The interplay of gut microbiota between donors and recipients determines the efficacy of fecal microbiota transplantation

ABSTRACT Fecal microbiota transplantation (FMT) is a promising treatment for microbiota dysbiosis associated diseases, such as Clostridioides difficile infection (CDI) and inflammatory bowel disease (IBD). The engraftment of donor bacteria is essential for the effectiveness of FMT, which to some extent depends on the matching of donors and recipients. However, how different types of donor-derived bacteria affect FMT efficacy has not been fully dissected. We recruited two longitudinal IBD cohorts of 103 FMT recipients and further analyzed 1,280 microbiota datasets from 14 public CDI and IBD studies to uncover the effect of donor-derived microbiota in recipients. We found that two enterotypes, RCPT/E and RCPT/B (dominated by Enterobacteriaceae and Bacteroides, respectively), consistently exist in both CDI and IBD patients. Based on a time-course-based multi-cohort analysis of FMT fecal samples, we observed the interplay between recipient and donor-derived microbiota during FMT, in which the FMT outcome was significantly associated with the enterotype and microbiota distance between donor and recipient after FMT. We proposed a new measurement, the ratio of colonizers to residents after FMT (C2R), to quantify the engraftment of donor-derived bacteria in the recipients, and then constructed an enterotype-based statistical model for donor-recipient matching, which was validated by both cross-validation and an additional IBD FMT cohort (n = 42). We believe that with the accumulation of FMT multi-omics datasets, machine learning-based methods will be helpful for rational donor selection for improving efficacy and precision FMT practices.

A history of psychiatric disorders, a definite or suspected psychological disorder and behavior abnormality.
(4) Living environment Living in geographic extremes (regions of high altitude, high temperature, alpine, cold, high humidity, severely polluted areas, and saline-alkaline areas); exposure to epidemic area within the past 3 months.

Public studies inclusion criteria
Our study inclusion and exclusion pipeline have been added to Supplementary Figure   S1, and copied as below. In brief, our procedure was composed of three steps: Firstly, we collected FMT studies from keyword searches in NCBI Bio-project and by following references in related studies. Our search terms are "((((fecal microbiota transplantation) AND (sequencing OR sequence OR metagenome))) AND human)" and "((((((((((Fecal microbial transplant) OR (Fecal microbiota transplantation) OR (FMT)))) NOT chicken) NOT mice)) NOT pig) NOT mouse)) NOT (Canine)".
Secondly, we manually checked these entries and collected them for the next step. Our criteria are: 1) datasets are freely accessible for download; 2) exclude any studies which required additional ethics committee approvals or authorizations for access; 3) exclude studies without CDI or IBD patients; 4) excluded studies with fewer than 20 samples. Thirdly, we manually excluded studies that are not capable of performing further analyses: 1) exclude studies without 16S rRNA sequencing samples; 2) exclude studies without samples of patient and paired donor before FMT; 3) exclude studies without metadata about which donor was transplanted to the patient; 4) include studies that best contain samples of patient after FMT; 5) include studies that best contain metadata about FMT efficacy. For some studies without key metadata, we have tried to acquire by personal email with the authors.

Outcome assessment of FMT
In our recruited IBD cohorts, efficacy of FMT was evaluated three months after treatment. The clinical response was defined as follows: (1) For UC patients, Partial Mayo score (except endoscopic scores) has a decrease of ≥ 2 points and ≥ 30% from baseline plus the rectal bleeding sub-score ≤ 1 point or the decrease of it ≥ 1; (2) The HBI score of CD patients decreased by > 3 points from baseline. Failure to meet the above criteria, or conversion of treatment (e.g. biologics therapy, surgery) were considered non-response.
For the public CDI study, the FMT response was defined as an absence of diarrhea or persistent diarrhea that could be explained by other causes with a negative stool test for C. difficile test in the follow-up after FMT. And for the public IBD study, the FMT response definition was the same as above based on the severity score provided in the paper.

Supplementary
Abx: whether use antibiotics before transplantation; Route: "Lower" means transplantation from down to the lower gut, like colonoscopy; "Mid" means transplantation from up to the mid gut, like endoscopic and nasojejunal tube.