Abstract Body (Do not enter title and authors here): Background: Recent animal studies connect high sodium intake to the gut-immune axis and highlight the gut microbiome as a potential therapeutic target to counteract salt-sensitive conditions and hypertension. However, the relationship between sodium intake on the gut-immune axis in humans is largely unknown. We previously showed that dietary sodium reduction increased circulating levels of gut-produced short-chain fatty acids (SCFAs), in persons with untreated hypertension. Therefore, we examined whether dietary sodium intake is associated with gut microbial taxonomic features.

Methods: The COcoa Supplement and Multivitamin Outcomes Study (COSMOS) is a recently completed randomized, double-blind, placebo-controlled, 2x2 factorial trial of a multivitamin and cocoa extract supplement (containing 500 mg/d flavanols, including 80 mg/day (-)-epicatechin) in 21,442 older adults. Dietary intake was assessed by a validated Food Frequency Questionnaires at baseline and year 2. We previously conducted a deep shotgun metagenomic sequencing in a pilot study of 30 COSMOS participants using fecal samples collected at baseline and year 2 to explore whether the interventions affected gut microbial composition and function. We leveraged available taxonomic profiling data and analyzed the association between energy-adjusted sodium intake and microbial features at baseline.

Results: We did not observe significant associations between sodium intake and alpha diversity parameters including Shannon Diversity Index and Inverse Simpson Index (P>0.05). The PERMANOVA analysis showed that sodium intake was significantly associated with the overall taxonomic beta diversity (Bray-Curtis dissimilarity) (R² = 0.067, p=0.031), suggesting 6.7% of the variation in beta diversity was explained by sodium intake. The Spearman’s rank-order correlation test showed several nominally significant associations (P<0.05) between sodium intake and taxonomic features (4 Family, 6 Genus, 15 Species, 16 Strains, 18 Pathways). At genus level, Bacteroides was associated with sodium intake (r=0.566, p=0.0037). A superpathway of geranylgeranyldiphosphatevbiosynthesis I (r=-0.527, p=0.0076) was associated with sodium intake, which play key roles in signaling pathways, cytoskeletal regulation, intracellular transport, and cell proliferation.

Summary: This pilot study suggests that dietary sodium intake may be related to beta diversity and some microbial taxa or pathways. Large studies are warranted.