Metagenomic and metabolomic profiling of laterally spreading tumors identifies a microbiome with putative pro-tumorigenic features in high-grade intraepithelial neoplasia.

INTRODUCTION

Laterally spreading tumors (LSTs) are pathologically classified into adenomas, including low-grade intraepithelial neoplasia (LGIN) and high-grade intraepithelial neoplasia (HGIN), and sessile serrated lesions (SSL). HGIN has a higher risk of progressing to colorectal cancer.

METHODS

This study compared the gut microbiome across these three pathological subtypes using fecal shotgun metagenomic sequencing and non-targeted metabolomics in 53 patients.

RESULTS

Overall community structure was similar among groups by Bray-Curtis NMDS and ANOSIM, although HGIN exhibited higher alpha diversity than SSL and enrichment of inflammation-associated and opportunistic taxa (e.g., Desulfovibrio, Bilophila, Helicobacter, Acinetobacter) alongside depletion of selected commensal taxa associated with mucosal homeostasis, including Bifidobacterium-, Lachnospiraceae-, and Ruminococcus-related species. Functionally, the HGIN-associated microbiome showed an expanded resistome and increased mobile genetic element-related potential, particularly in the HGIN versus LGIN comparison, with enrichment of beta-lactamase genes, MCR-family genes, and mobileOG features related to DNA transfer, recombination, transposition, plasmid maintenance, secretion, pilus-associated functions, and phage-linked mobility. In exploratory analyses, untargeted metabolomics suggested a bile- and lipid-rich metabolic pattern in HGIN, with nominal increases (P < 0.05; none significant after FDR correction) in lithocholyltaurine, LysoPE(P-16:0/0:0), tridecanoic acid and cortexolone. GSEA revealed nominal enrichment of unsaturated fatty acid biosynthesis, pyruvate metabolism, and propanoate metabolism. Exploratory species-metabolite correlations linked HGIN-enriched pathobionts with lipid/steroid-, bile-acid-, amino-acid-, and fatty-acid-related metabolites, while HGIN-depleted commensals were associated with amino-acid and organic-acid metabolic features.

DISCUSSION: Together, these findings identify microbial and metabolic features associated with high-grade histopathology within the LST spectrum, including FDR-supported microbial remodeling-pathobiont enrichment and expanded resistome and mobile genetic potential-accompanied by exploratory, nominally significant metabolomic alterations involving bile/lipid- and SCFA-related metabolites.