Diet, microbiome, and inflammation predictors of fecal and plasma short-chain fatty acids in humans

Authors: OLIVER, ANDREW - Orise Fellow; Alkan, Zeynep; Stephensen, Charles; Newman, John; Kable, Mary; Lemay, Danielle

Submitted to: Journal of Nutrition
Publication Type: Peer Reviewed Journal
Publication Acceptance Date: 8/13/2024
Publication Date: 8/20/2024
Citation: Oliver, A.S., Alkan, Z., Stephensen, C.B., Newman, J.W., Kable, M.E., Lemay, D.G. 2024. Diet, microbiome, and inflammation predictors of fecal and plasma short-chain fatty acids in humans. Journal of Nutrition. 154(11):3298-3311. https://doi.org/10.1016/j.tjnut.2024.08.012.
DOI: https://doi.org/10.1016/j.tjnut.2024.08.012

Interpretive Summary: Dietary fiber is crucial for nourishing the gut microbiota, which plays an important role in human health. When fiber is fermented by these gut bacteria, it produces short-chain fatty acids (SCFAs), linked to various health benefits like better gut health, lower cancer and type 2 diabetes risks, and has anti-inflammatory effects. Despite interest, predicting SCFA levels accurately remains challenging. We studied 330 healthy people, measuring SCFAs in their feces and plasma. We looked at how diet, gut bacteria, and inflammation affect SCFAs. We found higher fecal butyrate levels linked to healthy eating and consumption of resistant starch found in potatoes. The production of SCFAs is a process, and our results suggest, for example, it is not only important to have butyrate-producing microbes, but also microbes which produce a form of vitamin B1 necessary for the butyrate enzymes to work. The more SCFAs these microbes produced, the less “leaky” the gut appeared to be, keeping inflammation-causing metabolites in our guts from crossing into the bloodstream. Ultimately, understanding how diet and the microbiome impact SCFAs can help scientists design diets and probiotics for better human health.

Technical Abstract: Gut microbes produce short-chain fatty acids (SCFAs), which are associated with broad health benefits, including improved gut barrier integrity, decreased risk of cancer and type 2 diabetes, and reduced inflammation. Despite widespread interest in SCFAs, it is not fully known how diet and/or the gut microbiome could be modulated to improve SCFA production. Therefore, the objective of the current study is to determine the dietary and microbial predictors of fecal and plasma SCFAs in healthy U.S. adults. We measured the fecal and plasma SCFAs from 330 healthy men and women, age 18-65 y, BMI 17-43 kg/m2, who participated in the cross-sectional, observational USDA Nutritional Phenotyping Study. Dietary intake was assessed in the 7-10 days prior to fecal/plasma collection via three ASA24 recalls (recent diet) and an FFQ (habitual diet). Using partial correlation and random forests, we investigated the ability of diet, microbiome (WGS), and inflammation biomarkers to predict the abundance of SCFAs. We first tested the hypothesis that diet quality, fiber abundance, or fiber diversity impact SCFA abundance. We found that a higher Healthy Eating Index for habitual diet was associated with more fecal butyrate than expected (r = 0.18, q = 0.013). We detected no difference in SCFA abundance between individuals with or without frank gut or systemic inflammation (fecal calprotectin >= 100'g/g, plasma C-reactive protein >= 10 mg/L). TaxaHFE-selected dietary and microbiome features weakly predicted fecal, but not plasma SCFAs. Fecal SCFAs were negatively associated with plasma lipopolysaccharide binding protein and fecal myeloperoxidase negatively associated with plasma propionate. The top diet and microbiome predictors of fecal butyrate included potatoes and the thiamine biosynthesis pathway, respectively. These findings illustrate the complex biology underpinning SCFA production in the gut. For example, thiamine is a critical cofactor and resistant starch is a substrate for microbial butyrate production. Both thiamine biosynthesis gene abundance and potato consumption positively correlated with fecal butyrate, suggesting potatoes may promote butyrate-producing microbes. Our findings also demonstrate the ability of hierarchical feature engineering and machine learning to identify diet and microbiome predictors.