Disorders of gut-brain interaction (DGBI) affect over 40% of children and adults and involve both gastrointestinal symptoms and altered brain function, including anxiety and depression as the most common psychiatric comorbidities. While the gut microbiome has been associated with their onset and development, the mechanisms driving abnormal brain function in patients with DGBI are not fully understood, hindering the design of treatments that target the causes. It is well established that perturbation of gut microbiota in pregnant mothers or offspring after birth can predispose to dysfunction of the gut and brain, leading to the development of anxiety, depression, as well as digestive problems, later in life.
New preclinical research from McMaster University found that intestinal dendritic cells can migrate to the brain and influence behavior. The findings shed light on how changes in gut bacteria can alter brain function and behavior and suggest that an altered host-microbial crosstalk during the initial phase of microbial colonization may have long-term consequences.
To overcome the complexity of microbiota-brain communication and the large inter-variability in bacterial profiles in humans, the authors used gnotobiotic mouse models (i.e., mice born and raised in sterile conditions in which a defined microbial community is deliberately introduced) and a reductionist approach to examine how introducing gut bacteria affects brain function and behavior. They colonized germ-free mice and studied their behavior before and after colonization with a single bacterial strain of Escherichia coli, a simplified microbial community (Altered Schaedler Flora, consisting of 9 bacterial strains), and complex microbiota originating from conventional healthy mice.
Germ-free mice behaved differently from conventional mice (i.e., born and raised in the presence of normal microbiota), displaying more exploratory behavior and being less cautious. Still, germ-free mice’s behavior and brain chemistry normalized within 2 weeks after bacterial colonization. Interestingly, this occurred when the mice were colonized with complex or simplified microbiota, or even a single bacterial strain. The altered behavior driven by transient or persistent bacterial colonization was accompanied by changes in the brain, including expression of neurotrophin BDNF (brain-derived neurotrophic factor) -it is a marker of neural plasticity- and neural activity marker c-fos -it is often used as a marker of neuronal activation- in the amygdala and hippocampus, which are areas associated with control of emotions and learning.
The researchers found that intestinal dendritic cells, activated through the cell membrane located toll-like receptor (TLR) or intracellular nucleotide-binding oligomerization domain (NOD) signaling, are crucial for establishing normal behavior after initial bacterial colonization. Further, they discovered that these specialized immune cells migrate from the gut, some of them transporting bacterial fragments, into the brain. Blocking the activation and/or migration of the intestinal dendritic cells prevented changes in behavior after bacterial colonization. Interestingly, using genetically modified bacteria that only transiently colonized the murine intestine, the study showed that gut bacteria are no longer needed to sustain the altered behaviour once the immune system is activated and behavioral changes occur.
These pre-clinical findings demonstrate that the innate immune system, but not T and B lymphocytes, is associated with activation of neuro-immune networks in the gut and the brain after bacterial colonization. They may also reveal why there is a rise in psychiatric diseases and disorders of gut-brain communication, such as IBS, laying the foundation for novel therapeutic targets. The described mechanisms of microbiome-gut-brain communication with activation and migration of intestinal immune cells to the brain might also occur in adulthood during infectious gastroenteritis, which might explain the development of psychiatric comorbidities in many of these patients.
Reference:
Philip V, Kraimi N, Zhang H, et al. Innate immune system signaling and intestinal dendritic cells migration to the brain underlie behavioral changes after microbial colonization in adult mice. Brain Behav Immun. 2025; 127:238-250. doi: 10.1016/j.bbi.2025.03.012.
