Enteric Microbiota Contribute to Behavioral Alterations Observed in Mice with Colitis

The enteric microbiota has been recognized as an essential regulator of both gut and brain physiology, a complex interaction generally termed the microbiota‐gut‐brain axis. Disturbances to gastrointestinal physiology lead to alterations in the composition of the enteric microbiota, whereas dysbiosis can also contribute to pathophysiology. Inflammatory bowel diseases (IBD) are chronic, relapsing and remitting inflammatory conditions of the gastrointestinal tract, associated with microbial dysbiosis. Interestingly, IBD patients exhibit an increased incidence of mental illness (i.e. anxiety and depression), often termed “sickness behavior”, even during the remitting phase of their disease. It is unclear if alterations in the enteric microbiota associated with IBD are responsible for the observed modification in brain function and behavior. Here, we hypothesized that sickness behavior is driven by alterations in microbial composition, which occur in the context of intestinal inflammation. We tested whether transfer of the microbiota from colitic mice, exhibiting sickness behaviour, into healthy counterparts would induce behavioral changes. Male mice (C57Bl/6J; 8 weeks old) were used in all experiments. Colitis was induced by administration of 2.5% dextran sodium sulfate (DSS) in the drinking water for 5 days. Colonic inflammation was assessed by measuring fecal lipocalin‐2 and the expression of pro‐inflammatory mediators via qPCR. Cecal matter from donor mice (control or DSS treated) were collected for fecal microbiota transplant (FMT). FMT was performed via oral gavage in antibiotic‐treated recipient mice. Gut bacteria were evaluated by 16S rRNA sequencing in cecal samples. Anxiety‐ and depression‐like behavior were assessed by elevated plus maze and tail suspension test, respectively. Brain samples were processed for qPCR analysis. DSS‐treated mice exhibited clinical disease, reflected by body weight loss, increased fecal lipocalin‐2 and elevated colonic pro‐inflammatory cytokine transcripts. An increase in anxiety‐like behavior was observed in mice with colitis, although no alterations in depression‐like behavior were detected. Colitic mice exhibited a unique microbial community. Transferring cecal material from colitic mice into recipient, antibiotic‐treated mice, recapitulated alterations in behavior seen in colitic donors, as shown by increased anxiety‐like behavior and unexpectedly, increased depression‐like behavior. These behavioral changes occurred in the absence of colonic or brain inflammation in the recipient mice, but were associated with changes in stress‐related gene expression (i.e. Crh ). Colitis‐associated sickness behavior can be transmitted to antibiotic‐treated recipients via FMT, which occurs in the absence of overt intestinal or neuroinflammation. Support or Funding Information This work was supported by Canadian Institutes of Health Research. F.A.V. is funded by the National Counsel of Technological and Scientific Development (CNPq, Brazil).

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