A new study done in mice sheds light on how mental stress contributes to intestinal problems by altering microbiome composition [1].
Mind over matter
Some experiences are not called “gut-wrenching” just metaphorically, as the brain can indeed influence gastrointestinal function in a myriad of ways. While most of them are adaptive, brain signals can also cause intestinal problems. For instance, mental stress is thought to contribute to IBS (irritable bowel syndrome), which affects hundreds of millions of people worldwide, along with inflammatory bowel disease (IBD), an umbrella term that includes Crohn’s disease, ulcerative colitis, and other conditions [2]. However, the exact mechanisms behind this brain-gut interplay are not sufficiently understood.
Impaired mitochondrial function and differentiation
In this new study published in Cell Metabolism, the researchers subjected mice to two weeks of chronic stress to study their intestinal responses. This caused notable morphological changes in the mice’s guts consistent with a loss of intestinal function, which were still present up to two weeks after the mice were no longer subjected to stress. Moreover, the researchers observed a substantial decrease of proliferative cells along the intestinal villi (tiny folds) following stress. “These data,” the researchers suggest, “indicate that chronic psychological stress in mice triggers intestinal epithelia disturbance that is not easily repairable.”
Intestinal epithelial cells have an especially high turnover rate, the highest in the body [3]. Their whole population is renewed every few days. This means that intestinal stem cells (ISC) must work hard and proliferate profusely to be able to replenish all the cells that are constantly being shed.
Stress was shown to only mildly affect the proliferation of ISCs. However, it had a more profound dampening effect on their differentiation. ISCs receive cues from another type of cell, Panet cells, but the researchers were able to prove that stress affected ISCs specifically.
RNA sequencing showed that stress altered numerous molecular pathways in ISCs, especially those related to mitochondrial function. As a result, oxygen consumption rate in affected cells was much lower than in controls. Electronic microscopy confirmed changes in mitochondrial morphology in ISCs from stressed mice, and single-cell RNA analysis helped establish the link between this mitochondrial dysfunction and the impaired ability of ISCs to differentiate.
The microbial connection
Clearly, stress affects ISCs, but the mechanisms were unclear. Several options, such as variations in caloric intake and signaling by stress hormones, were ruled out. What if an intermediary were involved? Signals from the sympathetic nervous system are known to remodel the microbiome [4], and the researchers discovered that this is exactly what had happened to stressed mice.
The researchers conducted a series of clever experiments, such as transplanting the microbiota of stressed mice to healthy controls, which then started showing similar intestinal symptoms. They then tried treating mice with various narrow-action antibiotics to see which bacteria strains were responsible. Their attention turned to bacteria of Lactobacillus genus. One of the strains, L. murinus, turned to be highly enriched in the stressed mice. Colonizing the guts of germ-free mice with L. murinus recapitulated many of the effects of stress.
Looking for the specific metabolite responsible, the researchers noticed that the levels of indoleacetic acid (IAA) were increased several-fold in the guts of the stressed mice as well as in germ-free mice that received L. murinus transplants.
Finally, intestinal specimens were directly treated with IAA in concentration that mimicked stress condition. The treatment impaired intestinal regeneration and largely mimicked the effects of stress on ISCs’ differentiation and mitochondrial homeostasis. The researchers then established that α-ketoglutarate (AKG), a molecule that recently emerged as a possible geroprotector, was effective in abrogating the effects of stress on ISCs and intestinal function.
To initially assess whether their findings were relevant to humans, the researchers analyzed a microbiome composition dataset on people with major depressive disorder (MDD). Both Lactobacillus content and IAA levels were markedly increased in people with MDD. Finally, the researchers recruited their own cohort of patients with several mood disorders and received similar results. “Overall,” the researchers conclude, “these findings reveal a microbially driven brain-to-gut metabolic axis that could be therapeutically targeted for gut-brain comorbidities driven by chronic stress.”
Psychological stress exerts a significant yet poorly understood impact on the gut-brain axis. In the clinic, stressful lifestyle is critically involved in the exacerbation of brain-gut comorbidities such as IBD and IBS. Here we reveal a pathway by which the gut microbiome relays stress signals from the brain to shape the susceptibility to intestinal epithelial injury in mice. Specifically, this brain-to-gut circuit entails microbial metabolite IAA as a niche signal that hampers mitochondrial respiration to skew ISC fate decision and epithelial renewal. Importantly, IAA is consistently elevated in the gut of patients with mental distress, and targeting IAA signals proves effective to protect mice from the detrimental effects of stress.
Literature
[1] Wei, W., Liu, Y., Hou, Y., Cao, S., Chen, Z., Zhang, Y., … & Hao, H. (2024). Psychological stress-induced microbial metabolite indole-3-acetate disrupts intestinal cell lineage commitment. Cell Metabolism.
[2] Bisgaard, T. H., Allin, K. H., Keefer, L., Ananthakrishnan, A. N., & Jess, T. (2022). Depression and anxiety in inflammatory bowel disease: epidemiology, mechanisms and treatment. Nature Reviews Gastroenterology & Hepatology, 19(11), 717-726.
[3] Williams, J. M., Duckworth, C. A., Burkitt, M. D., Watson, A. J. M., Campbell, B. J., & Pritchard, D. M. (2015). Epithelial cell shedding and barrier function: a matter of life and death at the small intestinal villus tip. Veterinary pathology, 52(3), 445-455.
[4] Gershon, M. D., & Margolis, K. G. (2021). The gut, its microbiome, and the brain: connections and communications. The Journal of clinical investigation, 131(18).
