Short Chain Fatty Acids are Reduced after Hematopoietic Stem Cell Transplant in Humans and are Associated with Modifications of the Gut Microbiome

Background: Acute GVHD is a associated with loss of diversity of the gut microbiome; moreover antibiotics increase risk of GVHD. We hypothesisized that loss of intestinal commensals that produce short chain fatty acids (SCFA) increase dysbiosis and mediate increased risk of GVHD. In contrast to this hypothesis, recent mouse data have shown no change in luminal SCFA in GVHD. Direct measurement of fecal SCFA in humans has not yet been reported. We hypothesized that SCFA would decline during the course of HSCT, and that this decline would be associated with important changes in the gut microbiota. We tested our hypothesis using weekly stool, blood and urine samples from 42 children receiving HSCT. Nuclear magnetic resonance (NMR)-based metabolomics was used to identify metabolites. 16S sequencing of stool identified changes in the gut microbiome. Results: Fecal butyrate levels were significantly decreased at days 7 and 14 compared to baseline fecal SCFA levels (Figure 1A; Baseline v. Day 14, P = .0039). Similarly, significant fecal propionate levels were reduced after HSCT (Figure 1B; Baseline v. Day 14, P = .0086). Univariate analyses found no correlations between reduced butyrate levels and age or intensity of conditioning. Low butyrate levels at Day 14 post-HSCT were associated with higher total exposure to anaerobic antibiotics (Figure 2A; P < .0025). Observed bacteria in stool were categorized into 2 groups, high and low butyrate producers, and found a significant difference between butyrate level at Day 14 and preservation of a butyrate high producing bacterial population (Figure 2B; P = .0028). Formate levels increased significantly post-HSCT (Figure 3A; Baseline v. Day 14, P = .0086). Higher fecal formate levels at Day 14 are significantly associated with higher levels of Enterobacteriaceae in the gut, likely increasing risk of bacterial translocation (Figure 3B; R2 = .1205, P = .0442). The levels of butyrate, propionate and acetate in the stool at Day 14 after HSCT were consistently reduced in those individuals that went on to develop GVHD (P = .07; .09 and .05 respectively).Figure 22A shows significant association between days of anaerobic antibiotic exposure and levels of stool butyrate. 2B shows relationship between stool butyrate and presence of butyrate producing microorganisms in the stool.View Large Image Figure ViewerDownload Hi-res image Download (PPT)Figure 33A shows increase in the SCFA formate during HSCT. Note data are shown on a logarithmic scale. 3B shows association of stool formate with "bloom" of enterobacteriaceae.View Large Image Figure ViewerDownload Hi-res image Download (PPT) Conclusions: These data demonstrate a mechanism for prior observations that loss of diversity and increased antibiotic use are associated with GVHD and offer potential modifiable targets to reduce risk of GVHD and improve survival after HSCT.

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