How exactly do gut bacteria influence immunotherapy outcomes?
The gut microbiome affects immunotherapy by modulating the immune system and the tumor microenvironment. Beneficial bacteria and their metabolites, such as short-chain fatty acids (SCFAs), can enhance the activity of immune cells like CD8+ T cells and natural killer cells, making them more effective at attacking tumors [4][5][7]. For example, in non-small cell lung cancer patients, responders had significantly higher levels of Faecalibacterium and SCFAs like butanoic acid, which correlated with better treatment outcomes [4]. In hepatobiliary cancers, patients with higher levels of Lachnospiraceae and Alistipes bacteria had longer progression-free and overall survival on anti-PD-1 therapy [1].
Conversely, certain bacteria can dampen the immune response. In the same hepatobiliary cancer study, patients with higher levels of Veillonellaceae had worse outcomes [1]. The gut microbiome also influences immune-related adverse events; for instance, low levels of Bacteroidetes were associated with a higher risk of colitis in melanoma patients on immunotherapy [2]. This dual role—boosting or suppressing immunity—is why the microbiome is now seen as a critical factor in personalized cancer treatment.
Can we use the microbiome to predict who will respond or even improve responses?
Yes, the gut microbiome can serve as a predictive biomarker for immunotherapy response. In a large study of 172 lymphoma patients receiving CAR-T cell therapy, machine learning models based on pre-treatment gut bacteria (including Bacteroides, Ruminococcus, and Akkermansia) accurately distinguished long-term responders from non-responders across different countries [3]. Similarly, in melanoma patients, higher dietary fiber intake was linked to significantly better progression-free survival on immune checkpoint inhibitors, especially when combined with no probiotic use [9]. This suggests that diet can modulate the microbiome to improve outcomes.
Fecal microbiota transplantation (FMT) is a promising strategy to convert non-responders into responders. In two studies, melanoma patients who did not respond to anti-PD-1 therapy showed improved response rates after receiving FMT from patients who had responded, with no added toxicity [2]. In mouse models, FMT from human responders also enhanced the anti-tumor effect of PD-1 inhibitors [4]. However, not all microbiome-based interventions work universally; for example, probiotic supplements were associated with worse outcomes in some melanoma patients, possibly because they disrupted the natural microbiome [9]. This highlights the need for personalized, evidence-based approaches.
What are the current limitations and what does the future hold?
While the evidence is strong, there are important caveats. Many studies are observational and cannot prove causation—confounding factors like prior antibiotic use, diet, and overall health can blur the picture. For instance, in CAR-T therapy, patients who received broad-spectrum antibiotics had worse outcomes, but this was partly because they also had higher tumor burden and inflammation [3]. This means the microbiome's effect can be masked by other factors. Additionally, the exact bacterial strains that matter vary between cancer types and even between individuals, making it hard to create a one-size-fits-all probiotic [10].
The future lies in precision microbiome modulation. Ongoing clinical trials are testing FMT, specific probiotics, dietary interventions, and even engineered bacteria to boost immunotherapy efficacy while reducing side effects [5][6][8]. For example, in colorectal cancer, differences in the microbiome between mismatch repair-deficient and -proficient tumors may explain why only some respond to immunotherapy, opening the door to microbiome-targeted therapies [11]. The goal is to move from broad associations to actionable, personalized treatments that can turn a non-responder into a responder.
Sources used in this answer
Gut microbiome is associated with the clinical response to anti-PD-1 based immunotherapy in hepatobiliary cancers
In 65 hepatobiliary cancer patients on anti-PD-1 therapy, higher levels of Lachnospiraceae and Alistipes bacteria were linked to longer progression-free and overall survival, while Veillonellaceae was linked to worse outcomes.
The Gut Microbiome and Cancer Immunotherapy: Can We Use the Gut Microbiome as a Predictive Biomarker for Clinical Response in Cancer Immunotherapy?
A review of 10 studies found that gut microbiome profiles before immune checkpoint inhibitor treatment consistently predicted clinical response, and low Bacteroidetes was associated with colitis.
A non-antibiotic-disrupted gut microbiome is associated with clinical responses to CD19-CAR-T cell cancer immunotherapy
In 172 lymphoma patients receiving CAR-T therapy, machine learning models using pre-treatment gut bacteria (e.g., Bacteroides, Akkermansia) accurately predicted long-term responders across German and US cohorts.
Gut microbiome affects the response to immunotherapy in non‐small cell lung cancer
In 71 non-small cell lung cancer patients, higher gut microbiome diversity and Faecalibacterium levels were linked to better immunotherapy response, and fecal microbiota transplant from responders enhanced anti-tumor effects in mice.
Gut microbiota shapes cancer immunotherapy responses
Review summarizing that gut microbiota modulates immunotherapy by influencing immune responses and the tumor microenvironment, with FMT, probiotics, and diet showing promise.
Critical role of the gut microbiota in immune responses and cancer immunotherapy
Review highlighting the gut microbiota's critical role in regulating immune responses to cancer immunotherapy and discussing five microbiota-targeted strategies to improve efficacy.
The gut microbiota in cancer immunity and immunotherapy
Review detailing how beneficial bacteria like Lactobacillus and Bifidobacterium can act as adjuvants for cancer therapy, while pathogenic bacteria promote immune evasion.
The gut microbiome modulate response to immunotherapy in cancer
Review presenting recent advances in understanding how gut microbiota and its metabolites modulate antitumor immunity and affect immunotherapy efficacy, with FMT and diet showing promise.
Dietary fiber and probiotics influence the gut microbiome and melanoma immunotherapy response
In 128 melanoma patients on immune checkpoint inhibitors, higher dietary fiber intake was linked to significantly better progression-free survival, but probiotic use was associated with worse outcomes.
Gut microbiome homeostasis and the future of probiotics in cancer immunotherapy
Review noting that dietary fiber, prebiotics, and FMT can enhance intratumoral CD8+ T cell to T-reg ratio, and that probiotic immunotherapy as a 'living adjuvant' is under investigation.
The Gut Microbiome, Microsatellite Status and the Response to Immunotherapy in Colorectal Cancer
Review proposing that differences in gut microbiota between mismatch repair-deficient and -proficient colorectal cancers may contribute to varied immunotherapy responses.