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. 2024 Nov:109:105427.
doi: 10.1016/j.ebiom.2024.105427. Epub 2024 Oct 30.

Gut microbiome metabolites, molecular mimicry, and species-level variation drive long-term efficacy and adverse event outcomes in lung cancer survivors

Xinyu Liu  1 , Bo Lu  2 , Hao Tang  2 , Xinmiao Jia  3 , Qingyang Zhou  2 , Yanlin Zeng  4 , Xiaoxing Gao  5 , Minjiang Chen  5 , Yan Xu  5 , Mengzhao Wang  5 , Bei Tan  6 , Jingnan Li  7
Affiliations

Gut microbiome metabolites, molecular mimicry, and species-level variation drive long-term efficacy and adverse event outcomes in lung cancer survivors

Xinyu Liu et al. EBioMedicine. 2024 Nov.

Abstract

Background: The influence of the gut microbiota on long-term immune checkpoint inhibitor (ICI) efficacy and immune-related adverse events (irAEs) is poorly understood, as are the underlying mechanisms.

Methods: We performed gut metagenome and metabolome sequencing of gut microbiotas from patients with lung cancer initially treated with anti-PD-1/PD-L1 therapy and explored the underlying mechanisms mediating long-term (median follow-up 1167 days) ICI responses and immune-related adverse events (irAEs). Results were validated in external, publicly-available datasets (Routy, Lee, and McCulloch cohorts).

Findings: The ICI benefit group was enriched for propionate (P = 0.01) and butyrate/isobutyrate (P = 0.12) compared with the resistance group, which was validated in the McCulloch cohort (propionate P < 0.001, butyrate/isobutyrate P = 0.002). The acetyl-CoA pathway (P = 0.02) in beneficial species mainly mediated butyrate production. Microbiota sequences from irAE patients aligned with antigenic epitopes found in autoimmune diseases. Microbiotas of responsive patients contained more lung cancer-related antigens (P = 0.07), which was validated in the Routy cohort (P = 0.02). Escherichia coli and SGB15342 of Faecalibacterium prausnitzii showed strain-level variations corresponding to clinical phenotypes. Metabolome validation reviewed more abundant acetic acid (P = 0.03), propionic acid (P = 0.09), and butyric acid (P = 0.02) in the benefit group than the resistance group, and patients with higher acetic, propionic, and butyric acid levels had a longer progression-free survival and lower risk of tumor progression after adjusting for histopathological subtype and stage (P < 0.05).

Interpretation: Long-term ICI survivors have coevolved a compact microbial community with high butyrate production, and molecular mimicry of autoimmune and tumor antigens by microbiota contribute to outcomes. These results not only characterize the gut microbiotas of patients who benefit long term from ICIs but pave the way for "smart" fecal microbiota transplantation. Registered in the Chinese Clinical Trial Registry (ChiCTR2000032088).

Funding: This work was supported by Beijing Natural Science Foundation (7232110), National High Level Hospital Clinical Research Funding (2022-PUMCH-A-072, 2023-PUMCH-C-054), CAMS Innovation Fund for Medical Sciences (CIFMS) (2022-I2M-C&T-B-010).

Keywords: Gut microbiome; Immune checkpoint inhibitor; Lung cancer; Metabolites; Molecular mimicry.

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Conflict of interest statement

Declaration of interests Authors declare that they have no competing interests.

Figures

Fig. 1
Fig. 1
Taxonomic characteristics of baseline gut microbiota in the benefit (n = 24), severe irAE (n = 13), and resistance (n = 17) groups. (A) Grouping scheme diagram. (B) Kaplan–Meier survival curves for PFS (log-rank P value was calculated after introduction of time-dependent interaction terms). (C) Shannon index of alpha diversities (compared by Wilcoxon rank sum tests with Benjamini-Hochberg correction). (D) Principal co-ordinates analysis (PCoA) plot (compared by adonis function with 999 permutations and Benjamini-Hochberg correction). (E) Cladogram of linear discriminant analysis effect size (LEfSe) analysis. (F) Differential genera by LEfSe analysis. (G) Co-occurrence networks of species (isolated nodes not shown). (H) Venn diagram of edge number of co-occurrence networks. #Good efficacy refers to patients with progression-free survival (PFI) ≥1 year or down-staged in postoperative pathology after neoadjuvant immunotherapy. ##Severe irAE refers to patients with ≥ grade 2 irAEs occurring within one year.
Fig. 2
Fig. 2
Predicted butyrate and butyrate-producing pathways in the benefit (n = 24), severe irAE (n = 13), and resistance (n = 17) groups. (A) Predicted propionate and butyrate/isobutyrate abundances (compared by Wilcoxon rank sum tests with Benjamini-Hochberg correction). (B) Abundance of pyruvate carboxylase (compared by Wilcoxon rank sum tests with Benjamini-Hochberg correction). (C) The enzyme counts of four butyrate-producing pathways (compared by Wilcoxon rank sum tests with Benjamini-Hochberg correction). (D) The enzyme counts of the acetyl-CoA butyrate-producing pathway (compared by Wilcoxon rank sum tests with Benjamini-Hochberg correction). Abbreviations: Thl, thiolase; Hbd, β-hydroxybutyryl-CoA dehydrogenase; Cro, crotonase; Bcd, butyryl-CoA dehydrogenase; EtfA and EtfB, electron transfer protein α, β subunits; But, butyryl-CoA:acetate CoA transferase; Ptb, phosphate butyryltransferase; Buk, butyrate kinase; irAE, immune-related adverse event.
Fig. 3
Fig. 3
Beneficial/harmful species in ICI efficacy groups and associations with butyrate-producing/consuming enzymes. (A) Heatmap and bubble plot of differential species in patients with good (n = 34) and poor (n = 20) ICI efficacy. (B) Correlation heatmap between species (beneficial and harmful) and butyrate-metabolizing (producing and consuming) genes.
Fig. 4
Fig. 4
Molecular mimicry of autoimmune and lung cancer antigenic epitopes and ACP in gut microbiota. (A) Heatmap and bubble plot of differential species in patients with (n = 23) or without (n = 22) irAEs. (B) Aligned autoimmune antigen counts in microbiota of irAE patients. (C) Sequence alignment diagram of FDNGRRGRPVTGP with harmful species enriched in irAE patients. (D and E) Lung cancer antigen and ACP counts aligned in microbiota from patients with good (n = 34) and poor (n = 20) efficacy (compared by Wilcoxon rank sum tests). Abbreviations: ACP, anticancer peptides; CT, connective tissue; SLE, systemic lupus erythematosus; irAE, immune-related adverse event.
Fig. 5
Fig. 5
Strain-level analyses of Escherichia coli, Faecalibacterium prausnitzii, and Alistipes shahii. (A) Phylogenetic trees of Escherichia coli, SGBs of Faecalibacterium prausnitzii, and Alistipes shahii species with different clinical phenotypes and groups. (B) Chord diagrams of 6 SGBs of Faecalibacterium prausnitzii within the three groups. (C) Heatmap of Escherichia coli gene families within the three groups. Abbreviations: SGB, species-level genome bins; irAE, immune-related adverse event.
Fig. 6
Fig. 6
Metabolome analyses of eleven SCFAs in the validation cohort. (A) Principal co-ordinates analysis (PCoA) plot by benefit (n = 14), severe irAE (n = 8), and resistance (n = 17) groups (compared by adonis function with 999 permutations and Benjamini-Hochberg correction). (B–D) Acetate, propionate, and butyrate abundances (compared by Wilcoxon rank sum tests with Benjamini-Hochberg correction). (E–G) Kaplan–Meier survival curves for PFS of patients with higher or lower acetate/propionate/butyrate. Abbreviations: SCFA, short chain fatty acids; irAE, immune-related adverse event.
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