Abstract
BackgroundGut microbiome alterations are closely related to human health and linked to a variety of diseases. Although great efforts have been made to understand the risk factors for multiple myeloma (MM), little is known about the role of the gut microbiome and alterations of its metabolic functions in the development of MM.ResultsHere, in a cohort of newly diagnosed patients with MM and healthy controls (HCs), significant differences in metagenomic composition were discovered, for the first time, with higher bacterial diversity in MM. Specifically, nitrogen-recycling bacteria such as Klebsiella and Streptococcus were significantly enriched in MM. Also, the bacteria enriched in MM were significantly correlated with the host metabolome, suggesting strong metabolic interactions between microbes and the host. In addition, the MM-enriched bacteria likely result from the regulation of urea nitrogen accumulated during MM progression. Furthermore, by performing fecal microbiota transplantation (FMT) into 5TGM1 mice, we proposed a mechanistic explanation for the interaction between MM-enriched bacteria and MM progression via recycling urea nitrogen. Further experiments validated that Klebsiella pneumoniae promoted MM progression via de novo synthesis of glutamine in mice and that the mice fed with glutamine-deficient diet exhibited slower MM progression.ConclusionsOverall, our findings unveil a novel function of the altered gut microbiome in accelerating the malignant progression of MM and open new avenues for novel treatment strategies via manipulation of the intestinal microbiota of MM patients.Ef13dgTkxr8yaT6cBDYXQ2Video abstract.
Highlights
Multiple myeloma (MM), the second most common hematological malignancy, has shown a uniformly increased incidence since 1990, especially in countries with middle and low-middle sociodemographic indices [1]
In subsequent fecal microbiota transplantation (FMT) experiments, we found that the mice with fecal microbiota from MM patient showed significantly accelerated progression of MM tumors, which was associated with the biosynthesis of L-glutamine from MM-enriched bacteria in the host
Poor interactions in MM suggested that the robustness of gut microbiome was downregulated and that some bacteria with low node degree was susceptible to the change in the intestinal environment, such as Citrobacter, Enterobacter, and Klebsiella (Figure S3c, Additional file 3)
Summary
Multiple myeloma (MM), the second most common hematological malignancy, has shown a uniformly increased incidence since 1990, especially in countries with middle and low-middle sociodemographic indices [1]. Infections are a major cause of morbidity and mortality in MM patients, and the risk of infection increases with active disease but decreases with responses to therapy [6]. Microbe-based strategies have been increasingly utilized, including the use of bacterial markers for clinical diagnosis and fecal microbiota transplantation (FMT) for disease treatment [8, 10, 11]. Empiric third-party FMT after allogeneic hematopoietic cell transplantation, which is the first-line strategy in MM treatment, appeared to be associated with an expansion of the recipient’s microbiome diversity [12]. Great efforts have been made to understand the risk factors for multiple myeloma (MM), little is known about the role of the gut microbiome and alterations of its metabolic functions in the development of MM
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