Marcel R. M. van Den Brink

Diet shapes the composition of the gut microbiota¹; however, the specific effects of distinct food groups on microbiome dynamics are unclear, particularly in circumstances of extreme perturbation. Here we evaluated the relationship between diet and intestinal microbiome dynamics by precisely tracking 9,419 meals consumed by 173 patients who were hospitalized for haematopoietic cell transplantation and analysing subsequent microbiome changes. Bayesian inference applied to data from 158 patients with paired longitudinal microbiome samples revealed that the intake of sweets and sugars during antibiotic exposure predicted exacerbated microbial dysbiosis, manifesting as lowered α-diversity and greater expansion of the pathobiont Enterococcus. Experiments in mice also showed that sucrose supplementation increased and prolonged antibiotic-induced Enterococcus expansion. These data suggest that avoiding a diet rich in simple sugars during antibiotic treatment may mitigate microbiota disruption. Further studies in independent cohorts will offer opportunities to generalize these findings and evaluate microbiota-sparing interventions.

Diet is linked to changes in gut microbiota and metabolite production with clinical relevance in several disease settings, although these effects remain poorly defined. We performed prospective, real-time diet monitoring (37,929 food items, 3,837 patient days) and longitudinal microbiome and metabolite profiling (1,230 fecal samples) in a clinical cohort of 173 patients undergoing allogeneic hematopoietic cell transplantation. Patients with pre-transplant fiber intake above the cohort average had significantly improved overall survival (p=0.014) and reduced incidence of grades 2–4 acute graft-versus-host disease (GVHD) (p=0.032) post-transplant. Those consuming insoluble fiber had increased microbial diversity, enriched butyrate-producing taxa, and depleted Enterococcus . Those who developed lower gastrointestinal GVHD had reduced fecal butyrate levels. In a GVHD preclinical model, we confirmed that a fiber-enriched diet increased survival, cecal butyrate, and regulatory-to-conventional T cell ratio. Thus, we demonstrated that dietary fiber has clinical significance as a modifiable factor with microbiome-mediated effects.

Figure S2 shows clinical biomarker changes including body composition, healthy eating index, paraprotein, LDL and IGF1.

Figure S7 shows the effect of SCFAs on myeloma cells and immunodeficient mice.

Figure S4 shows change in peripheral blood CRP and inflammatory biomarkers, bone marrow cell proportions and differentially expressed genes in paired samples by BMI and microbiome diversity as well as cell interactions.

Consumption of a Western diet and high body mass index (BMI) are risk factors for progression from premalignant phenotypes to multiple myeloma, a hematologic cancer. In the NUTRIVENTION trial (NCT04920084), we administered a high-fiber, plant-based diet (HFPBD; meals for 12 weeks, coaching for 24 weeks) to 23 participants with myeloma precursor states and elevated BMI. The intervention was feasible and improved quality of life and modifiable risk factors: metabolic (BMI, insulin resistance), microbiome (diversity, composition), and immune (inflammation, monocyte subsets). Disease progression trajectory improved (n = 2) or was stable. Findings were translated to Vk*MYC mice modeling the myeloma precursor state, in which a high-fiber diet (HFD) delayed disease progression through improved metabolism and microbiome composition, leading to increased short-chain fatty acid production that reinvigorated antitumor immunity and inhibited tumor growth. These effects from fiber consumption were independent of calorie restriction and weight loss. A HFD is a low-risk intervention that may delay progression to myeloma.Significance:A HFPBD in participants with precursor plasma cell disorders and an elevated BMI improved metabolic, microbiome, and immune biomarkers of disease. In a subset, it may delay progression to myeloma. In mouse models, a HFD delayed progression to myeloma independent of calorie restriction.See related commentary by Fairfield and Reagan, p. 623

Figure S1 shows the meals provided, CONSORT Diagram and sample timepoints analyzed.

Figure S6 shows the effect of high-fiber diet on the gut microbiota composition and immune response in Vk*MYC mice.