Brain-gut photobiomodulation restores cognitive alterations in chronically stressed mice through the regulation of Sirt1 and neuroinflammation

Background: Chronic stress is an important risk factor for the development of major depressive disorder (MDD). Recent studies have shown microbiome dysbiosis as one of the pathogenic mechanisms associated with MDD. Thus, it is important to find novel non -pharmacological therapeutic strategies that can modulate gut microbiota and brain activity. One such strategy is photobiomodulation (PBM), which involves the non-invasive use of light. Objective/hypothesis: Brain -gut PBM could have a synergistic beneficial effect on the alterations induced by chronic stress. Methods: We employed the chronic unpredictable mild stress (CUMS) protocol to induce a depressive -like state in mice. Subsequently, we administered brain -gut PBM for 6 min per day over a period of 3 weeks. Following PBM treatment, we examined behavioral, structural, molecular, and cellular alterations induced by CUMS. Results: We observed that the CUMS protocol induces profound behavioral alterations and an increase of sirtuin1 (Sirt1) levels in the hippocampus. We then combined the stress protocol with PBM and found that tissuecombined PBM was able to rescue cognitive alterations induced by CUMS. This rescue was accompanied by a restoration of hippocampal Sirt1 levels, prevention of spine density loss in the CA1 of the hippocampus, and the modulation of the gut microbiome. PBM was also effective in reducing neuroinflammation and modulating the morphology of Iba1-positive microglia. Limitations: The molecular mechanisms behind the beneficial effects of tissue -combined PBM are not fully understood. Conclusions: Our results suggest that non-invasive photobiomodulation of both the brain and the gut microbiome could be beneficial in the context of stress -induced MDD.