The role of short-chain fatty acids in microbiota–gut–brain communication


Short-chain fatty acids (SCFAs), the main metabolites produced by bacterial fermentation of dietary fibre in the gastrointestinal tract, are speculated to have a key role in microbiota–gut–brain crosstalk. However, the pathways through which SCFAs might influence psychological functioning, including affective and cognitive processes and their neural basis, have not been fully elucidated. Furthermore, research directly exploring the role of SCFAs as potential mediators of the effects of microbiota-targeted interventions on affective and cognitive functioning is sparse, especially in humans. This Review summarizes existing knowledge on the potential of SCFAs to directly or indirectly mediate microbiota–gut–brain interactions. The effects of SCFAs on cellular systems and their interaction with gut–brain signalling pathways including immune, endocrine, neural and humoral routes are described. The effects of microbiota-targeted interventions such as prebiotics, probiotics and diet on psychological functioning and the putative mediating role of SCFA signalling will also be discussed, as well as the relationship between SCFAs and psychobiological processes. Finally, future directions to facilitate direct investigation of the effect of SCFAs on psychological functioning are outlined.

Key points

  • Short-chain fatty acids (SCFAs) are speculated to have a mediational role in the microbiota–gut–brain axis crosstalk.

  • SCFAs might influence psychological functioning via interactions with G protein-coupled receptors or histone deacetylases and exert their effects on the brain via direct humoral effects, indirect hormonal and immune pathways and neural routes.

  • Dietary intervention studies indirectly implicate a mediational role for SCFAs in cognition and emotion.

  • Animal studies provide direct evidence of the effects of SCFAs on neuropsychiatric disorders and psychological functioning, whereas human studies are sparse, suffer from methodological limitations and offer inconsistent conclusions.

  • SCFAs should be quantified in the systemic circulation in dietary intervention studies, in which the effects on psychological functioning and psychopathology are an outcome of interest.

  • SCFAs could ultimately be used as interventional substances to target microbiota–gut–brain interactions in humans.

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Fig. 1: Metabolism of SCFAs from dietary fibre to systemic circulation.
Fig. 2: SCFA cellular signalling pathways.
Fig. 3: Potential gut–brain pathways through which SCFAs might modulate brain function.


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The financial support for B.D. from an unrestricted grant from Nestlé is highly appreciated.

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B.D. performed the literature review and wrote the manuscript. L.V.O., B.V. and K.V. revised the intellectual content of the manuscript critically.

Correspondence to Kristin Verbeke.

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Dalile, B., Van Oudenhove, L., Vervliet, B. et al. The role of short-chain fatty acids in microbiota–gut–brain communication. Nat Rev Gastroenterol Hepatol 16, 461–478 (2019).

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