Stress, Depression, the Microbiome: A Possible Mechanism of Action Revealed!

For years, I’ve covered the developing story about the relationship between the gut biome and depression and mood disorders.  With a son diagnosed with autism, who has severe anxiety issues (like so many of my students with autism diagnoses), research into this is one of my primary interests.  For several years now, we’ve known that you can actually transfer anxiety and depression to a rodent by using fecal microbiota transplant from another animal, or a human, with a mood disorder.  However, the exact mechanism has not as yet been elucidated…which brings me to today’s paper.[i]

French researchers at the Pasteur Institute and several universities wanted to figure out how the gut bacteria actually influence mood and behavior.  Their findings stunned me:  at least part of the answer is that it changes the animals’ endocannabinoid system!  This system was not even discovered in humans until 1992 (you can read more about that here):  it involves cannabis-like molecules that are naturally made by our bodies that are critical in regulating behavioral, neurological and immune processes.  (For those interested in this topic in particular, you may want to check out this post from 2018 where I wrote about how helminths manipulate this system for both their benefit (i.e. ensuring their survival) and ours.  See here.  Changes to the endocannabinoid system, particularly in the hippocampus, have already been linked to depression and mood disorders.  In this case, the researchers found that the microbiome alterations led to a reduction in endocannabinoid signaling in the hippocampus.  Interestingly, disruptions to the hippocampal endocannabinoid system has already been connected to other neurological disorders.[ii]

To summarize: stress induced changes to the gut bacteria, which resulted in a reduction in production of fatty acid metabolites  that are precursors to endocannabinoids.  They found that in depressed animals, a particular strain of Lactobacillus, plantarum, was dramatically reduced.  This has also been found in humans.  In some good news, supplementing the rodents with the probiotic increased endocannabinoids in the brain of the rodents and alleviated their depression.  The animals were supplemented for 5 weeks and the researchers found this restored normal levels of hippocampal fatty acids, reversed the depressive behaviors, partially restored the production and survival of new neurons:   “Lactobacilli are more prominent in the small intestine, the primary site of lipid absorption. Studies in rodents have shown that Lactobacilli species modulate lipid metabolism. In addition, Lactobacilli may indirectly influence lipid absorption by modulating intestinal transit.”  L. plantarum is believed to regulate fatty acid metabolism; other Lactobaccilus strains may do so as well.  Further research is needed.

In the introductory paragraph of this paper, the authors point out – as I have many times on this blog – that depression is the leading cause of disability in the world and currently affects more than 300 million people.   Their conclusion most certainly inspires some hope that help is not far off:  “In sum, our data show that microbiota dysbiosis induced by chronic stress affects lipid metabolism and the generation of  eCBs [endocannabinoids], leading to decreased signaling in the eCB system and reduced adult neurogenesis in the hippocampus. This might be the pathway, at least in part, that links microbiota dysbiosis to mood disorders, which in turn, may affect the composition of the gut microbiota through physiological adjustments and modulation of the immune system…our study supports the concept that dietary or probiotic interventions might be effective levers in the therapeutic arsenal to fight stress-associated depressive syndromes.”

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[i] Chevalier, G., Siopi, E., Guenin-Macé, L. et al. Effect of gut microbiota on depressive-like behaviors in mice is mediated by the endocannabinoid system. Nat Commun 11, 6363 (2020). https://doi.org/10.1038/s41467-020-19931-2

[ii] https://newatlas.com/science/gut-microbiome-brain-depression-endocannabinoid/