vinegarScience is filled with historical examples of serendipitous discoveries that changed the world, and in modern laboratories, such moments continue to pave the way for scientific advancement.
In one recent such example, immunologist Caetano Reis e Souza of the Francis Crick Institute and his team discovered a link between vitamin D and cancer through the bacterial ecosystem.1 They discovered that vitamin D acts through the binding protein Gc globulin and resident gut bacteria. Bacteroides fragilis stimulates antitumor immunity in mice. These findings demonstrate for the first time a link between vitamin D metabolism, specific species of the microbiome, and the immune response to cancer in vivo.
“This was purely by chance – we weren’t interested in vitamin D,” said Reis e Souza, who presented the results of the study. Science.
Vitamin D is best known for its role in bone growth and development, promoting the absorption of calcium, phosphate, and magnesium. Over a century ago, a deficiency of this vitamin was found to be the cause of the bone disease rickets. Since then, researchers have discovered that vitamin D may also play a role in many other diseases, including cardiovascular disease, autoimmunity, and cancer.2-4 However, vitamin D does not act alone: Recent evidence suggests that the gut microbiota, located at the intestinal lumen-epithelium interface where dietary vitamin D is absorbed, acts synergistically with this vitamin to modulate the immune system.Five
Initially, Reis e Souza’s group also did not focus on the microbiome. An effective response to foreign invaders depends on the ability of cells to mobilize quickly. The cytoskeletal protein actin is essential for cell mobility and the changes in cell shape that characterize cellular immune responses. When Reis e Souza and his team investigated the secreted form of the actin-severing protein gelsolin (sGSN), produced by damaged and cancer cells, they found that reduced levels of sGSN expression, or mutations in actin-related proteins, correlated with enhanced anti-tumor immunity and increased patient survival.6
“This coincidence arose from the fact that Gc globulin has a distinct actin-binding domain and functions as an actin scavenger together with secreted gelsolin,” he noted.
The researchers wondered whether Gc globulin-deficient mice would exhibit tumor resistance similar to that observed in sGSN-deficient animals.
In their experiments, the team found that Gc-deficient mice developed enhanced immune-dependent resistance to transplanted tumors and also responded better to immune checkpoint inhibitors. They then noticed that mice without Gc deficiency acquired this tumor resistance when housed alongside Gc-deficient mice, raising the possibility that this resistance was dependent on the mice’s gut microbiome. They then wanted to experimentally confirm this hypothesis. “We were worried that it might just be our mice, so we transplanted feces from mice that had high vitamin D into wild-type mice from different sources and in two locations,” says Reis e Sousa. “It was like a detective story.”
Fecal transplant experiments confirmed that tumor resistance is transmissible. The team also observed that treating Gc-deficient mice with antibiotics reduced tumor resistance after fecal transplantation, further suggesting the involvement of gut microbiota. The team found that feeding the mice a high-vitamin D diet enhanced this resistance. This effect was not observed in mice with defects in other immune-related genes that received the same treatment, demonstrating that Gc is the protein that links vitamin D metabolism to gut microbiota.
Next, Reis e Souza and his colleagues zeroed in on which microbial species might confer this resistance. Using shotgun metagenomic analysis, they found that B. fragilisFecal samples from mice that had received the high-vitamin D diet showed a slight increase. B. fragilis When administered orally to mice, it conferred immunity to tumors in mice on a standard vitamin D diet, but not in mice on a vitamin D-deficient diet.”[B. fragilis] “It is a candidate because we can phenocopy the effect, but it may also work in other microbes and we need to repeat the experiments in germ-free mice to assess whether other species are involved,” Reis e Souza said.
By analyzing The Cancer Genome Atlas and a large Danish patient dataset, the researchers found evidence supporting their findings that vitamin D boosts cancer immunity. However, Reis e Souza stressed that the findings should not be interpreted as a recommendation for vitamin D supplementation. “More studies are needed to fully assess the impact of these findings on human health.”
“What’s novel about this study is not that vitamin D modulates immune responses or is involved in cancer; the mechanisms of how it does this have not yet been reported,” said Alessio Fasano, a gastroenterologist and nutritionist at Harvard Medical School, who was not involved in the study. “This paper shows how this happens, using both animal models and human studies, and that’s really important.”
“While this has yet to be explored in clinical trials, their findings have applications in terms of incorporating vitamin D into cancer treatment and being able to report on vitamin D levels over time…There’s a new appreciation for vitamin D,” Fasano said.
References
1. Giampazolias E, et al. Vitamin D regulates microbiome-dependent cancer immunity. Science2024;384(6694):428–437.
2. Carbone F et al. Vitamin D in atherosclerosis and cardiovascular events. Euro Heart J2023;44(23):2078–2094.
3. Johnson CR, Thacher TD. Vitamin D: Immune function, inflammation, infection, autoimmunity. Paediatr Int Children’s Health2023;43(4):29-39.
4. Kenichi Kanno et al. Effect of vitamin D supplementation on recurrence or death in p53-immunoreactive subgroups of gastrointestinal cancer: a post hoc analysis of the AMATERASU randomized clinical trial. JAMA Network Open.2023;6(8):e2328886.
5. Yamamoto EA, Jorgenson TN. The relationship between vitamin D, gut microbiota, and systemic autoimmunity. Front Immunol2019;10:3141.
6. Giampazolias E, et al. Secreted gelsolin inhibits DNGR-1-dependent cross-presentation and cancer immunity.. Cell2021;184(15):4016–4031.e22.
