Effects of short-chain fatty acids on intestinal function in an enteroid model of hypoxia

Authors: Pearce, Sarah; KARL, J. PHILIP - Us Army Combat Capabilities Development Command (CCDC) Army; WEBER, GREGORY - Us Army Combat Capabilities Development Command (CCDC) Army

Submitted to: Frontiers in Physiology
Publication Type: Peer Reviewed Journal
Publication Acceptance Date: 11/21/2022
Publication Date: 12/5/2022
Citation: Pearce, S.C., Karl, J.P., Weber, G.J. 2022. Effects of short-chain fatty acids on intestinal function in an enteroid model of hypoxia. Frontiers in Physiology. 13. https://doi.org/10.3389/fphys.2022.1056233.
DOI: https://doi.org/10.3389/fphys.2022.1056233

Interpretive Summary: The gastrointestinal tract is a naturally low oxygen environment and this helps bacteria to survive. However, certain stressors can further decrease oxygen in the intestine and this can lead to intestinal damage, among other things. Short-chain fatty acids (SCFA) which are fiber digestion by-products, in many studies have been shown to increase intestinal health and function. Thus, this study aimed to see whether providing SCFA during, or prior to, low oxygen exposure could help rescue intestinal damage caused by low oxygen itself. Although pre-treating with SCFA increased intestinal function, it was still not sufficient to prevent damage after 72 hours and in some cases it appears that SCFA's may actually make the problem worse. It is known that butyrate is an energy source for intestinal cells and metabolism of this SCFA consumes oxygen, perhaps in a negative manner under stress. Further studies need to be done to examine this more closely but SCA may not be a good nutritional intervention strategy under low oxygen/hypoxic stress.

Technical Abstract: The healthy gastrointestinal (GI) tract is physiologically hypoxic, but this may be perturbed by certain acute and chronic stressors that reduce oxygen availability systemically. Short-chain fatty acids (SCFA) have been shown to have beneficial effects on intestinal barrier function and inflammation. Therefore, our objective was to see whether SCFA would improve GI barrier function, reduce production of pro-inflammatory cytokines and increase the expression of genes regulating GI barrier function in enteroids exposed to hypoxia. Human duodenal enteroid monolayers were placed under hypoxia (1.0% oxygen) for 72 hours with either 24 or 48 hour pre-treatment with a high acetate ratio of SCFA’s or high butyrate ratio or placed under hypoxia concurrently. The data showed that transepithelial electrical resistance (TER) increased with SCFA pre-treatment, especially 48 hour of pre-treatment and this was maintained through the first 48 hour of hypoxia, while cells saw barrier function dramatically decrease by 72 hour of hypoxia exposure. Inflammatory protein secretion largely decreased with exposure to hypoxia, regardless of SCFA pre-treatment. Gene expression of several genes related to barrier function were decreased with exposure to hypoxia, and with concurrent and 24 hour SCFA pre-treatment. However, 48 hour SCFA pre-treatment with a high butyrate ratio increased expression of several metabolic and differentiation related genes. Overall, pre-treatment or concurrent treatment with SCFA mixtures were not able to overcome the negative impacts of hypoxia on intestinal function and cells ultimately still cannot be sustained under hypoxia for 72 hour. However, 48 hour pre-treatment maintains TER for up to 48 hour of hypoxia while upregulating several metabolic genes.