Diet, Genetics, and the Gut Microbiome Drive Dynamic Changes in Plasma Metabolites

Abstract

SUMMARY Diet, genetics, and the gut microbiome are determinants of metabolic status, in part through production of metabolites by the gut microbiota. To understand the mechanisms linking these factors, we performed LC-MS-based metabolomic analysis of cecal contents and plasma from C57BL/6J, 129S1/SvImJ, and 129S6/SvEvTac mice on chow or a high-fat diet (HFD) and HFD-treated with vancomycin or metronidazole. Prediction of the functional metagenome of gut bacteria by PICRUSt analysis of 16S sequences revealed dramatic differences in microbial metabolism. Cecal and plasma metabolites showed multifold differences reflecting the combined and integrated effects of diet, antibiotics, host background, and the gut microbiome. Eighteen plasma metabolites correlated positively or negatively with host insulin resistance across strains and diets. Over 1,000 still-unidentified metabolite peaks were also highly regulated by diet, antibiotics, and genetic background. Thus, diet, host genetics, and the gut microbiota interact to create distinct responses in plasma metabolites, which can contribute to regulation of metabolism and insulin resistance.

Gut microbiota compositional and functional fingerprint in patients with alcohol use disorder and alcohol‐associated liver disease

“…Indeed, consistent with the knowledge that Bacteroides is one of the main GABA‐producing bacteria, GABA/glutamate pathway resulted enhanced in the gut microbiota of our AUD patients. GABA levels are decreased in germ free mice and can be modulated by antibiotic treatment, confirming a role of the gut microbiota in the production of this neurotransmitter . GABAergic/glutamatergic dysregulation may play a role in alcohol craving and in the development and maintenance of AUD and medications acting on the GABA system may be effective treatments for AUD.…”

“…GABA levels are decreased in germ free mice and can be modulated by antibiotic treatment, confirming a role of the gut microbiota in the production of this neurotransmitter. 48 GABAergic/glutamatergic dysregulation may play a role in alcohol craving and in the development and maintenance of AUD 49 and medications acting on the GABA system may be effective treatments for AUD. Alcohol may enhance the central inhibitory effects of GABA not only by increasing its release or acting on the GABAA postsynaptic receptors but also inducing an intestinal dysbiotic phenotype that implements the GABAergic system.…”

The Gut Microbiome in Pancreatic Disease

“…The interplay between the gut microbiota, immune system and intestinal barrier limits the growth of pathogenic flora 4 and disruption of this homeostasis leads to microbial imbalance known as ‘dysbiosis’. 5 The gut microbiome is known to have major effects on systemic metabolism 67 but there are thousands of metabolites in the plasma and in the gut, many of which remain uncharacterized. 7 A large portion of the variance in fecal metabolites can be explained by the composition of the fecal microbiome.…”

“…5 The gut microbiome is known to have major effects on systemic metabolism 67 but there are thousands of metabolites in the plasma and in the gut, many of which remain uncharacterized. 7 A large portion of the variance in fecal metabolites can be explained by the composition of the fecal microbiome. 7, 8 Dysbiosis is associated with the pathogenesis of several gastrointestinal diseases (inflammatory bowel disease, irritable bowel syndrome) 9 , as well as other diseases such as obesity, the metabolic syndrome, diabetes 10–12 and pancreatic diseases including pancreatic cancer.…”

Physical fitness in community‐dwelling older adults is linked to dietary intake, gut microbiota, and metabolomic signatures

“…Albeit conditioning for physical activity, the remaining set of selected features explained up to 45% of the total variance of the stratifying variables. In particular, dietary intake (17% of explained variance), GM composition (24%), and host metabolome (25%) signatures are important drivers of phenotypic differentiation ( Figure 5) and also described in animal models (Fujisaka et al, 2018). Accordingly, HF subjects showed a higher proportion of GM members commonly known for their protective roles, such as Bifidobacterium adolescentis and Christensenella species (Goodrich et al, 2014), and whose abundance corresponded negatively with glucose and lipid metabolism biomarkers (proinsulin, HbA1c, vLDL, triglycerides).…”