Early life intestinal inflammation alters gut microbiome, impairing gut-brain communication and reproductive behavior in mice

Abstract

AbstractDespite recent advances in understanding the connection between the gut microbiota and the brain, there remains a wide knowledge gap in how gut inflammation impacts brain development. Microbiota-derived metabolite signaling from the gut to the brain is required for normal development of microglia, the brain’s resident immune cells. Disruption of the microbiota-brain communication has been linked to impaired behaviours and Autism Spectrum Disorder. We hypothesized that intestinal inflammation in early life would negatively affect neurodevelopment through dysregulation of microbiota communication to brain microglia. To test this hypothesis, we developed a novel pediatric model of Inflammatory Bowel Disease (IBD). IBD is an incurable condition affecting millions of people worldwide, characterized by chronic intestinal inflammation, and has comorbid symptoms of anxiety, depression and cognitive impairment. Significantly, 25% of IBD patients are diagnosed during childhood, and the effect of chronic inflammation during this critical period of development is largely unknown. We developed a chemical model of pediatric chronic IBD by repeatedly treating juvenile mice with dextran sodium sulfate (DSS) in drinking water. DSS-treated mice displayed increased intestinal inflammation, altered microbiota and changes in circulating metabolites. We also found that alterations in gut microbiota had long-term impacts on female microglia and male sex-specific behaviours and testosterone regulation, consistent with delayed puberty observed in male IBD patients. Our research expands our understanding of microbiota-microglia communication underlying development. The gut-brain axis is an exciting target for personalized medicine as microbiome manipulations could be feasible for early intervention to reverse deficits due to juvenile inflammation.HighlightsEarly life gut inflammation produces sex-specific i) microbiome, ii) sex hormone and iii) behavioural impactsBoth sexes show disrupted gut bacterial members that regulate sex hormone levelsMale mice demonstrate deficits in mate seeking, which may be mediated by reduced seminal vesicle mass and reduced androgen levelsFemale mice lack behavioural deficits, but demonstrate increased amoeboid microglia in the hippocampus