Short-chain fatty acids: microbial metabolites that alleviate stress-induced brain-gut axis alterations

Marcel van de Wouw, Marcus Boehme, Joshua M. Lyte, Niamh Wiley, Conall Strain, Orla O'Sullivan, Gerard Clarke, Catherine Stanton, Timothy G. Dinan, John F. Cryan

There is a growing recognition of the involvement of the gastrointestinal microbiota in the regulation of physiology and behaviour. Microbiota-derived metabolites play a central role in the communication between microbes and their host with short-chain fatty acids (SCFAs) being perhaps the most studied. SCFAs are primarily derived from fermentation of dietary fibres and play a pivotal role in host gut, metabolic and immune function. All these factors have previously been demonstrated to be adversely affected by stress. Therefore, we sought to assess whether SCFA supplementation could counteract the enduring effects of chronic psychosocial stress. C57BL/6J male mice received oral supplementation of a mixture of the three principle SCFAs (acetate, propionate and butyrate). One week later, mice underwent 3 weeks of repeated psychosocial stress, followed by a comprehensive behavioural analysis. Finally, plasma corticosterone, faecal SCFAs and caecal microbiota composition were assessed. SCFA treatment alleviated psychosocial stress-induced alterations in reward-seeking behaviour, increased responsiveness to an acute stressor and in vivo intestinal permeability. In addition, SCFAs exhibited behavioural test-specific antidepressant and anxiolytic effects, which were not present when mice had also undergone psychosocial stress. Stress-induced increases body weight gain, faecal SCFAs and the colonic gene expression of the SCFA receptors free fatty acid receptor 2 and 3 remained unaffected by SCFAs supplementation. Moreover, there were no collateral effects on caecal microbiota composition. Taken together, these data show that SCFAs supplementation alleviates selective and enduring alterations induced by repeated psychosocial stress and these data may inform future research into microbiota-targeted therapies for stress-related disorders. This article is protected by copyright. All rights reserved.