 2011;Longato et al, 2012); (ii) five N-acyl amino acids or polyamides (including arachidoyl glycine, N-stearoyl proline, N-oleoyl (iso)leucine, N-stearoyl tyrosine and N-palmitoyl threonine), the absence of which promotes dysfunction in the regulation of host temperature, locomotion and inflammation (Tan et al, 2010); (iii) ferroxamine and five metabolites implicated in porphyrin and iron metabolism, the deficiency of which decreases the concentration of beneficial gut microbiota and induces iron deficiency anaemia (Dostal et al, 2014); (iv) 12 presumptive secondary metabolites and bioactive peptides, such as methionine enkephalin and a number of tripeptides, the metabolism failure of which has been shown to lead to failure in immune and neuroactive ligand-receptor interactions (Yoshimasa et al, 1982;Salzet and Tasiemski, 2001); (v) inosine, pseudouridine and hypoxanthine, nucleoside and purine derivatives, the depletion of which may negatively influence the initiation of translation and nucleic acid synthesis in human gut microbiota and in gut mucosal defence (Grimble, 1994); and (vi) six ceramide/sphingolipid derivatives, creatinine, N-acetylhistamine, glyoxylate and succinate-ceramide and creatinine deficits in the gut have been associated with liver and renal dysfunctions (Peral et al, 2002; Longato et al, . Notably, the production of the above metabolites was observed in patients carrying toxin + C. difficile strains (Supplementary Table 2).…”