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

• Published in: The Journal of physiology 2018-10, Vol.596 (20), p.4923-4944
• Main Authors: de Wouw, Marcel, Boehme, Marcus, Lyte, Joshua M., Wiley, Niamh, Strain, Conall, O'Sullivan, Orla, Clarke, Gerard, Stanton, Catherine, Dinan, Timothy G., Cryan, John F.
• Format: Article
• Language: English
• Subjects: Acetic acid; Behaviour; Body weight gain; Chronic Stress; Corticosterone; Dietary supplements; Digestive system; Fatty acids; Fermentation; Gastrointestinal tract; Gene expression; Gut Microbiota; Immune response; Intestine; Metabolites; Microbiota; Neuroscience; Permeability; Propionic acid; Reinforcement; Research Paper; Social interactions
• ISSN: 0022-3751; 1469-7793
• DOI: 10.1113/JP276431

Key points Chronic (psychosocial) stress changes gut microbiota composition, as well as inducing behavioural and physiological deficits. The microbial metabolites short‐chain fatty acids (SCFAs) have been implicated in gastrointestinal functional, (neuro)immune regulation and host metabolism, but their role in stress‐induced behavioural and physiological alterations is poorly understood. Administration of SCFAs to mice undergoing psychosocial stress alleviates enduring alterations in anhedonia and heightened stress‐responsiveness, as well as stress‐induced increases in intestinal permeability. In contrast, chronic stress‐induced alterations in body weight gain, faecal SCFAs and the gene expression of the SCFA receptors FFAR2 and FFAR3 remained unaffected by SCFA supplementation. These results present novel insights into mechanisms underpinning the influence of the gut microbiota on brain homeostasis, behaviour and host metabolism, informing the development of microbiota‐targeted therapies for stress‐related disorders. 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, and 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 in body weight gain, faecal SCFAs and the colonic gene expression of the SCFA receptors free