Author’s Reply: “Oral Butyrate in IBD: From enterotype stratification to a multi-omic and long-term clinical dialogue”

We appreciate the constructive commentary from authors Yan An and Pengfei E, who raise important points regarding temporal stability of enterotypes, mechanistic pathways, and long-term clinical outcomes [ 1 ].The temporal stability of enterotype classification represents a methodologically relevant aspect.IBD is characterized by a fluctuating clinical course, which may drive dynamic changes in the composition of the gut microbiota.In the present study and similarly in our pilot investigation, baseline enterotype classification at a single time point provided a pragmatic stratification approach that is applicable in clinical practice [ 2 , 3 ].However, we acknowledge that serial longitudinal assessments would allow a more accurate characterization of microbial dynamics over time.In this context, future studies-currently under evaluation by the Ethics Committee-will incorporate shotgun metagenomic approaches, enabling in-depth analysis of metabolic pathways and strain-level characterization of microorganisms, thereby supporting a more precise functional definition of microbial profiles associated with treatment response.As highlighted by the Authors, butyrate administration was associated with a significant reduction in potential pathobionts and an increase in short-chain fatty acid (SCFA)-producing microorganisms, specifically in patients with CD-Enterotype 1.This pattern supports the hypothesis that butyrate may act as a true "microbial landscape architect"; never has this definition appeared more appropriate, as our data confirm its osmoregulatory capacity and its ability to remodel the colonic microbial ecosystem [ 4 , 5 ].However, distinguishing direct epithelial effects from microbiota-mediated effects remains challenging without integrated multi-omics data.Unfortunately, a substantial proportion of the samples were collected during the COVID-19 pandemic, when, due to logistical and organizational constraints at our research center, it was not possible to preserve fecal material suitable for metagenomic and metabolomic analyses [ 6 , 7 ].We fully support the recommendation to incorporate shotgun metagenomics and targeted metabolomics in future studies to address this mechanistic question.The suggestion to evaluate BLM as an adjunct to biologic therapy is particularly compelling.Given the observed effects on gut barrier function and microbiota composition, butyrate supplementation could potentially enhance biologic efficacy or delay loss of response [8][9][10].We are currently designing follow-up studies to explore this synergistic approach, with endpoints including