Gut Microbiome Could Play Key Role in Multiple Myeloma

The bone marrow (BM) microenvironment is believed to play a key role in the evolution of monoclonal gammopathy of undetermined significance (MGUS) to multiple myeloma (MM), but a new commentary calls attention to another factor that might be involved in the chain of evolution: the gut microbiome.

Writing in the Journal for ImmunoTherapy of Cancer,¹ corresponding author Nausheen Ahmed, MD, of the University Hospitals Seidman Cancer Center, in Cleveland, and colleagues said there is much more to be explored regarding a potential role of the gut microbiome in fostering the pathogenesis of MM and determining how a patient responds to treatment.

“A growing body of evidence suggests that immune activity within the gut, influenced by the microbiome, has the capacity to impact immune cells in distant organs/the bone marrow (BM), and may play a role in myelogenesis,” Ahmed and colleagues wrote.

The evolution of MGUS to MM is not fully understood, but it is believed to be nonlinear and dependent upon what Ahmed and colleagues referred to as a “permissive” microenvironment in the bone marrow.

“In fact, chronic antigen stimulation may be a mechanism which can affect BM microenvironment and promote progression of plasma cell dyscrasias,” they wrote.

Another factor that can influence the BM microenvironment is microbiome composition, and Ahmed and colleagues said small studies have noted differences in microbiome composition between patients with MM and those with MGUS.²

There are a number of potential ways by which the microbiome can influence the BM microenvironment, Ahmed and colleagues said. One is through synthesis of bioactive metabolites like short-chain fatty acids (SCFAs).

“SCFAs can suppress nuclear factor kappa-light chain enhancer of activated B cells (NF-ƙB) and proinflammatory cytokines like interleukin-6 (IL-6), and tumor necrosis factor α (TNF-α); conversely they may increase IL-10, T helper 17 cells (Th17) and Th1 cells,” Ahmed and colleagues wrote.

One study found SFCA-producing bacteria were reduced and nitrogen-cycling bacteria were enriched in patients with MM compared to healthy controls.³

Ahmed and colleagues said cytokines may be another method by which the gut microbiome modulates the BM microenvironment. The question warrants additional research, the authors said.

Other evidence suggests the gut microbiome affects treatment responses and toxicities in patients with MM. For instance, a 2019 study⁴ found patients who were minimal residual disease-negative after induction therapy tended to have higher levels of Eubacterium hallii versus those who had positive minimal residual disease MRD. Another study showed patients who had higher populations of Bacteroides in their stool samples after 7 days had less severe diarrhea after autotransplant.⁵

The authors also noted that the common MM therapy dexamethasone (DXM) has been linked with reduced IL-17 production.⁶

“Since IL-17 production is also mediated by gut flora, the changes in microbiota induced by chronic DXM use may contribute to the activity of this agent in treating DXM in myeloma,” they wrote.

Ahmed and authors also argued that the mycobiome, and the interaction between mycobiome and bacteria communities deserves additional attention from researchers.

In their conclusion, the authors said study into these questions remains limited, and therefore it is difficult to draw concrete conclusions about links between the gut microbiome and MM. Still, they argued that sufficient circumstantial evidence exists to warrant significant investigation.

“A better understanding of dysbiosis, its role in disease propagation in MM, and its effects on response and toxicity, is essential,” they wrote.

References

1. Ahmed N, Ghannoum M, Gallogly M, de Lima M, Malek E. Influence of gut microbiome on multiple myeloma: friend or foe?. J Immunother Cancer. 2020;8(1):e000576. doi:10.1136/jitc-2020-000576

2. Pepeljugoski C. Analysis of intestinal microbiome in multiple myeloma reveals progressive dysbiosis compared to MGUS and healthy individuals. ash 2019 Abstract, 2019. Available: https://ash.confex.com/ash/2019/webprogram/Paper130643.html

3. Jian X, Zhu Y, Ouyang J, et al. Alterations of gut microbiome accelerate multiple myeloma progression by increasing the relative abundances of nitrogen-recycling bacteria. Microbiome. 2020;8(1):74. Published 2020 May 28. doi:10.1186/s40168-020-00854-5

4. Calcinotto A, Brevi A, Chesi M, et al. Microbiota-driven interleukin-17-producing cells and eosinophils synergize to accelerate multiple myeloma progression. Nat Commun. 2018;9(1):4832. Published 2018 Dec 3. doi:10.1038/s41467-018-07305-8

5. El Jurdi N, Filali-Mouhim A, Salem I, et al. Gastrointestinal Microbiome and Mycobiome Changes during Autologous Transplantation for Multiple Myeloma: Results of a Prospective Pilot Study. Biol Blood Marrow Transplant. 2019;25(8):1511-1519. doi:10.1016/j.bbmt.2019.04.007

6.Huang EY, Inoue T, Leone VA, et al. Using corticosteroids to reshape the gut microbiome: implications for inflammatory bowel diseases. Inflamm Bowel Dis. 2015;21(5):963-972. doi:10.1097/MIB.0000000000000332