Gut microbiota profile and response to neoadjuvant chemoradiotherapy in patients with rectal cancer: a systematic review

Background: Rectal cancer (RC) accounts for approximately 30% of all colorectal cancers, with pathological complete response (pCR) rates following neoadjuvant chemoradiotherapy (nCRT) ranging from 10–15% and reaching up to 38% with total neoadjuvant therapy. The intestinal microbiota has emerged as a potential modulator of treatment efficacy, offering opportunities for patient stratification and personalized therapy. This review aimed to the best of our knowledge, no robust systematic review has focused on the microbiota profile as a biomarker of response to nCRT in RC. Most studies focus on the effect of the microbiota on the adjuvant response to chemotherapy. To synthesize the available evidence and fill the gap in knowledge on the role of the intestinal microbiota in modulating treatment response and prognosis in patients with RC undergoing nCRT.

Methods: This systematic review was registered in PROSPERO (CRD420251174787). A comprehensive search was conducted across PubMed, PubMed Central (PMC), Virtual Health Library (BVS), Scopus, Web of Science, Embase, and Cochrane Library. Studies evaluating the association between the intestinal microbiota and treatment response or prognosis in adult patients with RC were included. Two independent reviewers selected studies, and data were extracted from eligible studies.

Results: Seventeen studies were included, all published after 2020, with 11 published between 2023 and 2025. Most studies originated from China (11/17). Sequencing methodologies included 16S rRNA sequencing (9 studies), shotgun metagenomics (6 studies), RNA-sequencing (2 studies), and whole-exome sequencing with Path-seq (1 study). A total of 868 patients were evaluated. Alpha-diversity did not differ significantly between responders and non-responders in most studies. Beta-diversity results were heterogeneous. Responders were associated with genera such as Bacteroides, Campylobacter, Faecalibacterium, and Lactobacillus, while non-responders showed enrichment of Akkermansia, Streptococcus, and Prevotella. Functional pathway analyses revealed that responders showed enrichment in pathways related to anaerobic energy metabolism, amino acid synthesis, and innate immune activation [cyclic GMP-AMP synthase-stimulator of interferon genes (cGAS-STING) pathway], whereas non-responders showed enrichment of fatty acid metabolism and anti-apoptotic pathways. Nine studies developed predictive models with AUC values ranging from 0.707 to 0.980.

Conclusions: The intestinal microbiota may play a relevant role in modulating response to nCRT in RC, particularly through functional metabolic pathways rather than taxonomic composition alone. Predictive models based on microbial signatures show promising accuracy, although standardization of methodologies and validation in diverse populations are needed before clinical implementation.