Vitamin D alters the gut microbiome and bile acid chemistry to help the immune system fight cancer in mice. This matters because while vitamin D supplements are cheap and widely available, no one understands exactly how they influence cancer immunity. The researcher has already shown that vitamin D protects against tumours in mice, but only when the gut bacteria are intact. The missing piece is the mechanism: how does vitamin D talk to the microbiome, and what role do bile acids play in that conversation? Bile acids share metabolic enzymes with vitamin D and can activate the same receptor, yet their immune effects in cancer are almost unexplored. If this work succeeds, it will map a new molecular pathway linking diet, gut bacteria, and immune defence. That could eventually guide smarter use of vitamin D supplementation in cancer patients—not as a cure, but as a low-cost way to boost existing therapies. The project is fundamentally curiosity-driven: it aims to understand a basic biological circuit. But similar fundamental discoveries about vitamin D and immunity have, in the past, led to clinical trials for autoimmune diseases and infection. A clearer picture here could open the same kind of translational path for cancer.
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Diet plays a central role in the development and function of immune cells and has been shown to affect immune responses against pathogens, as well as in autoimmunity and cancer. Understanding how nutritional components affect immune processes could be highly beneficial, considering the cost-effectiveness and applicability of dietary supplementation. Diet is also a major regulator of the gut microbiota, with multiple consequences on host immunity. Recent work in the lab has established a protective role for dietary vitamin D in cancer using transplantable tumour mouse models. Remarkably, this phenomenon was found to be both immune and microbiota dependent. While the effect of vitamin D on immune cell function has been explored for the past three decades, it is not yet clear how vitamin D shapes host immunity in cancer. Interestingly, vitamin D metabolism involves enzymes that are also key in bile acid metabolism, and bile acids can bind and activate the vitamin D receptor in the intestine. Nevertheless, whether and how the vitamin D receptor modulates inflammation via bile acids remains largely unknown and is one of the key knowledge gaps in the field. In this proposed work, mouse models of increased vitamin D bioavailability, as well as diet manipulation together with a novel metabolomics approach will be used to unravel the mechanism by which vitamin D shapes the microbiota and supports host immunity. Cellular characterisation and metabolomic profiling of bile fluid will delineate novel players in the underlying mechanism of vitamin D immune protection in cancer. In parallel, I will examine the immune-modulatory effects of bile acids on the immune system and its role in cancer progression by targeting primary and secondary bile acid signalling pathways. Altogether, the work proposed here will contribute to the fundamental understanding of the roles of vitamin D and bile acids in immune cell function and may open new avenues in the development of cancer therapies.
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