The lung-gut-brain axis in non-small-cell lung cancer: a narrative review with a systematic search of three signaling pathways.
5 affiliations
- 1West China School of Medicine, Sichuan University, Chengdu, China.
- 2Department of Endocrinology and Metabolism, The Fourth Affiliated Hospital of Harbin Medical University, Harbin, China.
- 3Out-patient Department, West China Hospital, Sichuan University, Chengdu, China.
- 4Department of Thoracic Surgery, West China Hospital, Sichuan University, Chengdu, China.
- 5Lung Cancer Center/Lung Cancer Institute, West China Hospital, Sichuan University, Chengdu, China.
Abstract
Background
The gut-lung axis, the long-range communication between the intestinal microbiota and the lungs, has been shown to influence immunotherapy responses in non-small-cell lung cancer (NSCLC). Existing reviews, however, focus almost exclusively on the chemical signaling dimension of microbial metabolites. The relay function of enteroendocrine hormones and the integrative role of the nervous system have yet to be incorporated into a unified framework.Methods
We searched seven databases (PubMed, EMBASE, Web of Science, Cochrane Library, CNKI, Wanfang, and VIP) from inception to June 2026 for original studies and reviews addressing gut microbiota and lung-gut-brain axis mechanisms in the context of NSCLC or small-cell lung cancer. Two authors independently performed study selection, data extraction, and thematic classification. A narrative synthesis was conducted, with evidence organized along three signaling axes: soluble metabolites, the metabolic-endocrine axis, and neuroimmune integration. As a narrative review with a systematic search, this study was registered on PROSPERO (CRD420261425826), while formal risk-of-bias assessment and GRADE evaluation were not performed.Results
A total of 168 studies was included (only a subset of these included studies cited in the main text). The volume of evidence across the three axes formed a pronounced gradient. Soluble metabolites (short-chain fatty acids, tryptophan metabolites, and bile acids) have been cross-validated in clinical cohorts, animal models, and in vitro experiments; fecal microbiota transplantation and prebiotic strategies have entered clinical trials. The metabolic-endocrine axis rests on a solid foundation in normal physiology, but the key bridging nodes in the NSCLC disease context remain untested. Evidence for the neuroimmune integration axis is the sparsest: the only support for a direct transport function of the vagus nerve comes from a non-peer-reviewed preprint in a non-cancer model, and the full neuroendocrine signal transduction chain remains hypothetical. To address this gap, we outline a pathway model annotated with evidence levels at each node.Conclusions
Research on the lung-gut-brain axis is heavily concentrated in the chemical dimension. The mechanistic gaps in the endocrine and neural dimensions represent the principal barrier for the field's transition from correlational description to causal mechanism studies.
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BibTeX
@article{fan2026lunggutbrain,
title = {{The lung-gut-brain axis in non-small-cell lung cancer: a narrative review with a systematic search of three signaling pathways.}},
author = {Yijun Fan and Lili Du and Qiuping Luo and Tingrui Mei and Aier Zhou and Hangyu Liu and Muhammad Quais Khan and Faxian Gao and Jingsi Dong},
journal = {Frontiers in immunology},
year = {2026},
month = sep,
doi = {10.3389/fimmu.2026.1932225},
url = {https://europepmc.org/article/MED/42852084},
note = {CC BY},
}
RIS
TY - JOUR
TI - The lung-gut-brain axis in non-small-cell lung cancer: a narrative review with a systematic search of three signaling pathways.
AU - Yijun Fan
AU - Lili Du
AU - Qiuping Luo
AU - Tingrui Mei
AU - Aier Zhou
AU - Hangyu Liu
AU - Muhammad Quais Khan
AU - Faxian Gao
AU - Jingsi Dong
PY - 2026
DA - 2026/09/11
JO - Frontiers in immunology
DO - 10.3389/fimmu.2026.1932225
UR - https://europepmc.org/article/MED/42852084
AB - Background The gut-lung axis, the long-range communication between the intestinal microbiota and the lungs, has been shown to influence immunotherapy responses in non-small-cell lung cancer (NSCLC). Existing reviews, however, focus almost exclusively on the chemical signaling dimension of microbial metabolites. The relay function of enteroendocrine hormones and the integrative role of the nervous system have yet to be incorporated into a unified framework.Methods We searched seven databases (PubMed, EMBASE, Web of Science, Cochrane Library, CNKI, Wanfang, and VIP) from inception to June 2026 for original studies and reviews addressing gut microbiota and lung-gut-brain axis mechanisms in the context of NSCLC or small-cell lung cancer. Two authors independently performed study selection, data extraction, and thematic classification. A narrative synthesis was conducted, with evidence organized along three signaling axes: soluble metabolites, the metabolic-endocrine axis, and neuroimmune integration. As a narrative review with a systematic search, this study was registered on PROSPERO (CRD420261425826), while formal risk-of-bias assessment and GRADE evaluation were not performed.Results A total of 168 studies was included (only a subset of these included studies cited in the main text). The volume of evidence across the three axes formed a pronounced gradient. Soluble metabolites (short-chain fatty acids, tryptophan metabolites, and bile acids) have been cross-validated in clinical cohorts, animal models, and in vitro experiments; fecal microbiota transplantation and prebiotic strategies have entered clinical trials. The metabolic-endocrine axis rests on a solid foundation in normal physiology, but the key bridging nodes in the NSCLC disease context remain untested. Evidence for the neuroimmune integration axis is the sparsest: the only support for a direct transport function of the vagus nerve comes from a non-peer-reviewed preprint in a non-cancer model, and the full neuroendocrine signal transduction chain remains hypothetical. To address this gap, we outline a pathway model annotated with evidence levels at each node.Conclusions Research on the lung-gut-brain axis is heavily concentrated in the chemical dimension. The mechanistic gaps in the endocrine and neural dimensions represent the principal barrier for the field's transition from correlational description to causal mechanism studies.
SN - 1664-3224
ER -