The Gut Microbiome, Microsatellite Status and the Response to Immunotherapy in Colorectal Cancer

Sep 24, 2026

Increasing evidence across cancer types shows the microbiome directly modulates anti-cancer immune responses at both gut and systemic levels. Gut microbiota differences correlate with immunotherapy outcomes, including in non-gastrointestinal cancers. DNA mismatch repair-deficient (dMMR) colorectal cancer differs clinically from mismatch repair-proficient (pMMR), with contrasting responsiveness; this is linked not only to mutational burden but also to radically different microbiome composition and diversity. Reviewing available literature, the work considers potential causal relationships and future study directions, highlighting microbiome targeting to improve responses and patient selection for immunotherapy.

LanguageEnglish

CategoryResearch & Report

FormatPDF

Pages15

Reading Time38 min

AccessFree to download

Abstract

Keywords

1. Introduction

Gut microbiota and immune interactions

Dysbiosis and disease associations

Gut mucosa and immune interface

Gut microbiome and colorectal cancer

Review The Gut Microbiome, Microsatellite Status and the Response to Immunotherapy in Colorectal Cancer Toritseju O. Sillo 1, *, Andrew D. Beggs 1, Gary Middleton 2 and Akinfemi Akingboye 3 Citation: Sillo, T.O.; Beggs, A.D.; Middleton, G.; Akingboye, A. The Gut Microbiome, Microsatellite Status and the Response to Immunotherapy in Colorectal Cancer. Int. J. Mol. Sci. 2023, 24, 5767 . [https://doi.org/10.3390/](https://doi.org/10.3390/)[ ](https://doi.org/10.3390/)ijms24065767 Academic Editors: Carmine Stolﬁ, Massimo Nabissi and Peter J. K. Kuppen Received: 17 February 2023 Revised: 9 March 2023 Accepted: 14 March 2023 Published: 17 March 2023 Copyright: © 2023 by the authors. Licensee MDPI, Basel, Switzerland. This article is an open access article distributed under the terms and conditions of the Creative Commons Attribution (CC BY) license ([https://](https://)[ ](https://)[creativecommons.org/licenses/by/](creativecommons.org/licenses/by/)[ ](creativecommons.org/licenses/by/)[4.0/](4.0/)) . 1 Institute of Cancer and Genomic Sciences, College of Medical and Dental Sciences, University of Birmingham, Birmingham B15 2TT, UK 2 Institute of Immunology and Immunotherapy, College of Medical and Dental Sciences, University of Birmingham, Birmingham B15 2TT, UK 3 Dudley Group NHS Foundation Trust, Dudley DY1 2HQ, UK * Correspondence: [t.sillo@bham.ac.uk](t.sillo@bham.ac.uk) Abstract: There is increasing evidence in a range of cancer types that the microbiome plays a direct role in modulating the anti-cancer immune response both at the gut level and systemically. Differences in the gut microbiota have been shown to correlate with differences in immunotherapy responsesin a range of non-gastrointestinal tract cancers. DNA mismatch repair-deﬁcient (dMMR) colorectal cancer (CRC) is radically different to DNA mismatch repair-proﬁcient (pMMR) CRC in clinical phenotype and in its very good responses to immunotherapy. While this has usually been thought tobe due to the high mutational burden in dMMR CRC, the gut microbiome is radically different indMMR and pMMR CRC in terms of both composition and diversity. It is probable that differences in the gut microbiota contribute to the varied responses to immunotherapy in dMMR versus pMMR CRC. Targeting the microbiome offers a way to boost the response and increase the selection of patients who might beneﬁt from this therapy. This paper reviews the available literature on the role of the microbiome in the response to immunotherapy in dMMR and pMMR CRC, explores the potential causal relationship and discusses future directions for study in this exciting and rapidly changing ﬁeld. Keywords: mismatch repair; colorectal cancer; microbiome; immunotherapy; immune environment 1. Introduction The role of the commensal microbiota in gut development, maintaining integrity, metabolism and immunity is critical. There are over 1013 commensals in the human gut [1] . The majority (99%) of species are bacterial, with Bacteroides and Firmicutes predominating, but there are also viruses, archaea and eukarya [2] . There is a bidirectional interaction between the gut microbiome and the host's genetics [3], with added interactions from environmental factors, lifestyle and dietary changes [4] . There is a signiﬁcant diversity in the microbiota amongst healthy individuals, and between healthy people and those with certain conditions. There is an extensive interaction between the gut microbiota and the gut immune environment, which modulates the response to and facilitates the tolerance of commensal bacteria and food antigens while allowing the recognition of and immune responses to harmful antigens. Dysbiosis, or an imbalance in the microbiome, can drive the development of some diseases. In particular, patients with inﬂammatory bowel disease are noted to have reduced faecal microbiota diversity [5] . A differential microbial gene expression is present in patients with ulcerative colit

FAQs

How does the gut microbiome influence immunotherapy responses?

The microbiome modulates anti-cancer immune responses through interactions at the gut level and systemically, and gut microbiota differences correlate with differences in immunotherapy outcomes.

What distinguishes dMMR colorectal cancer from pMMR colorectal cancer in this context?

dMMR colorectal cancer differs from pMMR in clinical phenotype and shows very good responses to immunotherapy, alongside markedly different gut microbiome composition and diversity.

Why is microbiome targeting considered promising for immunotherapy?

Targeting the microbiome is proposed as a way to boost immunotherapy responses and improve selection of patients likely to benefit.

Sep 24, 2026

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