This study investigates the clinical relevance of the gut microbiome at taxonomic and metabolic levels in anti-CD19 CAR-T cell therapy, both in patients and in a preclinical syngeneic tumor model. B cell lymphoma patients treated with CD19-CAR-T cells exhibited profound intestinal dysbiosis, exacerbated after CAR-T infusion. This dysbiosis was characterized by low bacterial richness, low sMAdCAM-1 and loss of Akkermansia species, associated with resistance to therapy. Mechanistically, oral Akkermansia massiliensis supplementation increased CAR-T cell infiltration into bone marrow, inverted the CD4/CD8 CAR-T ratio, favored Tc1 CD8+ T cell polarization and promoted release of tryptophan-derived indole metabolites, leading to better tumor control. The clinical benefit of Akkermansia spp. supplementation was abolished when CAR-T cells were genetically deficient for the indole receptor, aryl hydrocarbon receptor (Ahr). Ahr-agonistic indoles alone failed to replicate the bacterium’s anticancer effects. These findings suggest Akkermansia supplementation could improve CAR-T cell potency in patients with intestinal Akkermansia deficiency.

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2025
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First page of Gut microbiota modulation through Akkermansia spp. supplementation increases CAR-T cell potency<alt-title alt-title-type="left-running">CAR-T cell potency increase by Akkermansia microbe</alt-title>

Supplementary data

Supplementary Figures S1 to S9

Supplementary Fig. 1: Patient Flow Diagram. Supplementary Fig. 2: Akkermansia muciniphila positive patients present a prolonged PFS and higher gut microbial diversity. Supplementary Fig. 3: Bioactivity of the CD19/CD28-ζ CAR-T cells in our mouse model. Supplementary Fig. 4: Exploration of TME in B-cell lymphoma patients receiving CD19 CAR-T cells. Supplementary Fig. 5: Comprehensive phenotypic characterization of CAR-T cells infiltrating organs in our immunocompetent mouse model. Supplementary Fig. 6: Characterization of bone marrow composition in B-cell lymphoma patients receiving CD19 CAR-T cells. Supplementary Fig. 7: Akkermansia spp. fails to translocate to distal organs. Supplementary Fig. 8: Tryptophan-derived indoles in mice and patients treated with CAR-T cell therapy. Supplementary Fig. 9: Graphical abstract.

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Table S1

Patient characteristics according to Akkermansia spp. prevalence in stool at baseline.

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Table S2

Metabolomic raw data.

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Table S3

Metagenomic raw data at visit 1.

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Table S4

Metagenomic raw data at visit 2.

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Table S5

Metagenomic raw data at visit 3.

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