Gut Bacteria Transplants Beat Placebo for Colitis — Donor Choice Matters Most

Ulcerative colitis (UC) affects millions worldwide and remains difficult to treat, with many patients failing or intolerant to immunosuppressive therapies. The gut microbiome is deeply dysbiotic in UC — reduced in diversity, depleted of beneficial taxa, and enriched in pathobionts — making microbiome restoration an attractive therapeutic target. Fecal microbiota transplantation (FMT) transfers a healthy donor's gut microbiome to a recipient and has shown promise in multiple randomized trials, though clinical outcomes are highly variable. Dietary fiber, particularly prebiotic fiber, is a known modulator of microbiome composition, but its role in augmenting FMT efficacy had not been formally tested in UC.

Researchers at Weill Cornell Medicine conducted a randomized, double-blind, placebo-controlled trial (NCT03998488) enrolling 27 patients with mild-to-moderate UC into three arms: FMT alone, FMT plus daily psyllium fiber supplementation (10g), or placebo with or without fiber. Patients received a single colonoscopic FMT using one of three independent donor preparations. The primary endpoint was clinical response at week 8 measured by total Mayo score, with secondary endpoints including endoscopic response and clinical remission. Metagenomic shotgun sequencing was performed at multiple timepoints to assess microbiome composition, diversity, and donor strain engraftment using SNP-based strain tracking.

FMT alone achieved clinical response in 56% of patients versus 11% in the placebo group (p<0.05), with statistically significant advantages also seen in partial Mayo score response and endoscopic improvement at week 8. Fiber supplementation did not meaningfully improve these endpoints, though interpretation is complicated by the loss of three FMT-plus-fiber patients to follow-up before week 8, and the trial itself was terminated early due to manufacturer discontinuation of the FMT product. Importantly, the microbiomes of all FMT recipients — both responders and non-responders — shifted significantly toward donor composition by week 4. However, only responders sustained this shift durably through week 12. Taxa enriched in durable responders included Bacteroides spp., Alistipes spp., and Faecalibacterium spp., consistent with findings in prior FMT trials for UC.

A critical finding was the striking donor-dependent variability in clinical outcomes. Donor 1, whose microbiome had the highest Shannon diversity and was characterized by a Ruminococcaceae-enriched enterotype, produced the highest rate of clinical response and the most durable shift in recipient microbiome composition. Donors 2 and 3 displayed features of the inflammatory Bact2 enterotype (high Bacteroides, low Faecalibacterium and Akkermansia, low diversity) and were associated with inferior outcomes. Strain-level tracking confirmed that donor 1 also achieved higher rates of successful strain engraftment. Engraftment success correlated inversely with recipient baseline diversity and positively with donor diversity — suggesting that dysbiotic recipients may paradoxically be more permissive to engraftment, while richer donor preparations transfer more robustly. Psyllium fiber supplementation was associated with engraftment of a distinct bacterial consortium, supporting the concept that prebiotic fiber can selectively shape which strains take hold.

These findings carry important implications for FMT design and personalized microbiome therapy. The data argue strongly for rigorous donor selection criteria — prioritizing high-diversity, Ruminococcaceae-enriched donors over those with Bact2-type profiles. The identification of specific engrafted strains associated with response offers a roadmap for developing defined bacterial consortia as next-generation therapies. While fiber did not improve clinical outcomes here, its ability to shape engraftment at the strain level supports further investigation of prebiotic priming in larger, adequately powered trials.