Higher Fecal Short-Chain Fatty Acid Levels Are Associated with Gut Microbiome Dysbiosis, Obesity, Hypertension and Cardiometabolic Disease Risk Factors

Jacobo de la Cuesta-Zuluaga, Noel T Mueller, Rafael Álvarez-Quintero, Eliana P Velásquez-Mejía, Jelver A Sierra, Vanessa Corrales-Agudelo, Jenny A Carmona, José M Abad, Juan S Escobar, Jacobo de la Cuesta-Zuluaga, Noel T Mueller, Rafael Álvarez-Quintero, Eliana P Velásquez-Mejía, Jelver A Sierra, Vanessa Corrales-Agudelo, Jenny A Carmona, José M Abad, Juan S Escobar

Abstract

Fiber fermentation by gut microbiota yields short-chain fatty acids (SCFAs) that are either absorbed by the gut or excreted in feces. Studies are conflicting as to whether SCFAs are beneficial or detrimental to cardiometabolic health, and how gut microbiota associated with SCFAs is unclear. In this study of 441 community-dwelling adults, we examined associations of fecal SCFAs, gut microbiota diversity and composition, gut permeability, and cardiometabolic outcomes, including obesity and hypertension. We assessed fecal microbiota by 16S rRNA gene sequencing, and SCFA concentrations by gas chromatography/mass spectrometry. Fecal SCFA concentrations were inversely associated with microbiota diversity, and 70 unique microbial taxa were differentially associated with at least one SCFA (acetate, butyrate or propionate). Higher SCFA concentrations were associated with a measure of gut permeability, markers of metabolic dysregulation, obesity and hypertension. Microbial diversity showed association with these outcomes in the opposite direction. Associations were significant after adjusting for measured confounders. In conclusion, higher SCFA excretion was associated with evidence of gut dysbiosis, gut permeability, excess adiposity, and cardiometabolic risk factors. Studies assessing both fecal and circulating SCFAs are needed to test the hypothesis that the association of higher fecal SCFAs with obesity and cardiometabolic dysregulation is due to less efficient SCFA absorption.

Keywords: SCFA; adiposity; butyrate; gut microbiota; gut permeability; hypertension; metabolic dysregulation.

Conflict of interest statement

While engaged in this project, J.d.l.C.-Z., E.P.V.-M., J.A.S., V.C.-A., and J.S.E. were employed by a food company; J.A.C. and J.M.A. were employed by health provider companies; N.T.M. and R.A.-Q. declare no conflicts of interest. The funders had no role in the design of the study; in the collection, analyses, or interpretation of data; in the writing of the manuscript, or in the decision to publish the results.

Figures

Figure 1
Figure 1
Distribution of gut microbiota diversity according to tertiles (T1: Low, T2: Intermediate, T3: High) of multivariable-adjusted fecal SCFA concentrations: (a) Total SCFAs; (b) acetate; (c) propionate; and (d) butyrate. SCFA concentrations were adjusted for age, city of origin, caloric intake, physical activity, and fiber intake. The raw data, average, and 95% confidence intervals are shown for each tertile.
Figure 2
Figure 2
Distribution of various cardiometabolic health indicators according to tertiles (T1: Low, T2: Intermediate, T3: High) of multivariable-adjusted fecal butyrate concentrations (left) and microbiota diversity (right). (a) BMI; (b) waist circumference; (c) triglycerides; (d) fasting insulin; (e) blood pressure; and (f) hs-CRP. Values were adjusted for age, city of origin, caloric intake, physical activity, and fiber intake. The raw data, mean, and 95% confidence intervals are shown for each tertile.
Figure 3
Figure 3
Heatmap showing the correlations between rarefied OTU abundances and multivariable-adjusted fecal SCFA concentrations. OTUs with moderate or strong association with at least one of the measured SCFAs are shown (|rho| > 0.2). The dendrogram to the left was obtained by hierarchical Ward-linkage clustering based on correlation coefficients of the relative abundances of the OTUs that had median abundances ≥0.001%. Models were adjusted for age, city of origin, caloric intake, physical activity, and fiber intake. The color scale indicates the Spearman’s correlation coefficients. FDR-adjusted p-values from quasi-Poisson generalized linear models are indicated (* =q < 0.10).

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