Lung-gut-brain axis in NSCLC: narrative review with systematic search of three signaling pathways
Evidence favors a role for soluble microbial metabolites (SCFAs, tryptophan, bile acids) in NSCLC immune modulation, while the endocrine and neuroimmune axes remain untested hypotheses in the oncological context.
| Population | NSCLC patients (SCLC as secondary); human, animal, and in vitro studies included |
|---|---|
| Intervention | Gut microbiota and its signaling mechanisms (soluble metabolites, metabolic-endocrine axis, neuroimmune integration) |
| Comparator | null |
| Outcome | Evidence for soluble metabolites (SCFAs, tryptophan, bile acids) in NSCLC immune modulation; Evidence for metabolic-endocrine axis in NSCLC context; Evidence for neuroimmune integration (vagus nerve function) in NSCLC; FMT and prebiotic clinical trials in NSCLC |
Summary of findings
| Outcome | Effect | 95% CI | Certainty | Clinical relevance | Notes |
|---|---|---|---|---|---|
| Evidence for soluble metabolites (SCFAs, tryptophan, bile acids) in NSCLC immune modulation | Qualitative cross-validation across clinical cohorts, animal models, and in vitro studies; in the quantitative effect size reported | — | Low | — | |
| Evidence for metabolic-endocrine axis in NSCLC context | Solid in normal physiology; bridging nodes in NSCLC untested; in the quantitative data | — | Very low | — | |
| Evidence for neuroimmune integration (vagus nerve function) in NSCLC | Only support from a single non-peer-reviewed preprint in a non-cancer model; neuroendocrine transduction chain hypothetical; in the quantitative data | — | Very low | — | 1 studies |
| FMT and prebiotic clinical trials in NSCLC | Trials reported as initiated; in the efficacy or safety data synthesized quantitatively in this review | — | Low | — |
Context
Only 20–30% of NSCLC patients achieve durable benefit from immune checkpoint inhibitors; gut microbiota has emerged as a systemic immune regulator. Prior reviews focused exclusively on microbial metabolites, omitting hormonal and neural dimensions. This paper attempts to unify all three axes into one mechanistic framework.
What the study showed
Of 168 included studies, evidence is unevenly distributed: soluble metabolites (SCFAs, tryptophan metabolites, bile acids) are cross-validated in clinical cohorts, animal models, and in vitro experiments, with FMT and prebiotic clinical trials already underway. The metabolic-endocrine axis has a solid physiological basis, but bridging nodes in the NSCLC disease context are untested. The neuroimmune axis has the sparsest support: the sole evidence for direct vagal transport comes from a non-peer-reviewed preprint in a non-cancer model; the full neuroendocrine transduction chain is hypothetical. No absolute numbers, 95% CIs, or effect sizes were reported — the study contains no quantitative meta-analysis.
How it was done
Narrative review with systematic search of seven databases (PubMed, EMBASE, Web of Science, Cochrane Library, CNKI, Wanfang, VIP) from inception to June 2026; two independent reviewers performed selection, extraction, and thematic classification; narrative synthesis organized around three signaling axes; registered on PROSPERO (CRD420261425826); formal risk-of-bias assessment and GRADE were not performed.
Effect magnitude
No quantitative effect sizes were calculated; evidence strength is classified qualitatively by axis only, with no 95% CIs or summary statistics.
Risk of bias
Absence of formal risk-of-bias assessment (RoB 2, ROBINS-I, and AMSTAR-2 not applied) and GRADE evaluation undermines confidence in conclusions; narrative synthesis is susceptible to selection and confirmation bias by authors. Heterogeneity of included studies (human, animal, in vitro) precludes any direct causal inference for NSCLC.
What this study does NOT prove
This study does not prove causality between gut microbiota, the neuroimmune axis, and immunotherapy response in NSCLC. Findings are not generalizable to clinical populations without prospective controlled validation.
In clinical practice
No change in clinical practice is warranted based on this review alone. Microbiota interventions (FMT, prebiotics) in NSCLC should be considered only within controlled clinical trials. Clinicians should treat endocrine and neuroimmune axes as hypotheses, not established mechanisms.
Limitations
Absence of formal risk-of-bias assessment (RoB 2, ROBINS-I, and AMSTAR-2 not applied) and GRADE evaluation undermines confidence in conclusions; narrative synthesis is susceptible to selection and confirmation bias by authors. Heterogeneity of included studies (human, animal, in vitro) precludes any direct causal inference for NSCLC.
What is still missing
Prospective mechanistic studies specifically testing endocrine and neural nodes in the NSCLC context, with measurable clinical endpoints. RCTs of microbiota interventions stratified by histological subtype and PD-L1 status are needed.
Technical appendix
Version history
- 1.0 · 2026-10-11 — Auto-generated under Evidence Standard v1.0