Project description:Patients with inflammatory bowel disease (IBD) are particularly susceptible to behavioral diagnoses, and the microbiome has been repeatedly implicated in the pathogenesis of IBD. The intestinal microbiome's ability to affect behavior has become increasingly recognized and studied. The so-called 'psychobiome' has been linked to a plethora of neurological and psychological diagnoses, including autism and Parkinson's disease. Despite the ability of many bacterial species within the human intestinal microbiome to synthesize neurotransmitters, it has never been previously reported that a single bacterial species is sufficient to induce depression. Here, we demonstrate that our mouse model of Crohn's disease (CD)-like ileitis, the SAMP1/YitFc (SAMP1), does not exhibit baseline behavioral abnormalities. By comparison, SAMP6 mice develop depressive-like behavior that is associated with a rise in the GABA-producing bacterial genus Parabacteroides. We finally demonstrate that administration of Parabacteroides distasonis into our SAMP1 mice induces depressive-like behavior. Colonization with P. distasonis was not associated with increased intestinal inflammation or alterations in other measures of behavior. The intestinal environment of CD may be particularly conducive to colonization with P. distasonis and subsequent induction of depressive-like behavior. To our knowledge, this is the first report of a bacterial species specifically inducing depressive-like behavior.
Project description:Non-alcoholic steatohepatitis (NASH) is the severe form of non-alcoholic fatty liver disease, and is characterized by liver inflammation and fat accumulation. Dietary interventions, such as fibre, have been shown to alleviate this metabolic disorder in mice via the gut microbiota. Here, we investigated the mechanistic role of the gut microbiota in ameliorating NASH via dietary fibre in mice. Soluble fibre inulin was found to be more effective than insoluble fibre cellulose to suppress NASH progression in mice, as shown by reduced hepatic steatosis, necro-inflammation, ballooning and fibrosis. We employed stable isotope probing to trace the incorporation of 13C-inulin into gut bacterial genomes and metabolites during NASH progression. Shotgun metagenome sequencing revealed that the commensal Parabacteroides distasonis was enriched by 13C-inulin. Integration of 13C-inulin metagenomes and metabolomes suggested that P. distasonis used inulin to produce pentadecanoic acid, an odd-chain fatty acid, which was confirmed in vitro and in germ-free mice. P. distasonis or pentadecanoic acid was protective against NASH in mice. Mechanistically, inulin, P. distasonis or pentadecanoic acid restored gut barrier function in NASH models, which reduced serum lipopolysaccharide and liver pro-inflammatory cytokine expression. Overall this shows that gut microbiota members can use dietary fibre to generate beneficial metabolites to suppress metabolic disease.
