Recipient microbiome-related features predicting metabolic improvement following fecal microbiota transplantation in adults with severe obesity and metabolic syndrome: a secondary analysis of a phase 2 clinical trial.

Microbial-based therapeutics in clinical practice are of considerable interest, and a recent study demonstrated fecal microbial transplantation (FMT) followed by dietary fiber supplements improved glucose homeostasis. Previous evidence suggests that donor and recipient compatibility and FMT protocol are key determinants, but little is known about the involvement of specific recipient factors. Using data from our recent randomized placebo-control phase 2 clinical trial in adults with obesity and metabolic syndrome, we grouped participants that received FMT from one of 4 donors with either fiber supplement into HOMA-IR responders (n = 21) and HOMA-IR non-responders (n = 8). We further assessed plasma bile acids using targeted metabolomics and performed subgroup analyzes to evaluate the effects of recipient parameters and gastrointestinal factors on microbiota engraftment and homeostatic model assessment of insulin resistance (HOMA2-IR) response. The baseline fecal microbiota composition at genus level of recipients could predict the improvements in HOMA2-IR at week 6 (ROC-AUC = 0.70). Prevotella was identified as an important predictor, with responders having significantly lower relative abundance than non-responders (p = .02). In addition, recipients displayed a highly individualized degree of microbial engraftment from donors. Compared to the non-responders, the responders had significantly increased bacterial richness (Chao1) after FMT and a more consistent engraftment of donor-specific bacteria ASVs (amplicon sequence variants) such as Faecalibacillus intestinalis (ASV44), Roseburia spp. (ASV103), and Christensenellaceae spp. (ASV140) (p < .05). Microbiota engraftment was strongly associated with recipients' factors at baseline including initial gut microbial diversity, fiber and nutrient intakes, inflammatory markers, and bile acid derivative levels. This study identified that responders to FMT therapy had a higher engraftment rate in the transplantation of specific donor-specific microbes, which were strongly correlated with insulin sensitivity improvements. Further, the recipient baseline gut microbiota and related factors were identified as the determinants for responsiveness to FMT and fiber supplementation. The findings provide a basis for the development of precision microbial therapeutics for the treatment of metabolic syndrome.

A Multi-Factorial Observational Study on Sequential Fecal Microbiota Transplant in Patients with Medically Refractory Clostridioides difficile Infection.

Fecal microbiota transplantation (FMT) is highly effective in recurrent Clostridioides difficile infection (CDI); increasing evidence supports FMT in severe or fulminant Clostridioides difficile infection (SFCDI). However, the multifactorial mechanisms that underpin the efficacy of FMT are not fully understood. Systems biology approaches using high-throughput technologies may help with mechanistic dissection of host-microbial interactions. Here, we have undertaken a deep phenomics study on four adults receiving sequential FMT for SFCDI, in which we performed a longitudinal, integrative analysis of multiple host factors and intestinal microbiome changes. Stool samples were profiled for changes in gut microbiota and metabolites and blood samples for alterations in targeted epigenomic, metabonomic, glycomic, immune proteomic, immunophenotyping, immune functional assays, and T-cell receptor (TCR) repertoires, respectively. We characterised temporal trajectories in gut microbial and host immunometabolic data sets in three responders and one non-responder to sequential FMT. A total of 562 features were used for analysis, of which 78 features were identified, which differed between the responders and the non-responder. The observed dynamic phenotypic changes may potentially suggest immunosenescent signals in the non-responder and may help to underpin the mechanisms accompanying successful FMT, although our study is limited by a small sample size and significant heterogeneity in patient baseline characteristics. Our multi-omics integrative longitudinal analytical approach extends the knowledge regarding mechanisms of efficacy of FMT and highlights preliminary novel signatures, which should be validated in larger studies.

Fecal microbial transplantation and fiber supplementation in patients with severe obesity and metabolic syndrome: a randomized double-blind, placebo-controlled phase 2 trial.

Fecal microbial transplantation (FMT) from lean donors to patients with obesity has been associated with metabolic benefits, yet results so far have been inconsistent. In this study, we tested the application of daily fiber supplementation as an adjunct to FMT therapy to modulate cardiometabolic outcomes. We performed a double-blind randomized trial in patients with severe obesity and metabolic syndrome receiving oral FMT, to test high-fermentable (HF) and low-fermentable (LF) fiber supplements (NCT03477916). Seventy participants were randomized to the FMT-HF (n = 17), FMT-LF (n = 17), HF (n = 17) and LF (n = 19) groups. The primary outcome was the assessment of change in insulin sensitivity from baseline to 6 weeks using the homeostatic model assessment (HOMA2-IR/IS). After 6 weeks, only patients in the FMT-LF group had significant improvements in HOMA2-IR (3.16 ± 3.01 at 6 weeks versus 3.77 ± 3.57 at baseline; P = 0.02). No difference in HOMA2-IR was observed over this period for those in the FMT-HF group (3.25 ± 1.70 at 6 weeks versus 3.17 ± 1.72 at baseline; P = 0.8), the HF group (3.49 ± 1.43 at 6 weeks versus 3.26 ± 1.33 at baseline; P = 0.8) or the LF group (3.76 ± 2.01 at 6 weeks versus 3.56 ± 1.81 at baseline; P = 0.8). Interventions were safe and well-tolerated with no treatment-attributed serious adverse events. We provide proof of concept for the use of a single-dose oral FMT combined with daily low-fermentable fiber supplementation to improve insulin sensitivity in patients with severe obesity and metabolic syndrome.