When Carolina Tropini, Assistant Professor of Microbiology and Immunology and Annie Ciernia Assistant Professor of Biochemistry and Molecular Biology, began a mouse study on how gut inflammation affects the brain they initially suspected a mix-up in the animals' sex. To their surprise and fascination they discovered that the male mice’s reproductive organs had failed to mature. The signal from the endocrine system was incredibly strong. We hadn’t set out to find that, but the data made it impossible to ignore said Tropini.

The gut microbiome the vast community of microbes in the digestive tract continues to reveal surprising and powerful links to other systems in the body. We’re beginning to see that the microbiota can influence nearly every organ Tropini explained. Much like oral medications that act systemically gut microbes release signaling molecules that enter the bloodstream and reach distant tissues. This communication is bidirectional as microbes also react to and modify incoming biological signals.

Driven by the unexpected findings, the Tropini and Ciernia labs set out to map the complex interactions between gut microbes the endocrine system and the brain. In their recent study published in Brain, Behavior, and Immunity they show how disruptions to the gut microbiome impact behavior sex hormones and brain development in a mouse model of pediatric inflammatory bowel disease (IBD).

About 25% of IBD cases begin in childhood or adolescence yet we know very little about how early-life inflammation affects the developing brain and body said Ciernia. Understanding these effects is crucial as they could have lasting consequences throughout a person’s life.

To mimic the intestinal injury seen in IBD the researchers exposed young mice to dextran sodium sulfate a chemical that damages the gut’s epithelial lining and triggers inflammation. Genetic analysis of the mice’s stool samples revealed a significant shift in the gut microbiome marked by reduced diversity and changes in microbial composition.

To assess the broader impact of this disruption the team evaluated the mice for behaviors related to memory, anxiety, depression, social interaction, and mating. While most behaviors remained unaffected the male mice notably lost their preference for the scent of female urine a critical factor in rodent mate-seeking behavior. This behavioral change helped explain the previously puzzling underdevelopment of reproductive organs observed in the male IBD mice prompting the researchers to explore the role of sex hormones.

Further analysis showed that early-life inflammation led to the loss of gut microbes responsible for producing β-glucuronidases and β-glucosidases enzymes essential for converting androgen hormones into their active forms. As a result male IBD mice exhibited reduced enzyme activity and lower levels of active testosterone likely contributing to their impaired sexual development and altered behavior.Many of the missing gut microbes in IBD mice produce short-chain fatty acids anti-inflammatory molecules that support gut health and communicate with the brain. These fatty acids can cross the blood-brain barrier and influence microglia the brain’s immune cells. The researchers observed sex-specific abnormalities in microglial shape likely linked to reduced short-chain fatty acid signaling. Brain imaging by Dr. J.P. Yu revealed distinct diffusion patterns in these altered regions suggesting a potential biomarker for treatment response. This highlights the gut-brain connection and the promise of microbiome-based therapies. Unlike isolated compounds beneficial bacteria can deliver therapeutic molecules naturally and precisely.The researchers aim to restore key gut microbes to reduce the neurological and hormonal effects of pediatric IBD focusing on creating a resilient microbial ecosystem through diet and targeted therapies. They also plan to study how altered testosterone impacts puberty, fertility, and long-term reproductive health.

Source: https://www.centreforbrainhealth.ca/news/exploring-the-microbiome-neuroendocrine-connection-in-early-life-gut-inflammation/