BMI, the Gut Microbiome and Immunotherapy: New Nature Study Explores the Obesity Paradox

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Written By Web Team

For years, cancer researchers have been trying to explain an unexpected observation.

Obesity is associated with an increased risk of developing many cancers and is linked to poorer health in countless ways. Yet several studies have reported that some people with a higher body mass index (BMI) appear to respond better to immune checkpoint inhibitors than those with a lower BMI. This surprising finding became known as the obesity paradox.

Now, a major study published in Nature suggests that BMI itself may not be the explanation. Instead, researchers found that the interaction between diet and the gut microbiome may play a much bigger role in determining how well immunotherapy works.

The research was carried out mainly in laboratory and animal models, so it will not change treatment today. However, it provides one of the strongest explanations yet for a question that has puzzled cancer researchers for years.

What is the obesity paradox in immunotherapy?

Immune checkpoint inhibitors have transformed the treatment of many cancers, including lung cancer. They work by helping the immune system recognise and attack cancer cells.

As researchers analysed outcomes from people receiving these treatments, an unexpected pattern began to emerge. In several studies, people with a higher BMI appeared to experience better responses than those with a lower BMI.

That seemed to contradict almost everything we know about obesity and health.

Was excess body weight somehow improving immunotherapy? Or was BMI simply acting as a marker for something much more complex?

That question has remained unanswered.

Why might BMI not explain immunotherapy response?

BMI is a useful way of estimating whether someone’s weight falls within a healthy range, but it has important limitations.

It tells us nothing about body composition, metabolism, diet or the trillions of bacteria that live naturally in the digestive system, collectively known as the gut microbiome.

Over the past decade, researchers have increasingly recognised that these microbes play an important role in shaping the immune system. Several studies have already suggested that differences in the gut microbiome may influence how well immunotherapy works.

This new study set out to investigate whether the obesity paradox might actually be explained by the relationship between diet, gut bacteria and the immune system, rather than body weight alone.

How did researchers investigate the obesity paradox?

Researchers developed twelve different dietary models using mice with lung tumours before treating them with anti-PD-1 immunotherapy. Each diet produced different metabolic changes and different gut microbiome profiles.

Rather than asking simply whether obesity influenced treatment, they examined how diet affected the immune system, the gut microbiome and response to immunotherapy.

This allowed them to separate the effects of body weight from the biological changes taking place inside the body.

What did the Nature study find?

The results suggested that BMI alone could not explain why some animals responded better than others.

Some diets that resulted in obesity produced strong responses to immunotherapy, while others did not. Equally, not every lean group responded poorly.

Instead, the strongest relationship was found between diet, the gut microbiome and treatment response.

In other words, body weight appeared to be a much less reliable predictor than the biological changes associated with different diets.

How could the gut microbiome influence immunotherapy?

The researchers found clear differences in the gut bacteria present in animals that responded well to immunotherapy compared with those that did not.

One bacterium, Lactobacillus johnsonii, consistently stood out.

Importantly, the researchers found that the strongest effects occurred when this bacterium was present alongside a supportive diet. This suggests it was the interaction between diet and the gut microbiome, rather than a single “beneficial” bacterium, that influenced treatment response.

The team also identified bacterial metabolites that may help explain how gut microbes influence immune cells, providing new insight into the biological mechanisms involved.

What happened when the researchers changed diet?

Perhaps the most striking result came when researchers changed the diets of mice during the study.

The gut microbiome changed rapidly, and these changes altered responses to immunotherapy before major changes in body weight occurred.

This strengthens the idea that the gut microbiome itself may play a more direct role in determining immunotherapy response than BMI alone.

The researchers also transferred gut microbes from people into mice. Again, the findings suggested that diet could reshape these microbial communities and influence how well immunotherapy worked.

What does this mean for people with lung cancer?

Although the findings are exciting, they should be interpreted carefully.

This study does not mean people should gain weight before starting immunotherapy.

It does not show that changing diet will improve treatment outcomes.

It does not support taking probiotics to make immunotherapy more effective.

Instead, it provides researchers with a much better understanding of why immunotherapy may work differently from one person to another.

Understanding these mechanisms could eventually lead to new ways of improving treatment, whether through dietary approaches, microbiome-based therapies or medicines that target the same biological pathways. However, much more research in people will be needed before any of these approaches could become part of routine cancer care.

What does this study not show?

  • It does not mean obesity improves cancer outcomes.

  • It does not mean people should gain weight.

  • It does not show changing diet will improve immunotherapy.

  • It does not support taking probiotics before treatment.

What's next for microbiome research?

The gut microbiome has become one of the most exciting areas of cancer research, and this study adds an important new piece to the puzzle.

Rather than suggesting obesity is beneficial, the findings point towards a far more complex interaction between diet, gut bacteria and the immune system.

For people affected by lung cancer, the research will not change treatment today. But by helping explain the long-standing obesity paradox, it moves scientists one step closer to understanding why immunotherapy works so well for some people and how more people might benefit from these life-extending treatments in the future.

Sources

Primary study

Background

Further reading

Sources

Primary study
Desharnais L, Swaby A, et al. Diet–microbiome synergy underlies obesity-associated immunotherapy efficacy. Nature. 2026.
Background
National Cancer Institute – Immune Checkpoint InhibitorsCancer Research UK – ImmunotherapyWorld Cancer Research Fund International – Body fatness and cancer

Further reading
Lung Cancer Europe – The microbiome and lung cancer: how gut bacteria could change treatment
Lung Cancer Europe – CAR T cells and lung cancer 
Lung Cancer Europe – Biomarker testing in lung cancer is moving faster than ever: Is Europe keeping up
Web Team
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