Work

Longitudinal Metaproteomic and Lysine Crotonylation Remodeling Defines Clinical Response to Fecal Microbiota Transplantation in Ulcerative Colitis

Year: 2026

Type: preprint

Abstract: ABSTRACT Background Fecal microbiota transplantation (FMT) can induce steroid-free clinical remission in a subset of patients with ulcerative colitis (UC), but treatment responses remain heterogeneous and are not fully explained by taxonomic microbiome shifts. To define functional molecular features associated with FMT efficacy, we performed integrated longitudinal fecal metaproteomic and lysine crotonylation (Kcr) profiling. Methods We analyzed 87 fecal samples from 23 patients with active UC collected at baseline and at weeks 1, 8, and 12 after FMT. Patients were classified as responders (n = 13) or non-responders (n = 10) according to steroid-free clinical remission at week 12. Across samples, we identified an average of 3,682 proteins and 562 Kcr sites per sample. Results Responders showed greater metaproteomic and meta-crotonylomic complexity at week 12, sustained enrichment of Prevotella and Faecalibacterium , and eight directionally consistent baseline-altered proteins with candidate prognostic value. After FMT, responders exhibited coordinated microbial functional remodeling, including increased proteins involved in short-chain fatty acid (SCFA) metabolism, acyl-CoA-centered pathways, nutrient transport, and polysaccharide degradation, together with attenuation of host neutrophil-related inflammatory protein and Kcr signatures. Non-responders showed minimal or opposing molecular changes. Conclusions These findings nominate longitudinal fecal metaproteomic and Kcr remodeling as functional molecular readouts of clinical response to FMT in UC and highlight lysine crotonylation as an underexplored metabolite-sensitive layer linking microbial metabolic restoration with host inflammatory resolution. Importance Fecal microbiota transplantation can send ulcerative colitis into remission, yet clinicians have no reliable way to predict who will respond. By tracking 23 patients for 12 weeks, researchers show that stool proteins and a chemical mark called lysine crotonylation reveal the answer. Future responders carried distinct baseline protein signatures, and after treatment their gut microbes restarted key metabolic engines—short-chain fatty acid and acyl-CoA pathways—while host neutrophil inflammation quieted down. Non-responders lacked this coordinated rebound. The work delivers a functional molecular toolkit to forecast and monitor transplant success, shifting the focus from cataloging gut bacteria to decoding the real-time dialogue between microbial restoration and immune calm.

Source: bioRxiv (Cold Spring Harbor Laboratory)

DOI: 10.64898/2026.10.13.758943