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

ABSTRACT

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.

KEYWORDS:

• Fecal microbiota transplantation
• gut microbiota
• dietary fiber
• metabolic syndrome
• obesity

Acknowledgments

We are very grateful to the Center of Excellence for Gastrointestinal Inflammation and Immunity Research (CEGIIR) for the infrastructure. We thank National & Local Joint Engineering Research Center of Deep Processing Technology for Aquatic Products for the support provided throughout the study analysis. We thank Changcan Feng for the excellent technical assistance. We also thank the volunteers who participated in the study.

Disclosure statement

No potential conflict of interest was reported by the author(s).

Author contributions

Conceptualization: ZZ and KLM; Methodology and data collection: ZZ, VM, ECD, NH, DHK, SK, DWB and JW; Led data analysis: ZZ; Assisted in data analysis: VM, ECD, YZ and SW; Bioinformatics: ZZ; Writing – Original draft: ZZ and KLM; All authors commented on and approved the final manuscript.

Data availability statement

The raw sequencing data have been deposited into the Sequence Read Archive (SRA) of the NCBI (http://www.ncbi.nlm.nih.gov/sra) under BioProject PRJNA708262. All other relevant data related to the current study are freely available from the corresponding author (K.L.M.) upon request, which does not include confidential patient information.

Supplementary material

Supplemental data for this article can be accessed online at https://doi.org/10.1080/19490976.2024.2345134

Additional information

Funding

This work was supported by the [W. Garfield Weston Foundation] under Grant [RES0048879]; [National Natural Science Foundation of China] under Grant [32202068]; and [Natural Science Foundation of Fujian Province] under Grant [2022J01332].