How Healthy Gut Microbiota Can Give CAR T-Cell Recipients a Leg Up

Broad-spectrum antibiotics, often used before, during, and after the administration of chimeric antigen receptor (CAR) T-cell therapy, ravage the gut microbiota that, when healthy and diverse, give patients the best chance of treatment response and survival.

Speakers at a session of the European Hematology Association 2026 Congress elaborated on how the gut microbiome contributes to response to immune therapy from the lymphoma and myeloma perspectives. Antibiotics are something of a necessary evil in the CAR T-cell treatment journey, but there are promising avenues to protect and heal the body’s microbiota reserves, including fecal transplantation.

Manipulating the Microbiome to Enhance CD19 CAR T Outcomes

According to Camille Bigenwald, MD, of Gustave Roussy Cancer Campus in Paris, research has revealed that the administration of broad-spectrum antibiotics prior to CAR T for leukemias and lymphomas is associated with poorer overall survival and increased neurotoxicity,¹ whereas a healthy composition—often marked by abundant Akkermansia species—is associated with better response and survival.² Bigenwald’s institution has implemented a patient biobank collecting blood, fecal, and tumor biopsy samples across visits to confirm and expand these findings among their population of patients undergoing CAR T-cell therapy.

In a cohort of 93 patients undergoing CD19-directed CAR T, mostly for diffuse large B-cell lymphoma, 78.5% received prophylactic sulfamethoxazole and trimethoprim (Bactrim) and 87.1% received wide-spectrum antibiotics after CAR T. These data confirmed an association between antibiotic receipt and poorer overall survival, though Bigenwald noted that antibiotics are administered during cytokine release syndrome, which occurs more often in uncontrolled disease.

The Gustave Roussy cohort confirmed that A muciniphila bacteria were associated with better response to the therapy, with a mouse model study showing that administration of these bacteria resulted in improved survival, apparently via greater migration of CAR T-cells to the bone marrow and tumor. In humans as well, those with higher levels of A muciniphila had increased infiltration of CAR T into the bone marrow. Bigenwald’s team is also investigating the prognostic potential of soluble MAdCAM-1, a protein that regulates immune cell trafficking and is reduced in cases of gut dysbiosis.

Trials of microbiome modulation with fecal microbiota transplants in solid tumor settings indicate encouraging safety and efficacy, Bigenwald said, but research in hematologic malignancies is in earlier stages. More evidence is needed to reveal whether the optimal approach involves material from healthy donors or long-term treatment responders and whether it should be delivered via oral capsules or colonoscopy.

How Microbiota Shape the Metabolic and Immune Determinants of CAR T in Myeloma

CAR T-cell therapy has revolutionized the treatment of multiple myeloma, but an enduring challenge is the question of why patients with similar disease burdens can experience such different trajectories—encompassing response, nonresponse, relapse, and variable persistence. According to Mireia Uribe-Herranz, PhD, of Hospital Clinic Barcelona, host factors including physiology, systemic metabolism, and the gut microbiota play a significant role in shaping this response. The bacteria accounting for roughly 1 kg of our body weight have important jobs in digestion, immune health, energy, molecular signaling, and much more.

In myeloma, recent evidence shows how gut microbiome makeup is associated with response to CAR T-cell treatment and even the severity of adverse effects like cytokine release syndrome.³ Research by Uribe-Herranz and colleagues is taking this further by using integrated multiomics to map the microbial signatures linked to delayed complete response.⁴ Here too A muciniphila plays a starring role, associated with better odds of achieving response to treatment—giving Uribe-Herranz hope that this strain is not only correlated with better outcomes but may represent a modifiable target to optimize efficacy and safety.

How Can Clinicians and Patients Prioritize the Microbiome During CAR T-Cell Treatment?

Amid this emerging evidence, audience questions centered on making these findings actionable in the hematology clinic. Bigenwald was careful to emphasize that antibiotics are a necessary part of the CAR T journey, where fevers and infections are commonplace. Instead, she said, the question is “how can we try to mitigate the negative effects of wide-spectrum antibiotics for CAR T patients rather than avoiding antibiotics?”

Uribe-Herranz agreed that the solution could lie in “preparing patients to have the best microbiota we want, so these cells are as good as they can be,” but more research is needed to find the unique recipe that will work best for each patient. The individualized nature of the microbiome means that there is no one-size-fits-all product to ensure a healthy composition, with Uribe-Herranz recommending against over-the-counter probiotics, which she noted have the potential to lower gut flora diversity by delivering a surplus of one particular strain thought to be helpful but developed with a healthy population in mind rather than the immunosuppressed patients undergoing CAR T-cell treatment for hematological malignancies.

References

1. Smith M, Dai A, Ghilardi G, et al. Gut microbiome correlates of response and toxicity following anti-CD19 CAR T cell therapy. Nat Med. 2022;28(4):713-723. doi:10.1038/s41591-022-01702-9
2. Stein-Thoeringer CK, Saini NY, Zamir E, et al. A non-antibiotic-disrupted gut microbiome is associated with clinical responses to CD19-CAR-T cell cancer immunotherapy. Nat Med. 2023;29(4):906-916. doi:10.1038/s41591-023-02234-6
3. Hu Y, Li J, Ni F, et al. CAR-T cell therapy-related cytokine release syndrome and therapeutic response is modulated by the gut microbiome in hematologic malignancies. Nat Commun. 2022;13(1):5313. doi:10.1038/s41467-022-32960-3
4. Uribe-Herranz M, Oliver-Caldés A, Martínez-Micaelo N, et al. Microbiota shape metabolic and immune determinants of CAR-T Therapy and correlate with outcomes in myeloma. Blood Cancer Discov. 2025;6(5):484-504. doi:10.1158/2643-3230.BCD-24-0203