Synthesis of multi-omic data and community metabolic models reveals insights into the role of hydrogen sulfide in colon cancer

Abstract

Multi-omic data and genome-scale microbial metabolic models have allowed us to examine microbial communities, community function, and interactions in ways that were not available to us historically. Now, one of our biggest challenges is determining how to integrate data and maximize data potential. Our study demonstrates one way in which to test a hypothesis by combining multi-omic data and community metabolic models. Specifically, we assess hydrogen sulfide production in colorectal cancer based on stool, mucosa, and tissue samples collected on and off the tumor site within the same individuals. 16S rRNA microbial community and abundance data were used to select and inform the metabolic models. We then used MICOM, an open source platform, to track the metabolic flux of hydrogen sulfide through a defined microbial community that either represented on-tumor or off-tumor sample communities. We also performed targeted and untargeted metabolomics, and used the former to quantitatively evaluate our model predictions. A deeper look at the models identified several unexpected but feasible reactions, microbes, and microbial interactions involved in hydrogen sulfide production for which our 16S and metabolomic data could not account. These results will guide future in vitro, in vivo, and in silico tests to establish why hydrogen sulfide production is increased in tumor tissue.

Growth rate alterations of human colorectal cancer cells by 157 gut bacteria

“…To rule out the possibility that these contrasting results were due to differences in methods, we compared our high-throughput MTT-based assay, used in this study, with the cell counting assay, that was employed in the referred studies, on 6 cell lines, using 6 different secretomes, and found a high correlation (Pearson's r=0.813, Supplementary Figure S5). These results confirm that the observed inhibitory effects by Fusobacteriaceae strains do not depend on the applied experimental techniques, but may partly be due to use of different Fusobacteriaceae strains(Fn12230, 26 ATCC25586, ATCC23726) isolated from extra-intestinal sites (80). Specifically HCT15 cell growth was significantly inhibited by 11/16 Fusobacteriaceae strains (nine cells and three secretomes).…”

“…In faeces of CRC patients, the genera Fusobacterium , Peptostreptococcus, Ruminococcus , and Escherichia/Shigella are enriched, while Bacteroides and Lachnospiraceae ( Roseburia, Lachnospira, Anaerostipes ) have a lower relative abundance (5,9,11,(21)(22)(23)(24)(25). Even though phyla such as Bacteroidetes are depleted, single species like enterotoxigenic Bacteroides fragilis may be enriched in some CRC patients (25)(26)(27). Comparing tumor tissue with adjacent normal tissue on the intestinal mucosa of CRC patients revealed that Fusobacterium, Prevotella, Streptococcus , and Peptostreptococcus were enriched in tumors while Blautia, Escherichia, Pseudomonas , and Faecalibacterium were enriched in the normal mucosa (5,7,9,11,(22)(23)(24)28).…”

Distinct microbes, metabolites, and ecologies define the microbiome in deficient and proficient mismatch repair colorectal cancers

“…Previous work has examined the role of other differentiating factors in the CRC microbiome including location [ 31 ], MSS/MSI status [ 12 ], and consensus molecular subtypes [ 32 ]. However few CRC microbiome studies account for MMR status [ 32 – 34 ] or microbial dynamics [ 35 ], and no studies, to our knowledge, have assessed both MMR status and microbial community dynamics. In addition, our study examines demographic, genetic, and tumor features together in a relatively large prospectively collected cohort.…”

Fecal Metabolomic Signatures in Colorectal Adenoma Patients Are Associated with Gut Microbiota and Early Events of Colorectal Cancer Pathogenesis

“…For example, a higher consumption of red and processed meats, which are high in sulfur-containing amino acids and inorganic sulfur, has been shown to increase abundances of sulfidogenic bacteria such as Bilophila wadsworthia and Pyramidobacter spp. ; these microbes are known to produce genotoxic hydrogen sulfide in the gut, thereby inducing DNA damage in intestinal epithelial cells and promoting carcinogenesis (10)(11)(12)(13). In another example, intake of dietary fibers results in enrichment of Bifidobacterium and Lactobacillus spp., which are capable of fermenting dietary fibers into short-chain fatty acids (SCFAs) (14).…”