Genetic and gut microbiome determinants of SCFA circulating and fecal levels, postprandial responses and links to chronic and acute inflammation

ABSTRACT

Short-chain fatty acids (SCFA) are involved in immune system and inflammatory responses. We comprehensively assessed the host genetic and gut microbial contribution to a panel of eight serum and stool SCFAs in two cohorts (TwinsUK, n = 2507; ZOE PREDICT-1, n = 328), examined their postprandial changes and explored their links with chronic and acute inflammatory responses in healthy individuals and trauma patients. We report low concordance between circulating and fecal SCFAs, significant postprandial changes in most circulating SCFAs, and a heritable genetic component (average h²: serum = 14%(SD = 14%); stool = 12%(SD = 6%)). Furthermore, we find that gut microbiome can accurately predict their fecal levels (AUC>0.71) while presenting weaker associations with serum. Finally, we report different correlation patterns with inflammatory markers depending on the type of inflammatory response (chronic or acute trauma). Our results illustrate the breadth of the physiological relevance of SCFAs on human inflammatory and metabolic responses highlighting the need for a deeper understanding of this important class of molecules.

KEYWORDS:

• Short-chain fatty acids
• postprandial
• heritability
• gut microbiota
• inflammatory response

Disclosure statement

TDS is co-founder and shareholder of ZOE Ltd (“Zoe”).SEB is a consultant to ZOE and has options in ZOE. AMV, WJB, PWF, FA, NS are consultants to Zoe. JW, GH, RD, FG are employees of Zoe. KW and GAM are employees of Metabolon Inc. Other authors have no conflict of interest to declare.

Supplementary material

Supplemental data for this article can be accessed online at https://doi.org/10.1080/19490976.2023.2240050

Additional information

Funding

This research was funded by the Chronic Disease Research Foundation and in part by the Wellcome Trust [Grant number: 212904/Z/18/Z] and by Diabetes UK [19/0006053]. For the purpose of open access, the authors have applied a CC BY public copyright licence to any Author Accepted Manuscript version arising from this submission. TwinsUK receives funding from the Wellcome Trust, the European Commission H2020 grants SYSCID (contract #733100); the National Institute for Health Research (NIHR) Clinical Research Facility and the Biomedical Research Centre based at Guy’s and St Thomas’ NHS Foundation Trust in partnership with King’s College London, the Chronic Disease Research foundation, the UKRI Medical Research Council (MRC)/British Heart Foundation Ancestry and Biological Informative Markers for Stratification of Hypertension (AIM-HY; MR/M016560/1), and Zoe Limited. This work was also supported by UKRI grant MR/W026813/1 to CM and AMV. MM is supported by the National Institute for Health Research (NIHR) Clinical Research Facility and the Biomedical Research Centre based at Guy’s and St Thomas’ NHS Foundation Trust in partnership with King’s College London. AN, PL and CM are funded by the Chronic Disease Research Foundation. CM is also supported by the UKRI Medical Research Council (MRC)/British Heart Foundation Ancestry and Biological Informative Markers for Stratification of Hypertension (AIM-HY; MR/M016560/1). AMV is supported by the National Institute for Health Research Nottingham Biomedical Research Centre. The collection of samples from trauma patients was supported by the NIHR Research Nottingham Biomedical Research Centre and by NIHR grants NIHR132240 (OPERA) and 16/61/10 (ORiF) to BJO. The ZOE PREDICT-1 cohort is supported by Zoe Limited. We thank all the participants of TwinsUK, ZOE PREDICT-1 and the acute trauma case-control cohorts for contributing and supporting our research.