Gut Reactions: How the Microbiome Is Rewriting the Rules of Immunotherapy

Immune checkpoint inhibitors (ICIs) such as anti-PD-1, anti-PD-L1, and anti-CTLA-4 antibodies have transformed cancer treatment, unleashing the immune system’s ability to tackle tumours that were once thought invincible. Yet despite their promise, only a fraction of patients see durable responses.

Why do some respond spectacularly while others barely budge? Increasingly, the answer appears to lie, in part, in our guts.

The Gut–Immunotherapy Connection

Over the past decade, multiple studies have unveiled a strong link between the gut microbiome - the community of bacteria, viruses, fungi (and their genes) living in our intestines -  and the efficacy of immune checkpoint blockade. Clinical cohorts have shown that patients with richer and more diverse gut bacterial communities tend to respond better to ICIs.

Key bacterial species have repeatedly shown up in responders. Among them are Akkermansia muciniphila, Faecalibacterium prausnitzii, and certain Bifidobacterium spp. These microbes seem to help shape immune environments that favor tumor control: promoting T-cell infiltration, enhancing antigen presentation, and boosting Type I interferon signalling.

On the flip side, when the microbiome is disrupted - for example, by recent antibiotic use or proton pump inhibitor (PPI) therapy -  response rates tend to drop. Dysbiosis (an imbalance in microbial composition) is being increasingly recognised not just as a consequence, but as a causal factor that undermines immunotherapy efficacy.

Translating Insight into Intervention

Knowing that the gut microbiome matters is one thing; manipulating it to improve outcomes is another. Recent work suggests several promising strategies:

1. Faecal Microbiota Transplantation (FMT)

Transplanting stool from a patient who responded well to ICIs into a non-responder has in some studies “rescued” responses. Mice receiving such transplants often exhibit reduced tumour growth compared to those who receive stool from non-responders.

Clinically, a recent meta-analysis (up to 2024) of around 164 patients with solid tumours showed that combining FMT with ICIs yielded an objective response rate (ORR) of ~43 %. It also showed that dual ICIs (e.g. anti-CTLA-4 + anti-PD-1) with FMT had higher ORRs (~60 %) than monotherapy.

2. Probiotics, Prebiotics, Diet & Lifestyle

Dietary modifications, use of specific probiotics or prebiotics, and other lifestyle factors (e.g. exercise) are under investigation as subtler ways to tip the microbial balance. They may shift the abundance of beneficial species, improve gut barrier function, or reduce inflammation, thereby enhancing immunotherapy effectiveness.

3. Small Molecule or Metabolite Interventions

Much of the effect of gut bacteria is mediated through their metabolic output - short-chain fatty acids (SCFAs), bacterial cell wall components, or other microbial metabolites that interact with immune cells. Manipulating these (via targeted prebiotic feeding, or maybe synthetic analogues) could improve immunotherapy responses.

Real-World Impacts & Success Stories

Some concrete outcomes demonstrate how these findings are portending real clinical shifts:

• Patients who had taken antibiotics within a certain window before starting ICIs often had worse progression-free and overall survival, pointing to the importance of preserving gut microbial diversity prior to immunotherapy.
• The meta-analysis of FMT + ICIs (solid tumours) showed a CR (complete response) rate of ~12% and PR (partial response) rate ~34%, with manageable safety profiles. This gives hope for patients who had been refractory to immunotherapy.
• Some trials are exploring whether prior microbiome profiling could predict which patients are likely to respond or develop immune-related adverse events (irAEs). For example, certain bacterial signatures correlate not just with efficacy but with risk of gut inflammation during ICI therapy.

Challenges, Unknowns & Future Directions

Despite the enthusiasm, there are still many open questions and hurdles to making microbiome-modulation a standard part of immunotherapy.

• Heterogeneity of Findings: Different studies often report different “beneficial” bacteria. What helps in melanoma may differ from lung cancer or renal cancer. Population differences (diet, geography, host genetics) complicate comparisons.
• Mechanistic Gaps: How exactly do certain bacterial species exert their effects? Which immune pathways are most critical? How do non-bacterial components (viruses, fungi) contribute?
• Safety & Standardisation of Interventions: FMT, for instance, must be carefully controlled (donor selection, timing, dose, frequency). Long-term effects are not fully mapped. There’s also risk of unforeseen adverse events.
• Biomarkers & Patient Stratification: To use microbiome modulation effectively, we’ll likely need reliable predictive biomarkers: a baseline microbiome signature, perhaps host immune markers, that tell us whether a patient is likely to benefit.

Looking Ahead

As the field evolves, several promising trends are worth watching:

• Larger randomized controlled trials combining FMT (or other microbiome-modulating interventions) with ICIs in different cancer types.
• Personalised microbiome interventions, possibly tailored to the patient’s baseline microbiome, diet, prior treatments (e.g. avoiding unnecessary antibiotics), and even tumour immune microenvironment.
• Integration of multi-omics (metagenomics, metabolomics, transcriptomics) to define microbial signatures and map causal mechanisms more clearly.
• Combining microbiome modulation with other immunotherapy modalities (vaccines, adoptive cell therapies, etc.) to see if synergistic effects emerge.

Immunotherapy has rewritten many cancer treatment scripts, but its variability in efficacy remains a major hurdle. The gut microbiome is now emerging not just as a spectator, but as a lever - one that might shift outcomes from partial to potent. Whether by FMT, diet, probiotics, or more refined metabolite interventions, microbiome modulation promises to become an integral part of next-generation cancer therapy.

For patients, clinicians, and researchers, the message is clear: when it comes to immunotherapy, sometimes the most important reactions happen in the gut.

 

Sources

1.        The role of the gut microbiome in immunotherapy outcomes
Frontiers in Microbiomes – Microbiome and immune checkpoint inhibitor therapy: current evidence and future directions
https://www.frontiersin.org/journals/microbiomes/articles/10.3389/frmbi.2023.1061193/full

2.      Meta-analysis of FMT plus immune checkpoint inhibitors
BMC Medicine – Fecal microbiota transplantation combined with immune checkpoint inhibitors in solid tumors: a meta-analysis (2025)
https://bmcmedicine.biomedcentral.com/articles/10.1186/s12916-025-04183-y

3.      Microbiota-centered interventions to boost immune checkpoint blockade
Journal of Experimental Medicine (JEM) – Microbiota-centered interventions to boost immune checkpoint blockade efficacy
https://rupress.org/jem/article/222/7/e20250378/277403/Microbiota-centered-interventions-to-boost-immune

4.     Recent review on microbiome-immunotherapy interactions
Med (Cell Press) – Microbiome modulation in cancer immunotherapy
https://www.cell.com/med/fulltext/S2666-6340%2824%2900405-7

5.      Gut microbiota, diet, and immune response in cancer
Cancers (MDPI) – The Gut Microbiome and Immunotherapy Response in Cancer
https://www.mdpi.com/2072-6694/16/24/4271

6.      Microbiome-metabolite interactions with immune pathways
Immunology & Cell Biology – Microbiota and metabolite interactions shaping antitumor immunity
https://onlinelibrary.wiley.com/doi/pdfdirect/10.1111/imcb.12423