Gut bacteria alter multiple myeloma progression
By interacting with the immune system, some types of gut bacteria can influence the progression of multiple myeloma, a tumor that affects the bone marrow causing pain, anemia and bone fragility. The discovery, limited so far to the animal model of the disease, is published today in Nature Communications by the team of Matteo Bellone, head of Cellular immunology Unit at IRCCS Ospedale San Raffaele. The study, supported by AIRC – The Italian Association for Cancer Research – is among the first to trace a direct link between intestinal microbiota and a tumor located in a different organ, thus demonstrating the capability of these bacteria to interact with the whole organism. Moreover, researchers identified a biological marker that could predict the aggressiveness of multiple myeloma in asymptomatic patients and suggest the efficacy of some anti-inflammatory drugs, already approved for other conditions, in slowing down the disease progression.
Multiple myeloma is a severe tumor affecting plasma cells, the immune cells responsible for antibody production. In patients with multiple myeloma, these cells accumulate inside the bone marrow, interfering with its normal blood regeneration activity and weakening the bones. The disease is preceded by a painless and asymptomatic phase, in which some plasma cells have already acquired tumor characteristics and release a specific protein that can be detected in both the blood and the urine of patients, even in the absence of other pathological manifestations.
To understand the process underlying the disease progression from its asymptomatic phase to the symptomatic one, researchers focused on the animal model of the disease and on the role played by commensal bacteria. They discovered that a specific type of bacteria, also present in humans and called Prevotella heparinolytica, promotes the multiplication of inflammatory lymphocytes Th17 and that these lymphocytes are directly involved in tumor progression inside the bone marrow.
According to the study, Th17 cells migrate from the gut to the bone marrow, where they foster plasma cells proliferation, facilitating the transition from the asymptomatic phase of multiple myeloma to the actual disease through the release of a cytokine – an inflammatory molecule –called IL-17. «Given the key role IL-17 plays in multiple myeloma progression, this molecule could become a predictive tool: the amount of IL-17 in the bone marrow of asymptomatic patients could be the first biomarker able to identify patients at high risk of developing multiple myeloma», explains Arianna Brevi, first author of the research together with Arianna Calcinotto.
To test their hypothesis on the role of Th17 lymphocytes and IL-17 cytokine, researchers performed two experiments: at first, they blocked IL-17 and other inflammatory molecules involved in tumor progression using anti-inflammatory drugs already approved for other conditions; secondly, they modified mice commensal microbiota, through the administration of antibiotics and the transplantation of bacteria species of known anti-inflammatory activity. In both cases, they managed to slow down the onset of multiple myeloma.
«The evidence collected suggests a way to identify patients at greater risk of developing multiple myeloma and to act in advance, thus containing the disease in its asymptomatic stage or, at least, slowing down its more severe manifestation», says Matteo Bellone. «Although the experimental results obtained so far have to be further confirmed in clinical settings, they provide new hopes for patients and clinicians.»
Arianna Calcinotto, Arianna Brevi, Marta Chesi, Roberto Ferrarese, Laura Garcia Perez, Matteo Grioni, Shaji Kumar, Victoria M. Garbitt, Meaghen E. Sharik, Kimberly J. Henderson, Giovanni Tonon, Michio Tomura, Yoshihiro Miwa, Enric Esplugues, Richard A. Flavell, Samuel Huber, Filippo Canducci, Vincent S. Rajkumar, P. Leif Bergsagel & Matteo Bellone, Microbiota-driven interleukin-17-prodcuing cells and eosinophils synergize to accelerate multiple myeloma progression, Nature Communications, 9, 4832 (2018).