Abstract Oral mucositis (OM) is a common debilitating dose-limiting toxicity of cancer treatment, including hematopoietic stem cell transplantation (HSCT). We hypothesized that the oral microbiome is disturbed during allogeneic HSCT, partially accounting for the variability in OM severity. Using 16S ribosomal RNA gene sequence analysis, metabolomic profiling, and computational methods, we characterized the behavior of the salivary microbiome and metabolome of 184 patients pre- and post-HSCT. Transplantation was associated with a decrease in oral α diversity in all patients. In contrast to the gut microbiome, an association with overall survival was not detected. Among 135 patients given methotrexate for graft-versus-host disease prophylaxis pre-HSCT, Kingella and Atopobium abundance correlated with future development of severe OM. Posttransplant, Methylobacterium species were significantly enriched in patients with severe OM. Moreover, the oral microbiome and metabolome of severe OM patients underwent distinct changes post-HSCT, compared with patients with no or mild OM. Changes in specific metabolites were well explained by microbial composition, and the common metabolic pathway was the polyamines pathway, which is essential for epithelial homeostasis. Together, our findings suggest that salivary microbial composition and metabolites are associated with the development of OM, offering new insights on pathophysiology and potential avenues of intervention.

ObjectiveGestational diabetes mellitus (GDM) is a condition in which women without diabetes are diagnosed with glucose intolerance during pregnancy, typically in the second or third trimester. Early diagnosis, along with a better understanding of its pathophysiology during the first trimester of pregnancy, may be effective in reducing incidence and associated short-term and long-term morbidities.DesignWe comprehensively profiled the gut microbiome, metabolome, inflammatory cytokines, nutrition and clinical records of 394 women during the first trimester of pregnancy, before GDM diagnosis. We then built a model that can predict GDM onset weeks before it is typically diagnosed. Further, we demonstrated the role of the microbiome in disease using faecal microbiota transplant (FMT) of first trimester samples from pregnant women across three unique cohorts.ResultsWe found elevated levels of proinflammatory cytokines in women who later developed GDM, decreased faecal short-chain fatty acids and altered microbiome. We next confirmed that differences in GDM-associated microbial composition during the first trimester drove inflammation and insulin resistance more than 10 weeks prior to GDM diagnosis using FMT experiments. Following these observations, we used a machine learning approach to predict GDM based on first trimester clinical, microbial and inflammatory markers with high accuracy.ConclusionGDM onset can be identified in the first trimester of pregnancy, earlier than currently accepted. Furthermore, the gut microbiome appears to play a role in inflammation-induced GDM pathogenesis, with interleukin-6 as a potential contributor to pathogenesis. Potential GDM markers, including microbiota, can serve as targets for early diagnostics and therapeutic intervention leading to prevention.

The consumption of teff (Eragrostis tef), a gluten-free cereal grain, has increased due to its dense nutrient composition including complex carbohydrates, unsaturated fatty acids, trace minerals (especially Fe), and phytochemicals. This study utilized the clinically-validated Gallus gallus intra amniotic feeding model to assess the effects of intra-amniotic administration of teff extracts versus controls using seven groups: (1) non-injected; (2) 18Ω H2O injected; (3) 5% inulin; (4) teff extract 1%; (5) teff extract 2.5%; (6) teff extract 5%; and (7) teff extract 7.5%. The treatment groups were compared to each other and to controls. Our data demonstrated a significant improvement in hepatic iron (Fe) and zinc (Zn) concentration and LA:DGLA ratio without concomitant serum concentration changes, up-regulation of various Fe and Zn brush border membrane proteins, and beneficial morphological changes to duodenal villi and goblet cells. No significant taxonomic alterations were observed using 16S rRNA sequencing of the cecal microbiota. Several important bacterial metabolic pathways were differentially enriched in the teff group, likely due to teff’s high relative fiber concentration, demonstrating an important bacterial-host interaction that contributed to improvements in the physiological status of Fe and Zn. Therefore, teff appeared to represent a promising staple food crop and should be further evaluated.

BMI and diabetes can affect the gut microbiome composition. Bariatric surgery has large variabilities in the outcome.

Background: Steroid-resistant (SR) intestinal acute graft versus host disease (aGVHD) is a devastating complication of allogeneic hematopoietic stem cell transplantation. Preliminary reports suggest that fecal microbiota transplantation (FMT) administered through a nasogastric tube or colonoscopy may be an effective treatment. We report the results of a single-arm pilot study (NCT 03214289) using FMT in capsules to treat SR or steroid dependent (SD) intestinal aGVHD. Methods: The primary outcome was the occurrence of severe adverse events (SAEs) at 28 days post last FMT course. Secondary outcomes included GVHD response. Complete response (CR) was defined as resolution of gastrointestinal symptoms or reduction of steroid dose to 5 mg of prednisone. Partial response was defined as a decrease in severity of GVHD by at least one stage or a ≥40% reduction in steroid dose. Patients were eligible if they had SR or SD gut aGVHD without active infection or neutropenia. Per-protocol, participants received a course of 30 frozen capsules of fecal matter over two consecutive days. FMT courses could be repeated from the same or a different donor, at the treating physician's discretion. Capsules are produced from healthy unrelated donors who underwent vigorous screening. They are taken orally and are flavorless and odor-free. To characterize the impact of the FMT on the gut microbiota, stool samples of recipients were serially collected and underwent 16s rRNA sequencing. Results: To date, we have enrolled 7 patients with intestinal aGVHD (6 SR, 1 SD) (Table). The median dose of methylprednisolone (MP) was 1 mg/kg (interquartile range [IQR] 0.8-1.3 mg/kg). FMT was administered at a median of 39 days (IQR 21-58 days) from aGVHD diagnosis. A total of 15 courses of FMT were given. Patients received a range of 1-3 FMT courses (median 2). The capsules were well tolerated. Patient #1 developed Enterococcus Faecium bacteremia 2 days following the second FMT. To track the source of bacteremia, we performed targeted metagenomic sequencing. The enterococcus strain from the blood culture was identified in the recipient's pre-FMT stool sample but not in the FMT inoculum (i.e., capsule), confirming that the bacteremia was not an FMT complication. Similarly, patient #6 developed Pseudomonas aeruginosa bacteremia 3 days after the 2nd FMT. 16s rRNA sequencing of the donor capsule failed to demonstrate Pseudomonas taxa. No other SAEs suspected to be related to the FMT were observed. Two patients achieved a CR with complete resolution of GVHD symptoms. Patient #6 had a partial improvement following the 1st FMT, with a reduction of MP from 2 mg/kg to 1.3 mg/kg. Three days after the 2nd FMT, she developed fatal pseudomonas bacteremia, not related to the FMT as detailed above. At last follow-up (median 61 days, IQR 40-99), 3/7 patients were alive. Three patients died from consequences of active GVHD, while one patients who responded to FMT and was free of GVHD, succumbed to an invasive Aspergillus infection of the brain. 16s rRNA sequencing of stool samples revealed bacterial domination (i.e., occupation of at least 40% of the microbiota by a single predominating taxon) of Escherichia(E) coli in four patients before FMT, with a major reduction following therapy. FMT was associated with the introduction of new bacteria and an increase in bacterial diversity in the recipient's stool (Figure). Conclusions: We demonstrate for the first time the utility of fecal microbiota transplantation in orally administered capsules for the treatment of severe intestinal acute GVHD. The capsules were well tolerated and safe. Metagenomic sequencing proved that a bacterial infection following FMT was not related to the procedure. Sequencing of the stool sample revealed bacterial domination with E.coli in 4/7 patients prior to the first FMT. Following FMT, bacterial diversity increased. Finally, 2/7 patients attained a complete response following therapy, suggesting a potential role of FMT in patient management. Figure. (A) Heatmap of operational taxonomics units (OTU). Each column marks a sequenced stool sample at a specific time point and rows individual taxas. The color code indicates relative abundance. Dotted lines represent an FMT course. Before FMT all patients, aside from patient #6, had markedly reduced diversity, with enrichment of OTUs following treatment. (B). Change of bacterial diversity, measured by the Shanon diversity index before and after FMTs. Figure. Figure. Disclosures No relevant conflicts of interest to declare.