Creatine and the Immune System: A New Frontier

Written by: Diego A. Bonilla, Richard B. Kreider, Kristen Drescher and Lili Yang

IN THIS ARTICLE

1. Why the conversation now goes beyond muscle
2. Fueling the Fight Against Cancer
3. A Different Angle: The Gut–Brain Axis
4. Where the Evidence Stands
5. Safety, Dosage, and the Bigger Picture
6. The Take-Home Message

When most people think of creatine, they think of muscle – strength, power, recovery, and lean mass. And for good reason: that is where the evidence is strongest. But a growing body of research is exploring a different question: what if creatine also talks to the immune system?

Why the conversation now goes beyond muscle

The immune system has enormous energy demands. When immune cells (whether they are T cells attacking a tumor or macrophages responding to an infection) become activated, they need to rapidly produce energy to divide, migrate, and release signaling molecules. The phosphocreatine/creatine kinase system is a well-known energy buffer in muscle and brain. The emerging question is whether it serves a similar role in immune cells.

At the same time, chronic inflammation is now recognized as a driver of many age-related and autoimmune conditions. The gut microbiome, which can be influenced by diet and metabolites, plays a central role in regulating systemic inflammation. This has led researchers to explore whether creatine or its breakdown products might influence immune function indirectly through the gut, or directly by supporting immune cell metabolism.

Fueling the Fight Against Cancer

One of the most interesting presentations at the CREATINE CONFERENCE 2025 came from Dr. Lili Yang at the University of California, Los Angeles. Her laboratory studies how creatine influences T cells, the immune system’s primary cancer-fighting cells.

Using mouse models, her team found that tumor-infiltrating immune cells express high levels of the creatine transporter (SLC6A8), suggesting they have an increased need for creatine. When they deleted this transporter specifically in CD8+ T cells, those cells failed to control tumor growth. They showed impaired proliferation, reduced production of effector molecules like IFN-γ and granzyme B, and accelerated signs of exhaustion.

The core problem turned out to be energy. Without the ability to import creatine, T cells had lower intracellular ATP. Supplementing with ATP partially restored their function. In essence, the phosphocreatine/creatine kinase system acts as a metabolic “battery” that helps T cells sustain the high energy demands of an effective anti-tumor response [1].

Importantly, when Professor Yang’s team gave creatine to tumor-bearing mice (either by injection or in the diet) tumor growth slowed, and CD8+ T cell activity inside the tumors increased. The effect was dependent on those T cells; it disappeared in mice lacking a functional immune system or depleted of CD8+ T cells.

Perhaps most promising, combining creatine with anti-PD-1 immunotherapy produced the strongest anti-tumor effects. This suggests that supporting T cell metabolism with creatine might enhance the effectiveness of existing immunotherapies.

While they often hold the frontline in an immune response, T cells aren’t the only immune cells involved in fighting the tumor, and they’re far from the only immune cells with high energy demands. A recent study from Dr. Yang’s lab indicated that dendritic cells, which are responsible for signaling for and activating the T cell response against cancer, also benefit from a creatine-derived energy buffer [2]. This dual benefit for two anti-tumor immune cell types is promising for creatine’s potential as a supplement for patients undergoing cancer therapy and suggests other key immune players may see a similar boon from the increased energy availability that creatine provides. And so, the research continues…

A Different Angle: The Gut–Brain Axis

A separate line of research, presented by Professor Kristen Drescher from Creighton University, approached immunity from a different direction. Her laboratory studies multiple sclerosis (MS) and uses a well-established mouse model called Theiler’s Murine Encephalomyelitis Virus (TMEV) infection. In this model, mice first experience a viral infection, then later develop an autoimmune attack on the spinal cord that resembles MS.

Professor Drescher’s group had previously shown in cell culture that creatine and its breakdown product creatinine could reduce the expression of Toll-like receptors (TLRs), the immune system’s danger sensors, and dampen the production of the pro-inflammatory molecule TNF-α. But would that effect hold up in a living animal?

They gave mice creatine (which converts to creatinine in solution after some time) in their drinking water starting before infection. At day 7, during the acute viral phase, treated mice showed substantially less inflammation in the brain. By day 35, during the autoimmune demyelinating phase, the difference was even more striking. Control mice had abundant T cells invading the spinal cord white matter. Creatinine-treated mice had T cells largely confined to the outer meninges, with minimal damage to the cord itself.

The question was how. The answer pointed to the gut. When the team sequenced the gut microbiome of the two groups, they found significant differences. Creatinine-treated mice had:

• Lower levels of Proteobacteria, a phylum often linked to intestinal barrier dysfunction.
• Decreased Parasutterella, a genus associated with chronic inflammation.
• Increased Aldercreutzia, which has anti-inflammatory properties.
• Higher levels of butyrate-producing genera like Lachnospiraceae NK4A136 and Roseburia. Butyrate is a short-chain fatty acid known to support gut barrier integrity and reduce inflammation.

The working hypothesis is that creatinine shifts the microbiome toward a less inflammatory, more barrier-supporting composition. A healthier gut barrier may mean less systemic inflammation, and in turn, less immune-mediated damage in the central nervous system.

Safety, Dosage, and the Bigger Picture

For most people, the practical takeaway remains unchanged. Creatine monohydrate at 3 to 5 grams per day has an established safety profile [3-5]. The research presented at the CREATINE CONFERENCE 2025 does not change dosing recommendations for general health or athletic performance. What it does change is the scope of the conversation. When we ask what creatine does in the body, the answer is no longer only about muscle. It now includes questions about immune cell metabolism, the gut microbiome, and how these systems interact.

As Professor Yang noted in her presentation, the phosphocreatine/creatine kinase system functions as a kind of battery, an energy reserve that cells can draw on when demand is high. For immune cells in a tumor, that reserve can mean the difference between an effective attack and exhaustion. For the gut microbiome, a metabolite of creatine may help tip the balance toward a more stable, less inflammatory community.

Both lines of research are undergoing, but they are part of a broader shift in how we understand creatine: not just as a supplement for athletes, but as a molecule that interacts with fundamental biological systems that govern health and physiological resilience.

The Take-Home Message

The strongest evidence for creatine remains in the domains of muscle strength, lean mass, and exercise performance, particularly when combined with resistance training. But the immune system is now part of the conversation. Ongoing research is exploring whether creatine can help T cells fight cancer more effectively, and whether a breakdown product of creatine can influence the gut microbiome in ways that dampen inflammation. These are not yet clinical applications, but they are scientifically important directions that will shape the next generation of creatine research.

Creatine is not a stand-alone solution for cancer or autoimmune disease. But as a well-tolerated, extensively studied molecule with a strong safety record, it is increasingly being recognized as a tool for understanding (and possibly supporting) the complex interface between metabolism and immunity.

This blog is based on presentations by Prof. Lili Yang (University of California, Los Angeles) and Prof. Kristen Drescher (Creighton University) at the Creatine Conference 2025. The Creatine Conference was organized by the Creatine for Health Scientific Advisory Board (Alzchem Group AG – Creapure® and Creavitalis®), the Exercise and Sport Nutrition Laboratory (Texas A&M University), and the DBSS Research Division.

Selected references

1. Di Biase, S., et al. (2019). Creatine uptake regulates CD8 T cell antitumor immunity. J Exp Med, 216(12), 2869–2882.
2. Kang, E., et al. (2026). Creatine uptake enhances dendritic cell activation and enhances antitumor immunity. iScience, 29(4), 115436.
3. Bredahl, E.C. et al. (2021). The Role of Creatine in the Development and Activation of Immune Responses. Nutrients, 13, 751.
4. Kreider, R. B., et al. (2025). Safety of creatine supplementation: analysis of the prevalence of reported side effects in clinical trials and adverse event reports. J Int Soc Sports Nutr, 22(sup1), 2488937.
5. de Souza E Silva, A., et al. (2019). Effects of Creatine Supplementation on Renal Function: A Systematic Review and Meta-Analysis. J Ren Nutr, 29(6), 480–489.

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