IDDF2024-ABS-0287 Structural variations in ulcerative colitis-associated E. coli reduce fructose utilization and aggravate inflammation under high fructose diet

Background

Structural variations (SVs) have significant effects on the microbial phenotypes.The underlying mechanism of functional changes caused by gut microbial SVs in the development of ulcerative colitis (UC) need further investigation.

Methods

To improve the resolution of gut metagenomic analysis and focus on SVs, the long-read and short-read metagenomic sequencing of stool samples from UC patients (n = 93) and healthy controls (HCs, n =100) was performed. The alteration of the gut microbiome, and the strain-level metabolic functional variations and differences by genomic SVs were analyzed. Then, we isolated target strains from fecal samples of UC and HCs, and finally validated the findings at the strains SV level in the clinical cohort by in vitro culture experiments and animal models.

Results

In addition to abundance changes in the gut microbial species, Escherichia coli (E. coli) with the highest fold change had SVs-affected functional differences on fructose metabolism to that of HCs (IDDF2024-ABS-0287 Figure 1 Increased abundances of gut Escherichia coli in UC patients compared with healthy donors). We isolated E. coli strains from fecal samples of UC patients (UC-strain) and healthy controls (HC-strain), and found that the deletion of the fructose utilization genes (sacA, scrK and cscB genes) was common in UC-strains that ostensibly decreases its ability of fructose utilization in vitro culture experiment. Under high fructose (10%), UC-strain led to higher residue fructose in the mouse intestine (IDDF2024-ABS-0287 Figure 2a, b Higher residual fructose and disturbed serum metabolites in UC-strain group under high-fructose diet.), caused higher levels of inflammation and impairment in the integrity of the gut barrier functions, worsening the colitis (IDDF2024-ABS-0287 Figure 3 Patient-derived E. coli increased the severity of colitis under high-fructose diet.). UC-strain induced significant gut microbiome changes under high fructose, mainly manifested as a decrease in short-chain fatty acid production and bile saline hydrolyzation-related bacteria and an increase in mucin-degrading bacteria (IDDF2024-ABS-0287 Figure 4 The altered composition of the gut microbiota is highly correlated with serum metabolites.), with the corresponding changes in the and serum metabolome as a significant decrease in secondary bile acid and glycerophospholipid related metabolites, and a significant increase in purine metabolism-related metabolites (IDDF2024-ABS-0287 Figure 2c-e Higher residual fructose and disturbed serum metabolites in UC-strain group under high-fructose diet.). However, under low fructose concentrations, UC-strain and HC-strain did not show significant difference in terms of colitis severity.

Conclusions

SV-caused difference in fructose utilization and proinflammatory properties in E. coli from UC patients influence the development of UC, emphasizing the importance of fine-scale metagenomic studies in disease.