Depicting the landscape of gut microbial-metabolic interaction and microbial-host immune heterogeneity in deficient and proficient DNA mismatch repair colorectal cancers

Abstract

BackgroundAccumulating evidence has indicated the role of gut microbiota in remodeling host immune signatures, but various interplays underlying colorectal cancers (CRC) with deficient DNA mismatch repair (dMMR) and proficient DNA mismatch repair (pMMR) remain poorly understood. This study aims to decipher the gut microbiome-host immune interactions between dMMR and pMMR CRC.MethodWe performed metagenomic sequencing and metabolomic analysis of fecal samples from a cohort encompassing 455 participants, including 21 dMMR CRC, 207 pMMR CRC, and 227 healthy controls. Among them, 50 tumor samples collected from 5 dMMR CRC and 45 pMMR CRC were conducted bulk RNA sequencing.ResultsPronounced microbiota and metabolic heterogeneity were identified with 211 dMMR-enriched species, such asFusobacterium nucleatumandAkkermansia muciniphila, 2 dMMR-depleted species, such asFlavonifractor plautii, 13 dMMR-enriched metabolites, such as retinoic acid, and 77 dMMR-depleted metabolites, such as lactic acid, succinic acid, and 2,3-dihydroxyvaleric acid.F. plautiiwas enriched in pMMR CRC and it was positively associated with fatty acid degradation, which might account for the accumulation of dMMR-depleted metabolites classified as short chain organic acid (lactic acid, succinic acid, and 2,3-dihydroxyvaleric acid) in pMMR CRC. The microbial-metabolic association analysis revealed the characterization of pMMR CRC as the accumulation of lactate induced by the depletion of specific gut microbiota which was negatively associated with antitumor immune, whereas the nucleotide metabolism and peptide degradation mediated by dMMR-enriched species characterized dMMR CRC. MMR-specific metabolic landscapes were related to distinctive immune features, such as CD8+T cells, dendritic cells and M2-like macrophages.ConclusionsOur mutiomics results delineate a heterogeneous landscape of microbiome-host immune interactions within dMMR and pMMR CRC from aspects of bacterial communities, metabolic features, and correlation with immunocyte compartment, which infers the underlying mechanism of heterogeneous immune responses.

The Role of SPEN Mutations as Predictive Biomarkers for Immunotherapy Response in Colorectal Cancer: Insights from a Retrospective Cohort Analysis

“…The potential for SPEN mutations to fulfill a similar function, particularly given their correlation with an elevated TMB, necessitates further investigation. A study conducted by Le et al demonstrated that patients afflicted with dMMR CRC displayed significantly extended progression-free survival and overall survival when administered pembrolizumab, as an ICI, compared to traditional chemotherapy [26]. Our findings suggest that, in a similar manner, SPEN mutations might classify patients who are likely to benefit from ICIs.…”

Mismatch repair-proficient tumor footprints in the sands of immune desert: mechanistic constraints and precision platforms

“…It revealed an MSI-MSS distinction of their communities. It also showed poor survival after ICB in the F. nucleatum high group in the case of NSCLC ( 109 , 122 ). However, there is a paucity of knowledge on the premises of MMRp ( 102 , 118 ).…”

Nanomaterials modulate tumor-associated macrophages for the treatment of digestive system tumors

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