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Microbiome and Immunotherapy

Targeting the Gut Microbiome and Metabolic Pathways to Enhance Immunotherapy Outcomes in Cancer Care

By Dr. Nalini Chilkov, L.Ac., O.M.D.
Founder, OutSmart Cancer® System

Introduction

Immunotherapy has revolutionized the treatment landscape for many types of cancer. Yet, response rates remain variable and unpredictable. Immune checkpoint blockade (ICB) therapies are often undermined by tumor-induced immunosuppression, systemic inflammation, and adverse effects stemming from immune hyperactivation. Emerging evidence highlights the gut microbiome and metabolic environment as critical modulators of immunotherapy efficacy and tolerance.

Response to immunotherapy  can be enhanced by optimizing  the health of the microbiome, supporting robust immunity, and promoting systemic metabolic health. These are fundamental elements of the OutSmart Cancer® System.

The Gut-Immune-Cancer Axis

The gut microbiome is now recognized as a powerful regulator of immunity, metabolism, and systemic inflammation. Composed of trillions of microorganisms, this ecosystem influences T-cell function, immune checkpoint pathways, and the tumor microenvironment (TME).

Key mechanisms include:

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  • Modulation of T-cell activation and exhaustion.
  • Regulation of dendritic cell antigen presentation.
  • Production of immunomodulatory metabolites (e.g., short-chain fatty acids, indoles, inosine).
  • Maintenance of gut barrier integrity, reducing systemic endotoxemia.

Clinical studies show that high microbial diversity (α-diversity) and the presence of specific beneficial strains—such as Faecalibacterium prausnitzii, Akkermansia muciniphila, and Bifidobacterium longum—are associated with improved response rates to immune checkpoint blockade and reduced risk of immune related adverse events【6】.

Conversely, gut dysbiosis—often caused by antibiotics, low-fiber diets, or systemic inflammation—can impair immune surveillance and reduce therapeutic benefit. Patients with Proteobacteria-dominant microbiomes show poorer outcomes and increased toxicity【6】.

Diet and the Microbiota-Immune Interface

The Mediterranean Diet: A Clinical Standard

The OutSmart Cancer Diet is a low glycemic modification of the well-studied Mediterranean Diet (MD) which emphasizes vegetables, legumes, whole grains, fruits, nuts, olive oil, and modest intake of fish and poultry. It has been shown to:

  • Increase SCFA-producing bacteria (e.g., Clostridium cluster XIVa, F. prausnitzii).
  • Reduce inflammation and enhance immune regulation.
  • Improve absorption of essential micronutrients (vitamin D, iron, folate).

The OutSmart Cancer® Diet reduces the carbohydrate intake of the Mediterranean Diet to achieve lower normal glucose and insulin levels to reduce the insulinogenic growth signaling and to support mitochondrial fatty acid rather than glucose dominant energy metabolism.

The OutSmart Cancer® Diet also encourages patients to include small portions of a variety of natural fermented foods in their daily diets as a source of a wide spectrum of healthy microorganisms to support a diverse and robust intestinal microbiome.

In a 2023 study published in JAMA Oncology, adherence to the MD was associated with significantly higher objective response rates and progression-free survival in advanced melanoma patients treated with ICB【6】.

High-Fiber Diets and Whole Plant Foods

Soluble dietary fiber from vegetables fuels beneficial microbes and promotes production of butyrate, a SCFA with anti-inflammatory and immune-supportive properties. High-fiber diets:

  • Increase microbial diversity.
  • Decrease gut permeability and systemic LPS levels.
  • Support regulatory T-cell activity and mucosal immunity.

A landmark 2021 Science study showed that patients with higher fiber intake and no probiotic use had significantly better responses to ICB (82% vs. 59%) and prolonged PFS【6】.

Metabolic Interventions: Fasting and Caloric Restriction

Cancer cells exhibit high metabolic demands and are less adaptable to nutrient scarcity. Modifying caloric intake alters host metabolism, immune cell dynamics, and the TME—shifting the balance in favor of immune activation and tumor suppression.

Short-Term Water Fasting (STWF)

STWF involves complete abstinence from food for 72–120 hours with maintained hydration. It:

  • Decreases IGF-1, insulin, and glucose levels.
  • Increases ketone bodies and autophagy.
  • Protects normal cells from chemotherapy-induced toxicity (differential stress resistance).
  • Enhances cytotoxic T-cell and NK cell activity【1,2】.

Fasting-Mimicking Diet (FMD)

The FMD replicates the benefits of fasting while providing limited caloric intake (plant-based, low-protein, high-fat) for 5 days. Clinical trials have demonstrated that FMD:

  • Lowers systemic inflammation and metabolic markers (glucose, IGF-1).
  • Depletes immunosuppressive cells (MDSCs, Tregs).
  • Enhances ICB efficacy and reduces irAEs in melanoma and NSCLC patients【3】.

Time-Restricted Eating (TRE)

TRE aligns eating patterns with circadian rhythms by confining caloric intake to 8–10 hours daily. Benefits include:

  • Improved insulin sensitivity, weight management, and lipid profiles.
  • Reduced inflammatory cytokines (TNF-α, IL-6).
  • Increased microbial diversity and butyrate-producing bacteria【4,5】.

Functional Nutrients and Immune Support

Vitamin D

Vitamin D (VD) modulates both innate and adaptive immunity. It enhances mucosal barrier integrity, reduces inflammatory cytokine production, and promotes regulatory T-cell function. VD deficiency is common in cancer patients and may:

  • Increase gut permeability and systemic inflammation.
  • Correlate with higher rates of irAEs.
  • Impair microbiome diversity【6】.

Omega-3 Fatty Acids

Omega-3 polyunsaturated fatty acids (PUFAs) such as EPA and DHA:

  • Suppress NF-κB activation and COX-derived pro-inflammatory mediators.
  • Increase SCFA-producing gut bacteria.
  • Are associated with improved B-cell and NK cell activity.

Safe dosing ranges from 1.5 to 3 g/day. These fatty acids are generally well-tolerated and help preserve lean body mass and immune tone【6】.

Clinical Integration: Actionable Strategies

Step 1: Dietary Guidance

  • Emphasize a low carb OutSmart Cancer® modified Mediterranean-style diet.
  • Encourage high-fiber, unprocessed plant foods.
  • Minimize processed meat, alcohol, and refined sugar.

Step 2: Fasting Protocols

  • STWF (72 hours) or FMD (5-day cycles) in supervised settings.
  • TRE (8–10 hour eating window) as a sustainable, daily intervention.

Step 3: Supplement Wisely

  • Test and correct vitamin D insufficiency.
  • Supplement omega-3s if inflammatory burden or cachexia is present.

Step 4: Preserve the Microbiome

  • Avoid non-essential antibiotic use near ICB initiation.
  • Favor food-based prebiotics over commercial probiotics unless indicated.

Step 5: Educate and Empower

  • Teach patients how lifestyle and nutrition influence outcomes.
  • Reinforce the message: Cancer is not in control. You are.

Conclusion

A paradigm shift is underway in oncology—one that embraces the whole patient, not just the tumor. By targeting the gut microbiome and metabolic pathways, we can optimize immunotherapy outcomes, reduce adverse effects, and empower patients to play an active role in their healing.

Create a body where cancer cannot thrive.
Support the Tumor Microenvironment. Strengthen the immune system. Transform outcomes.

Bibliography

  1. Brandhorst S., Longo V. D. (2019). Fasting and fasting-mimicking diets for chemotherapy augmentation. GeroScience, 41(4), 387–398. https://doi.org/10.1007/s11357-019-00072-5
  2. Dorff T. B., et al. (2016). Safety and feasibility of fasting in combination with platinum-based chemotherapy. BMC Cancer, 16, 360. https://doi.org/10.1186/s12885-016-2370-6
  3. Vernieri C., et al. (2022). Fasting-mimicking diet is safe and reshapes metabolism and antitumor immunity in patients with cancer. Cancer Discovery, 12(1), 90–107. https://doi.org/10.1158/2159-8290.CD-21-0030
  4. Wilkinson M. J., et al. (2020). Ten-hour time-restricted eating reduces weight, blood pressure, and atherogenic lipids in patients with metabolic syndrome. Cell Metabolism, 31(1), 92–104.e5. https://doi.org/10.1016/j.cmet.2019.11.004
  5. Di Francesco A., et al. (2018). A time to fast. Science, 362(6416), 770–775. https://doi.org/10.1126/science.aau2095
  6. David A., Lev-Ari S. (2024). Targeting the Gut Microbiome to Improve Immunotherapy Outcomes: A Review. Integrative Cancer Therapies, 23:1–10. https://doi.org/10.1177/15347354241269870