Pea hull fiber supplementation does not modulate uremic metabolites in adults receiving hemodialysis: a randomized, double-blind, controlled trial.

Background: Fiber is a potential therapeutic to suppress microbiota-generated uremic molecules. This study aimed to determine if fiber supplementation decreased serum levels of uremic molecules through the modulation of gut microbiota in adults undergoing hemodialysis. Methods: A randomized, double-blinded, controlled crossover study was conducted. Following a 1-week baseline, participants consumed muffins with added pea hull fiber (PHF) (15 g/d) and control muffins daily, each for 4 weeks, separated by a 4-week washout. Blood and stool samples were collected per period. Serum p-cresyl sulfate (PCS), indoxyl sulfate (IS), phenylacetylglutamine (PAG), and trimethylamine N-oxide (TMAO) were quantified by LC-MS/MS, and fecal microbiota profiled by 16S rRNA gene amplicon sequencing and specific taxa of interest by qPCR. QIIME 2 sample-classifier was used to discover unique microbiota profiles due to the consumption of PHF. Results: Intake of PHF contributed an additional 9 g/d of dietary fiber to the subjects' diet due to compliance. No significant changes from baseline were observed in serum PCS, IS, PAG, or TMAO, or for the relative quantification of Akkermansia muciniphila, Faecalibacterium prausnitzii, Bifidobacterium, or Roseburia, taxa considered health-enhancing. Dietary protein intake and IS (r = -0.5, p = 0.05) and slow transit stool form and PCS (r = 0.7, p < 0.01) were significantly correlated at baseline. PHF and control periods were not differentiated; however, using machine learning, taxa most distinguishing the microbiota composition during the PHF periods compared to usual diet alone were enriched Gemmiger, Collinsella, and depleted Lactobacillus, Ruminococcus, Coprococcus, and Mogibacteriaceae. Conclusion: PHF supplementation did not mitigate serum levels of targeted microbial-generated uremic molecules. Given the high cellulose content, which may be resistant to fermentation, PHF may not exert sufficient effects on microbiota composition to modulate its activity at the dose consumed.

Gut Microbiota Dysbiosis Associated with Persistent Fatigue in Hematopoietic Cell Transplantation Survivors.

Fatigue is one of the most prevalent and distressing complications among hematopoietic stem cell transplantation (HCT) survivors, negatively affecting physical, social, and emotional domains of quality of life. Chronic systemic inflammation has been linked to alterations in nervous system activity and initiation of distressing symptoms, such as fatigue. Damage to gut mucosa due to alteration in gut microbiota (GM) composition and microbial translocation has been shown to increase systemic proinflammatory cytokines. The aim of this study was to evaluate the relationship between fatigue and GM by measuring the differences in GM composition in HCT survivors with and without persistent fatigue. This cross-sectional study included 30 adults who underwent HCT for a hematologic disease and were at least 1 year post-HCT. Patients with chronic graft-versus-host disease were excluded. Fatigue severity was assessed by the Brief Fatigue Inventory (BFI). Based on the BFI score, patients were grouped into 2 categories: 0 to 3 (without fatigue) and ≥4 (with fatigue). The V1 to V3 region of the 16S rRNA gene from fecal specimens was sequenced using the Illumina MiSeq. Sequencing reads were processed, denoised, and replicated, chimeras were filtered, amplicon sequence variants (ASVs) were generated, and taxonomy was assigned using DADA2. Beta diversity analysis through principal coordinate analysis was generated using the Bray-Curtis dissimilarity matrix, and the difference was tested using linear model with generalized least squares in R. An alpha diversity analysis was performed using Chao1. Linear discriminant analysis effect size (LEfSe) was used to find markers that differ between the 2 groups. Based on the BFI results, patients were categorized into 2 cohorts: with fatigue (n = 14) and without fatigue (n = 16). The 2 cohorts were similar in terms of demographics, disease, and transplant characteristics. Based on the GM analysis, there was a significant difference in GM composition (beta diversity) between the 2 cohorts (P = .001). Alpha diversity (richness) was also significantly lower in survivors with fatigue (P =.002). LEfSe analysis identified 46 discriminative features (P < .05; linear discriminant analysis score >2) whose relative abundance varied significantly among individuals with fatigue and those without fatigue. Ten ASVs were associated with the patients with fatigue, and 36 ASVs were associated with those without fatigue. Several ASVs enriched in survivors with fatigue included organisms such as Klebsiella and Enterococcus, which have been implicated in inflammatory bowel diseases. The ASVs enriched in the cohort without fatigue were members of the Ruminococcaceae family (Oscillospira spp) and the Lachnospiraceae family (Fusicatenibacter and Coprococcus spp), which are known to have the ability to ferment complex plant carbohydrates. These findings show an association between GM composition and fatigue and suggest a microbial contribution to clinically significant fatigue post-HCT, which may guide the development of new approaches to treating fatigue based on manipulation of the GM.

Global Metabolomics in Allogeneic Hematopoietic Cell Transplantation Recipients Discordant for Chronic Graft-versus-Host Disease.

Chronic graft-versus-host disease (cGVHD) remains a significant late effect issue for allogeneic hematopoietic cell transplantation (allo-HCT) survivors, contributing to morbidity and mortality. The etiology of cGVHD is not well elucidated. Owing to a lack of early diagnostic tests and pathophysiology ambiguity, targeted treatments remain limited. Biomarkers for prediction, control response, or prognostication have not yet been identified. Metabolomics, the quantification of metabolites, is a potential biomarker of cGVHD but has not been evaluated in this population. In this study, we examined global metabolites of stored plasma to identify differentially expressed metabolites of individuals discordant for cGVHD following allo-HCT. A descriptive, comparative, cross-sectional study design was used to examine differentially expressed metabolites of plasma samples obtained from 40 adult allo-HCT recipients (20 with cGVHD and 20 without cGVHD) from 2 parent studies. Metabolomics profiling was conducted at the University of Florida's Southeast Center for Integrative Metabolomics. Full experimental methods followed a previously published method. All statistical analyses were performed by a PhD-prepared, trained bioinformatics statistician. There were 10 differentially expressed metabolites between participants with cGVHD and those without cGVHD. Differential metabolites included those related to energy metabolism (n = 3), amino acid metabolism (n = 3), lipid metabolism (n = 2), caffeine metabolism (n = 1), and neurotransmission (n = 1). Serotonin had the greatest fold change (21.01). This study suggests that cGVHD may be associated with expanded cellular energy and potentially mitochondrial dysfunction. The differential metabolic profile between patients with and without cGVHD indicates metabolic perturbations that merit further exploration as potential biomarkers of cGVHD. These findings support the need for further examination using a larger, prospective study design to identify metabolomic risk factors that may signal the need for earlier preventive measures and earlier treatment to reduce cGVHD.