Early-life gut inflammation drives sex-dependent shifts in the microbiome-endocrine-brain axis

Abstract

Despite recent advances in understanding the connection between the gut microbiota and the adult brain, significant knowledge gaps remain regarding how gut inflammation affects brain development. We hypothesized that gut inflammation during early life would negatively affect neurodevelopment by disrupting microbiota communication to the brain. We therefore developed a novel pediatric chemical model of inflammatory bowel disease (IBD), an incurable condition affecting millions of people worldwide. IBD is characterized by chronic intestinal inflammation, and is associated with comorbid symptoms such as anxiety, depression and cognitive impairment. Notably, 25% of patients with IBD are diagnosed during childhood, and the effects of chronic inflammation during this critical developmental period remain poorly understood. This study investigated the effects of early-life gut inflammation induced by DSS (dextran sulfate sodium) on a range of microbiota, endocrine, and behavioral outcomes, focusing on sex-specific impacts. DSS-treated mice exhibited increased intestinal inflammation and altered microbiota membership, which correlated with changes in microbiota-derived circulating metabolites. The majority of behavioral measures were unaffected, with the exception of impaired mate-seeking behaviors in DSS-treated males. DSS-treated males also showed significantly smaller seminal vesicles, lower circulating androgens, and decreased intestinal hormone-activating enzyme activity compared to vehicle controls. In the brain, DSS treatment led to chronic, sex-specific alterations in microglial morphology. These results suggest that early-life gut inflammation causes changes in gut microbiota composition, affecting short-chain fatty acid (SCFA) producers and glucuronidase (GUS) activity, correlating with altered SCFA and androgen levels. The findings highlight the developmental sensitivity to inflammation-induced changes in endocrine signalling and emphasize the long-lasting physiological and microbiome changes associated with juvenile IBD.

Keywords: Androgens; Development; Gut inflammation; Gut-brain axis; Inflammatory bowel disease; Microbiome; Microglia; Sexual behaviours.