Abstract (as presented by the authors of the scientific work):
"Depressive disorders often run in families, which, in addition to the genetic component, may point to the microbiome as a causative agent. Here, we employed a combination of behavioral, molecular and computational techniques to test the role of the microbiota in mediating despair behavior. In chronically stressed mice displaying despair behavior, we found that the microbiota composition and the metabolic signature dramatically change. Specifically, we observed reduced Lactobacillus and increased circulating kynurenine levels as the most prominent changes in stressed mice. Restoring intestinal Lactobacillus levels was sufficient to improve the metabolic alterations and behavioral abnormalities. Mechanistically, we identified that Lactobacillus-derived reactive oxygen species may suppress host kynurenine metabolism, by inhibiting the expression of the metabolizing enzyme, IDO1, in the intestine. Moreover, maintaining elevated kynurenine levels during Lactobacillus supplementation diminished the treatment benefits. Collectively, our data provide a mechanistic scenario for how a microbiota player (Lactobacillus) may contribute to regulating metabolism and resilience during stress."
Covered topics (the letter size corresponds to the frequency of mentioning in the text):
Discussion (as presented by the authors of the scientific work):
"Taken together, our results demonstrate that microbiome homeostasis was robustly altered in animals undergoing UCMS, with a consistent decrease in Lactobacilli. This finding was shared across three strains of mice (C57BL/6J, as BALB/cJ and C57BL/6N). Moreover, our data suggest that the production of H2O2 by Lactobacillus may be protective against the development of despair behavior by direct inhibition of intestinal ido1 expression and decrease in the circulating level of kynurenine, a metabolite associated with depression26.
Our results are in agreement with recent literature demonstrating that microbiome composition is modified with acute and chronic stress20,33,34. Microbiome dysbiosis is also detected in humans affected by major depressive disorders and the transplantation of the biota from these patients in germ free mice can induce despair behavior9. Beyond describing microbiome fluctuation as a consequence of UCMS, we further demonstrated that levels of Lactobacillus correlate with the susceptibility to and severity of despair behaviors. Indeed, animals exhibiting low (i.e. Taconic C57BL/6N mice) intestinal Lactobacillus levels present with a basal despair phenotype, when compared to animals with higher levels of Lactobacillus (i.e. Jackson C57BL/6J mice). Accordingly, therapeutic administration of a probiotic Lactobacillus species during UCMS was sufficient to improve the despair symptoms. Further works will be needed to explore the role of other populations of bacteria affected by UCMS, as well as Lactobacillus strain differences and their abilities to improve behavior.
Recently, members of the Lactobacillus genus have been shown to affect a multitude of aspects of human physiology, as they colonize several sites of the body, including the skin, the vagina, and the entirety of the gastrointestinal tract, starting with the oral cavity35. Perhaps best studied in the vagina, Lactobacilli protect against infection by producing a diversity of antimicrobial factors, including lactic acid, peroxide, bacteriocins, as well as by resource competition35,36,37. Although in a few contexts increased levels of Lactobacilli are associated with pathology, e.g. dental cavities38, the bacteria are largely non-pathogenic or beneficial. From dysbioses or probiotic studies, Lactobacilli are associated with protection against infection, improved recovery after enteric infections, decreased colitis pathology, and better cognitive function25,39,40,41.
While Lactobacilli are able to control other microbial communities through secretion of antimicrobial factors, genetic limitations make them more sensitive to environmental conditions. In particular, many Lactobacillus genus members are unable to synthesize amino acids and purines and thus rely on nutrient rich environments and other bacteria for supply of essential building blocks42,43,44,45. We hypothesize that, in the context of a faster intestinal transit, such as the one observed in stressed animals, fluctuating availability of nutrients and symbiotic bacteria will impact the renewal of the Lactobacillus niche46. Further studies will be able to determine whether there is indeed a causal relationship between increased intestinal motility and microbiota alteration in the context of stress, or rather if the dysbiosis induced during stress causes altered intestinal physiology.
We found that the level of kynurenine is increased after chronic stress, in a manner dependent on Lactobacillus levels. Kynurenine can readily cross the blood-brain barrier to drive depression within the CNS by disrupting neurotransmitter balance and driving neuroinflammation27,47. A recent study by Agudelo et al.26 identified this pathway as also being disrupted in stressed mice using the same model of UCMS. Taken together, these new findings point to disruptions in tryptophan-kynurenine metabolism as an important factor in mediating despair behavior. IDO1 is the main enzyme responsible for conversion of tryptophan to kynurenine outside of the liver, and its expression and activity can be directly inhibited by reactive oxygen species (ROS)32. Members of the Lactobacillus family have the capacity to produce high levels of ROS, as a means of maintaining their niche36,37. In our study, we have shown that decreased levels of ROS in stressed animals correlate with an increase in intestinal ido1 transcripts, thus potentially explaining our observed increase in circulating kynurenine. Moreover, several studies have shown that inhibiting IDO1 activity (such as with the small molecule 1-methyl tryptophan) has potent effects in ameliorating depressive-like behaviors both in chronic stress and inflammation-induced sickness behavior models48,49,50.
The inhibition of IDO1 by Lactobacillus-derived ROS is likely just one of the mechanisms through which Lactobacilli, and L. reuteri in particular, contribute to host physiology and modulate behavior. Our findings are in accordance with the previously reported beneficial effect of L. reuteri administration on despair and anxiety-like behaviors25. Nevertheless, in their study, Bravo and colleagues have shown that L. reuteri can modulate GABA receptor expression in the CNS, via the vagus nerve25. The vagus nerve has been shown to carry peripheral signals and modulate inflammatory and stress reponses51,52,53,54. Whether the two results are connected remains to be investigated. It is possible that intestinal kynurenine can signal on the afferent vagal terminals and modulate its effects in the CNS, including its modulation of the hypothalamus-pituitary adrenal (HPA) axis. To this point, it is important to consider the contribution of liver TDO to peripheral kynurenine levels. TDO expression and activity are increased by glucocorticoids and in response to acute stress, and play a role in glucocorticoid levels homeostasis55,56,57. Whether TDO levels decrease chronically in our long-term stress model (following an expected decrease of corticosterone) or what effect the Lactobacillus administration has remains to be investigated. We have also considered other possible mechanisms for the behavioral effects of L. reuteri supplementation, mediated by the immune system, or other populations of commensals affected by the treatment. Further studies will be necessary to assess the chronological and the hierarchical role of each pathway during despair behavior development, as well as how these pathways affect the CNS.
Full-text access of the referenced scientific work:
Marin IA, Goertz JE, Ren T, Rich SS, Onengut-Gumuscu S, Farber E, Wu M,
Overall CC, Kipnis J, Gaultier A. Microbiota alteration is associated with the
development of stress-induced despair behavior. Sci Rep. 2017 Mar 7;7:43859. doi:10.1038/srep43859. PubMed PMID: 28266612; PubMed Central PMCID: PMC5339726.
Prof. Atanas G. Atanasov (Dr. habil., PhD)