越来越多的证据表明肠道微生物群在重塑宿主免疫特征中的作用，但残缺的DNA错配修复(DNA mismatch repair, dMMR)和完整的DNA错配修复(pMMR)与结直肠癌(CRC)之间的各种相互作用仍不清楚。本研究旨在解析dMMR和pMMR CRC之间的肠道菌群-宿主免疫相互作用。我们对包括21例dMMR CRC、207例pMMR CRC和227例健康对照的455名参与者的粪便样品进行了宏转录组测序和代谢组分析。其中，我们对来自5例dMMR CRC和45例pMMR CRC的50个肿瘤样本进行了RNA测序。我们鉴定出明显的菌群和代谢异质性，其中包括211个dMMR富集物种，如核上菌属(nucleatum)和黏膜Ak属(muciniphila)、2个dMMR缺失物种，如flavonifractor plautii属，13个dMMR富集代谢物，如视黄酸(retinoic acid)，以及77个dMMR缺失代谢物，如乳酸(lactic acid)、琥珀酸(succinic acid)和2,3-二羟基戊酸(2,3-dihydroxyvaleric acid)。FLAVONifractor plautii富集在pMMR CRC中，并与脂肪酸降解正相关，这可能解释了pMMR CRC中短链有机酸(乳酸、琥珀酸和2,3-二羟基戊酸)的堆积。微生物代谢关联分析揭示了pMMR CRC的特征，即乳酸的积聚与特定肠道微生物的耗竭负相关，而核苷酸代谢和肽降解则由dMMR富集物种介导，这是dMMR CRC的特征。MMR特异性代谢景观与特定的免疫特征(如CD8+T细胞、树突状细胞和M2型巨噬细胞)相关联。我们的多组学结果从细菌群落、代谢特征和与免疫细胞组分的相关性等方面描绘了dMMR和pMMR CRC内肠道菌群-宿主免疫相互作用的异质性景观，这揭示了异质性免疫应答的潜在机制。 © 作者(或其雇主) 2023。在CC BY-NC下允许再使用。不得进行商业再利用。由BMJ出版。

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.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.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.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.© Author(s) (or their employer(s)) 2023. Re-use permitted under CC BY-NC. No commercial re-use. See rights and permissions. Published by BMJ.