Sex Differences in Gut Microbiota Fatty Acid Metabolism in Human Salt Sensitivity of Blood Pressure
Authors: Ishimwe Jeanne , Ferguson Jane , Kirabo Annet 
Published: May 2023

Salt sensitivity is a trait in which high dietary sodium (Na+) intake causes an increase in blood pressure. We previously demonstrated that in the gut, elevated dietary Na+ causes dysbiosis. The mechanistic interplay between excess dietary Na+-induced alteration in the gut microbiome and sex differences is less understood. The goal of this study was to identify novel metabolites in salt sensitivity and sex differences in response to a high dietary Na+ intake. We hypothesized that excess dietary salt-induced dysbiosis is associated with distinct metabolomic changes in men and women. We performed plasma metabolomics analysis and measured blood pressure of human volunteers who completed a validated 3-day food record to estimate dietary Na+ intake. Based on the recommendations by the American Heart Association, we classified daily Na+ intake of <2.3g as normal salt and high salt for subjects consuming ≥ 2.3g Na+. Spearman correlation was used to assess the relationship between Na+ intake and blood pressure. We also performed RNA sequencing on human (N=11) monocytes treated with high salt in vitro. The relationship between dietary Na+ intake and mean arterial pressure was different in women (r=0.3422, p=0.0022, N=81) and men (r=0.4552, p=0.0010, N=49). Network analysis of human plasma untargeted metabolome revealed fatty acids as top subnetworks differentially changed with salt intake. In subjects consuming a high Na+ diet, levels of linoleate (1.211 ± 0.330 vs. 0.869 ± 0.170; p<0.001); palmitate (1.155 ± 0.292 vs. 0.924 ± 0.233; p= 0.003); arachidonic acid (1.119 ± 0.242 vs. 0.965 ± 0.201; p=0.015); and 12-hydroxyeicosatetraenoic acid (1.329 ± 0.925 vs. 0.902 ± 0.520; p=0.0469) were higher in women (28) than men (25). In contrast, we observed no sex differences in these parameters between men and women consuming a normal salt diet. RNA sequencing analysis revealed that exposure of human monocytes to high salt in vitro upregulated transcription of fatty acid receptors and arachidonic acid-related genes. Specifically, ALOX12 (277.8 ± 13.8 vs. 169.5 ± 16.7, p<0.0001) which encodes for arachidonate 12-lipoxygenase, ALOX5AP (6459 ± 1553 vs. 2598 ± 30, p=0.0310) which encodes for 5-lipoxygenase activating protein, and FFR2 (418.1 ± 97.8 vs. 115.9 ± 29.4, p=0.0078) which encodes for free fatty acids receptor 2 were increased in human monocytes, and this was associated with a pro-inflammatory phenotype. These findings suggest that excess dietary Na+ is associated with fatty acid metabolism dysregulation, and that the arachidonic acid pathway may potentially play a role in sex differences of salt-sensitive hypertension. This work was supported by American Heart Association grants POST9034281 (to JAI) and 15SDG24890015 (to JFF) and NIH grants K01HL130497 (to AK) as well as Venture Pilot Funding (to AK) from Vanderbilt Microbiome Initiative and Vanderbilt Institute for Infection, Immunology, and Inflammation (VI4) and a P&F award (to JFF) from Vanderbilt University Medical Center's Digestive Disease Research Center supported by NIH grant P30DK058404. This is the full abstract presented at the American Physiology Summit 2023 meeting and is only available in HTML format. There are no additional versions or additional content available for this abstract. Physiology was not involved in the peer review process.