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. 2025 Jul 24;188(15):3927-3941.e13.
doi: 10.1016/j.cell.2025.05.014. Epub 2025 Jun 6.

Microbiome mismatches from microbiota transplants lead to persistent off-target metabolic and immunomodulatory effects

Orlando DeLeon  1 , Mora Mocanu  1 , Alan Tan  1 , Ashley M Sidebottom  2 , Jason Koval  1 , Hugo D Ceccato  1 , Sarah Kralicek  3 , John J Colgan  1 , Marissa M St George  1 , Joash M Lake  1 , Michael Cooper  1 , Jingwen Xu  1 , Julia Moore  3 , Qi Su  4 , Zhilu Xu  4 , Siew C Ng  5 , Francis K L Chan  4 , Hein M Tun  4 , Candace M Cham  1 , Cambrian Y Liu  1 , David T Rubin  1 , Kristina Martinez-Guryn  6 , Eugene B Chang  7
Affiliations

Microbiome mismatches from microbiota transplants lead to persistent off-target metabolic and immunomodulatory effects

Orlando DeLeon et al. Cell. .

Abstract

Fecal microbiota transplant (FMT) is an increasingly used intervention, but its suitability to restore regional gut microbiota, particularly in the small bowel (SB), must be questioned because of its predominant anaerobic composition. In human subjects receiving FMT by upper endoscopy, duodenal engraftment of anaerobes was observed after 4 weeks. We hypothesized that peroral FMTs create host-microbe mismatches that impact SB homeostasis. To test this, antibiotic-treated specific-pathogen-free (SPF) mice were given jejunal, cecal, or fecal microbiota transplants (JMTs, CMTs, or FMTs, respectively) and studied 1 or 3 months later. JMT and FMT altered regional microbiota membership and function, energy balance, and intestinal and hepatic transcriptomes; JMT favored host metabolic pathways and FMT favored immune pathways. MTs drove regional intestinal identity (Gata4, Gata6, and Satb2) and downstream differentiation markers. RNA sequencing (RNA-seq) of metabolite-exposed human enteroids and duodenal biopsies post-FMT confirmed transcriptional changes in mice. Thus, regional microbial mismatches after FMTs can lead to unintended consequences and require rethinking of microbiome-based interventions.

Keywords: FMT; engraftment; intestine; jejunum; metabolism; microbiome; mucosa; regional ecosystem; regional mismatch; small bowel microbiota.

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Conflict of interest statement

Declaration of interests The authors declare no competing interests.

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