SScience is full of historical examples of accidental discoveries that changed the world. In modern laboratories, such moments continue to pave the way for scientific progress.
In one such incident that occurred recently, Caetano Race in SousaAn immunologist at the Francis Crick Institute and his team accidentally discovered a link between: Vitamin D and Cancer Through the bacterial ecosystem.One They found that vitamin D acts through a binding protein called Gc globulin and a gut-resident protein. Bacteroides fragilis To stimulate antitumor immunity in mice. These findings demonstrate for the first time a link between vitamin D metabolism, specific species of the microbial community, and the immune response to cancer in living organisms.
“It was purely coincidental, because we weren’t interested in vitamin D,” said Reis e Sousa, who published the study results. science.
Vitamin D is best known for its role in promoting the absorption of calcium, phosphate, and magnesium in bone growth and development. More than a century ago, a deficiency of this vitamin was identified as the cause of the bone disease rickets. Since then, researchers have found that vitamin D may play a potential role in several other diseases, including: Cardiovascular disease, Autoimmuneand cancer.2-4 However, vitamin D does not act alone. Recent evidence suggests that the gut microbiota, located at the interface between the intestinal lumen and the epithelium where dietary vitamin D is absorbed, may act synergistically with this vitamin. Regulate the immune system.5
Initially, Rice and Sousa’s group did not look at the microbiome. An effective response to foreign invasion depends on the ability of cells to move quickly. The cytoskeletal protein actin is essential for cell motility and the changes in cell shape that characterize cellular immune responses. When Rice and Sousa’s team examined the secreted form, Actin severing protein gelsolin (sGSN) is produced by damaged cells and cancer cells, and the researchers found that low levels of sGSN expression or mutations in actin-related proteins were associated with enhanced anti-tumor immunity and improved patient survival.6
He noted, “This coincidence arises from the fact that Gc globulins have a separate actin-binding domain and act together with secreted gelsolin as actin removers.”
The researchers wondered whether Gc globulin-deficient mice would have tumor resistance similar to that observed in sGSN-deficient animals.
In experiments, the team found that Gc-deficient mice had enhanced immune-dependent resistance to transplanted tumors and were more responsive to immune checkpoint inhibitors. They then found that mice without Gc deficiency acquired this tumor resistance when bred alongside Gc-deficient mice, raising the possibility that this resistance might depend on the mice’s gut microbiota. They then wanted to test this hypothesis experimentally. “We were worried that it might be our mice, so we transplanted feces from vitamin D-enriched mice into wild-type mice from two different sources,” Reis e Sousa said. “It was like a detective story.”
Fecal transplant experiments confirmed that tumor resistance could be transmitted. The team also observed that treating Gc-deficient mice with antibiotics reduced tumor resistance after fecal transplantation, further suggesting a gut microbiome link. They found that this resistance was enhanced when the mice were fed a high-vitamin D diet. The fact that this effect was not observed in mice deficient in other immune-related genes that received the same treatment demonstrated that Gc is the protein that links vitamin D metabolism and the gut microbiome.
Next, Reis e Sousa and his colleagues focused on which microbial community species could confer this resistance. Shotgun metagenomic analysis revealed that one species B. FragilisA slight increase was found in fecal samples from mice fed a diet rich in vitamin D. The team B. Fragilis When administered orally to mice, tumor immunity was observed in mice fed a standard vitamin D diet, but not in mice fed a vitamin D-deficient diet.[B. fragilis] It is a candidate because the effect can be replicated phenotypically, but it may also be effective in other microbes, and the experiment needs to be repeated in germ-free mice to assess whether other species are involved,” Reis e Sousa said.
Researchers analyzed the Cancer Genome Atlas and a large Danish patient data set to find evidence supporting the finding that vitamin D enhances cancer immunity. However, Reis e Sousa stressed that their study should not be interpreted as a recommendation for vitamin D supplementation. “Far more research is needed to fully assess the relevance of these findings to human health.”
“The novelty of this study is not that vitamin D modulates immune responses or plays a role in cancer. The mechanism of how vitamin D does this has not yet been reported,” he said. Alessio Fasano“This article uses both animal models and human studies to show how this happens, and that’s why it’s so important,” says Dr. David G. Schwartz, a gastroenterologist and nutritionist at Harvard Medical School who was not involved in the study.
“While this has yet to be captured in clinical trials, their findings have applicability in that vitamin D could be included in cancer treatment and that vitamin D levels are reported over time… There is a newfound respect for vitamin D,” Fasano said.
references
1. Giampazolias E, et al. Vitamin D modulates microbiome-dependent cancer immunity. science. 2024;384(6694):428–437.
2. Carbone F etc. Vitamin D in Atherosclerosis and Cardiovascular Disease. Euro Heart J. 2023;44(23):2078–2094.
3. Johnson CR, Tatcher TD. Vitamin D: Immune function, inflammation, infection, and autoimmunity. Pediatrics International Child Health. 2023;43(4):29-39.
4. Kanno Kei et al. Effect of vitamin D supplementation on recurrence or death in the p53 immunoreactive subgroup of gastrointestinal cancers: a post hoc analysis of the AMATERASU randomized clinical trial. JAMA Net Open. 2023;6(8):e2328886.
5. Yamamoto EA, Jorgensen TN. The Relationship Between Vitamin D, Gut Microbiota, and Systemic Autoimmunity. Front Immunol. 2019;10:3141.
6. Giampazolias E, et al. Secreted gelsolin inhibits DNGR-1-dependent cross-presentation and tumor immunity.. cell. 2021;184(15):4016–4031.e22.
