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

Jinming Li; Yangyang Guo; Jianqiang Liu; Fanying Guo; Lutao Du; Yongzhi Yang; Xinxiang Li; Yanlei Ma

doi:10.1136/jitc-2023-007420

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

J Immunother Cancer. 2023 Aug;11(8):e007420. doi: 10.1136/jitc-2023-007420.

Authors

Jinming Li^#^{1

2}, Yangyang Guo^#^{1

2}, Jianqiang Liu^#^{2

3}, Fanying Guo^{1

2}, Lutao Du⁴, Yongzhi Yang^{1

2}, Xinxiang Li^{1

2}, Yanlei Ma^{5

2}

Affiliations

¹ Department of Colorectal Surgery, Fudan University Shanghai Cancer Center, Shanghai, China.
² Department of Oncology, Shanghai Medical College, Fudan University, Shanghai, China.
³ Department of Endoscopy, Fudan University Shanghai Cancer Center, Shanghai, China.
⁴ Department of Clinical Laboratory, The Second Hospital of Shandong University, Jinan, Shandong province, China.
⁵ Department of Colorectal Surgery, Fudan University Shanghai Cancer Center, Shanghai, China yanleima@fudan.edu.cn.

^# Contributed equally.

Abstract

Background: Accumulating 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.

Method: We 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.

Results: Pronounced microbiota and metabolic heterogeneity were identified with 211 dMMR-enriched species, such as Fusobacterium nucleatum and Akkermansia muciniphila, 2 dMMR-depleted species, such as Flavonifractor 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. plautii was 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.

Conclusions: Our 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.

Keywords: gastrointestinal neoplasms.

Publication types

Research Support, Non-U.S. Gov't

MeSH terms

CD8-Positive T-Lymphocytes
Colorectal Neoplasms* / genetics
DNA Mismatch Repair / genetics
Gastrointestinal Microbiome* / genetics
Humans
Lactic Acid
Succinic Acid

Substances

Succinic Acid
Lactic Acid