Title : The microbiota–gut–brain axis and neuropsychological outcomes in gastrointestinal cancers: A systematic review of emerging human evidence
Abstract:
Background and objective: Neuropsychological outcomes, including fatigue, sleep disturbance, pain, cognitive impairment, delirium, and emotional symptoms, often occur concomitantly in patients with gastrointestinal cancers. In recent years, the microbiota–gut–brain axis has been proposed as one of the possible biological mechanisms of this comorbidity, but human evidence in gastrointestinal oncology is still sparse and heterogeneous. The aim of this systematic review was to synthesize new evidence on the association of structural and functional characteristics of the gut microbiome and its modulating interventions with neuropsychological outcomes in patients with gastrointestinal cancers.
Method: The review was designed based on PRISMA 2020. MEDLINE/PubMed, Embase, Web of Science Core Collection, Scopus, and PsycINFO were searched for human studies published from January 2024 to August 2026. Observational and interventional studies in adult patients with gastrointestinal malignancies were eligible if they assessed at least one direct indicator of the gut microbiome, microbial diversity, taxon abundance, microbiome-associated metabolites such as short-chain fatty acids, or a specific microbiome-modulating intervention, along with at least one neuropsychological outcome. Primary outcomes included fatigue, sleep, pain, cognitive function, and delirium, and secondary outcomes included depression, anxiety, and stress. Animal studies, oncological-only studies, and studies without neuropsychological outcomes were excluded. Risk of bias was assessed with tools appropriate to the study design, and due to significant heterogeneity in microbiome measurement methods, cancer types, and outcomes, a structured narrative synthesis rather than a pooled meta-analysis was considered.
Findings: The eligible evidence was primarily related to colorectal cancer and overall supported an association between gut dysbiosis and a greater burden of neuropsychological outcomes, although the causal direction of these relationships remains unclear. Based on the findings, colorectal cancer patients undergoing chemotherapy had lower microbial diversity compared with their caregivers, with a decrease in short-chain fatty acid-producing taxa and an increase in opportunistic taxa; microbial changes in patients were more strongly associated with the severity of a cluster of fatigue, pain, and depressive symptoms. Independent evidence on sleep also showed that colorectal cancer patients with higher sleep efficiency had greater microbial diversity based on Shannon and Inverse Simpson indices, and several taxa showed specific associations with sleep efficiency. Also, multimodal phenotypes consisting of microbial diversity, SCFA concentrations, circadian rhythm, inflammation, autonomic activity, and sleep characteristics showed significant differences in the incidence of postoperative delirium, fatigue, and sleep improvement; microbial diversity and SCFAs were important variables distinguishing these phenotypes. Early interventional evidence has also shown that the use of psychobiotic formulations in surgical patients with gastrointestinal malignancies receiving chemotherapy was associated with improvements in symptoms of depression, anxiety, and stress, and in subsequent analyses with modulation of pain perception; however, the heterogeneity of interventions and the limitations of the available evidence prevent definitive conclusions about clinical efficacy.
Conclusion: Emerging evidence suggests that the association of the microbiome with the experience of patients with gastrointestinal cancer is likely not limited to “mood” and is best considered in the context of a multisystem neuropsychological phenotype. Reduced microbial diversity, reduced SCFA-producing microbes, and functional alterations of the microbiome may be associated with sleep disturbance, fatigue, pain, and cognitive impairment, and this association is likely mediated by interactions with inflammatory, circadian, and autonomic pathways. However, the predominance of small, cross-sectional studies, the strong focus of evidence on colorectal cancer, differences in sequencing methods, and inadequate control of diet, antibiotics, and cancer treatment limit causal inference. The next generation of studies should employ longitudinal and multiomic designs and examine metagenomics, microbial metabolomics, SCFAs, the tryptophan–kynurenine pathway, inflammation, actigraphy, and objective measures of cognition simultaneously with neuropsychological outcomes. Accordingly, the microbiota–gut–brain axis could be proposed as a potential target for identifying vulnerable phenotypes and developing precision supportive care interventions in gastrointestinal cancers, but its clinical application still requires stronger interventional evidence.
Keywords: gastrointestinal cancer; colorectal cancer; gut microbiome; microbiota–gut–brain axis.
