Resistant Starch Alters Gut Microbiome and Metabolomics Profiles Concurrent with Amelioration of Chronic Kidney Disease in Rats

1 Patients and animals with chronic kidney disease (CKD) exhibit profound alterations in 2 the gut environment including shifts in microbial composition, increased fecal pH, and increased 3 blood levels of gut microbe-derived metabolites (xeno-metabolites). The fermentable dietary 4 fiber—high amylose maize resistant starch type 2 (HAMRS2)—has been shown to alter the gut 5 milieu, and in CKD rat models leads to markedly improved kidney function. The aim of the 6 current study was to identify specific cecal bacteria and cecal, blood, and urinary metabolites 7 that associate with changes in kidney function, in order to identify potential mechanisms 8 involved with CKD amelioration in response to dietary resistant starch. Male Sprague-Dawley 9 rats with adenine induced CKD were fed a semi-purified low fiber or a high fiber diet (59% w/w 10 of HAMRS2) for 3 weeks (n=9/grp). The cecal microbiome was characterized, and cecal 11 contents, serum, and urine metabolites were analyzed. HAMRS2-fed rats displayed decreased 12 cecal pH, decreased microbial diversity, and an increased Bacteroidetes to Firmicutes ratio. 13 Several URS solutes were altered in the cecal contents, serum, and urine, many of which had 14 strong correlations with specific gut bacteria abundances: i.e., serum and urine indoxyl sulfate 15 were reduced by 36% and 66%, respectively in HAMRS2-fed rats, and urine p-cresol was 16 reduced by 47% in HAMRS2-fed rats. Outcomes from this study were coincident with 17 improvements in kidney function indices and amelioration of CKD outcomes previously reported 18 for these rats, suggesting an important role for microbial-derived factors and gut microbe 19 metabolism in regulating host kidney function. 20