Short-chain fatty acids are key mediators of the favorable effects of the Mediterranean diet on intestinal barrier integrity: data from the randomized controlled LIBRE trial

• Published in: The American journal of clinical nutrition Vol. 116; no. 4; pp. 928 - 942
• Main Authors: Seethaler, Benjamin, Nguyen, Nguyen K, Basrai, Maryam, Kiechle, Marion, Walter, Jens, Delzenne, Nathalie M, Bischoff, Stephan C
• Format: Journal Article
• Language: English
• Published: United States Elsevier Inc 01.10.2022; Oxford University Press; American Society for Clinical Nutrition, Inc
• Subjects: Algorithms; breast cancer; Butyrates; Cardiovascular diseases; Customization; Diabetes mellitus; Diet; Diet, Mediterranean; dietary fibers; Fatty acids; Fatty Acids, Volatile - analysis; Feces; Feces - chemistry; Female; gut barrier; Humans; Impairment; Integrity; Intestine; Learning algorithms; Lipopolysaccharides; Machine learning; mediation analyses; Mediterranean diet; Multivariate analysis; Nutrition; Permeability; personalized nutrition; Population studies; precision nutrition; Propionates; Propionic acid; short-chain fatty acids; MEDAS; MedD-Score; Mediterranean diet; precision nutrition; breast cancer; LIBRE; machine learning; dietary fibers; PERMANOVA; SCFA; BRCA; MLR; LBP; gut barrier; short-chain fatty acids; mediation analyses; personalized nutrition
• ISSN: 0002-9165; 1938-3207
• DOI: 10.1093/ajcn/nqac175

The Mediterranean diet is associated with the prevention of diabetes, cardiovascular disease, and cancer, all of which are linked to intestinal barrier impairment. Here, we hypothesize that the Mediterranean diet, possibly via the induction of short-chain fatty acids (SCFAs), improves intestinal barrier integrity. Furthermore, we aim to establish novel personalized nutrition advice based on machine learning algorithms. We studied 260 women with intestinal barrier impairment. The women were allocated to follow either a Mediterranean diet or a control diet for 3 mo. Intestinal permeability was assessed by measuring lipopolysaccharide binding protein (LBP) in plasma and zonulin in feces. SCFA concentrations were analyzed in feces. Bi- and multivariate analyses and machine learning algorithms (random forest classification) were conducted. Particularly in the intervention group, adherence to the Mediterranean diet increased, whereas plasma LBP and fecal zonulin concentrations decreased (all q < 0.001 for the intervention group, all q < 0.1 for control group). In the intervention group, fecal SCFA concentrations increased (propionate + 19%; butyrate + 44%; both q < 0.001). Multivariate analyses showed that adherence to the Mediterranean diet was associated with SCFA concentrations (all q < 0.001) and inversely associated with LBP and zonulin concentrations (all q < 0.02). Mediation analyses identified propionate and butyrate as the key mechanistic link between diet and intestinal permeability integrity. Accordingly, using baseline SCFA data, we could predict the effect of the Mediterranean diet on intestinal permeability using a machine learning algorithm (receiver operating characteristic AUC: 0.78–0.96). Our data suggest that SCFAs are key mediators for the relation between diet and gut health. Assessment of SCFAs may form a basis for personalized nutrition in future clinical care. These results need to be verified in larger studies powered for this purpose, comprising different study populations. The trial was registered at clinicaltrials.gov as NCT02087592 and NCT02516540.