Depicting the landscape of gut microbial-metabolic interaction and microbial-host immune heterogeneity in deficient and proficient DNA mismatch repair colorectal cancers
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...
| Main Authors: | , , , , , , , |
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| Format: | Article |
| Language: | English |
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BMJ Publishing Group
2023-08-01
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| Series: | Journal for ImmunoTherapy of Cancer |
| Online Access: | https://jitc.bmj.com/content/11/8/e007420.full |
| _version_ | 1827861403039432704 |
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| author | Jinming Li Yanlei Ma Yongzhi Yang Lutao Du Jianqiang Liu Xinxiang Li Yangyang Guo Fanying Guo |
| author_facet | Jinming Li Yanlei Ma Yongzhi Yang Lutao Du Jianqiang Liu Xinxiang Li Yangyang Guo Fanying Guo |
| author_sort | Jinming Li |
| collection | DOAJ |
| description | 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. |
| first_indexed | 2024-03-12T13:37:22Z |
| format | Article |
| id | doaj.art-72114f470a464cdebc97e952cba8639f |
| institution | Directory Open Access Journal |
| issn | 2051-1426 |
| language | English |
| last_indexed | 2024-03-12T13:37:22Z |
| publishDate | 2023-08-01 |
| publisher | BMJ Publishing Group |
| record_format | Article |
| series | Journal for ImmunoTherapy of Cancer |
| spelling | doaj.art-72114f470a464cdebc97e952cba8639f2023-08-24T02:50:07ZengBMJ Publishing GroupJournal for ImmunoTherapy of Cancer2051-14262023-08-0111810.1136/jitc-2023-007420Depicting the landscape of gut microbial-metabolic interaction and microbial-host immune heterogeneity in deficient and proficient DNA mismatch repair colorectal cancersJinming Li0Yanlei Ma1Yongzhi Yang2Lutao Du3Jianqiang Liu4Xinxiang Li5Yangyang Guo6Fanying Guo7Department of Colorectal Surgery, Fudan University Shanghai Cancer Center, Shanghai, ChinaDepartment of Colorectal Surgery, Fudan University Shanghai Cancer Center, Shanghai, ChinaDepartment of Colorectal Surgery, Fudan University Shanghai Cancer Center, Shanghai, ChinaDepartment of Clinical Laboratory, The Second Hospital of Shandong University, Jinan, Shandong province, ChinaDepartment of Oncology, Shanghai Medical College, Fudan University, Shanghai, ChinaDepartment of Colorectal Surgery, Fudan University Shanghai Cancer Center, Shanghai, ChinaDepartment of Colorectal Surgery, Fudan University Shanghai Cancer Center, Shanghai, ChinaDepartment of Colorectal Surgery, Fudan University Shanghai Cancer Center, Shanghai, ChinaBackground 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.https://jitc.bmj.com/content/11/8/e007420.full |
| spellingShingle | Jinming Li Yanlei Ma Yongzhi Yang Lutao Du Jianqiang Liu Xinxiang Li Yangyang Guo Fanying Guo Depicting the landscape of gut microbial-metabolic interaction and microbial-host immune heterogeneity in deficient and proficient DNA mismatch repair colorectal cancers Journal for ImmunoTherapy of Cancer |
| title | Depicting the landscape of gut microbial-metabolic interaction and microbial-host immune heterogeneity in deficient and proficient DNA mismatch repair colorectal cancers |
| title_full | Depicting the landscape of gut microbial-metabolic interaction and microbial-host immune heterogeneity in deficient and proficient DNA mismatch repair colorectal cancers |
| title_fullStr | Depicting the landscape of gut microbial-metabolic interaction and microbial-host immune heterogeneity in deficient and proficient DNA mismatch repair colorectal cancers |
| title_full_unstemmed | Depicting the landscape of gut microbial-metabolic interaction and microbial-host immune heterogeneity in deficient and proficient DNA mismatch repair colorectal cancers |
| title_short | Depicting the landscape of gut microbial-metabolic interaction and microbial-host immune heterogeneity in deficient and proficient DNA mismatch repair colorectal cancers |
| title_sort | depicting the landscape of gut microbial metabolic interaction and microbial host immune heterogeneity in deficient and proficient dna mismatch repair colorectal cancers |
| url | https://jitc.bmj.com/content/11/8/e007420.full |
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