Mucosal microbiota and gene expression are associated with long-term remission after discontinuation of adalimumab in ulcerative colitis

Toshiharu Sakurai,Hiroshi Kashida,Masatoshi Kudo,Hiroki Nishiyama,Marco A De Velasco,Kazuko Sakai,Akiyoshi Okada,Yoriaki Komeda,Isao Kawai,Tomoyuki Nagai,Hiroyuki Ogata,Kazuto Nishio

doi:10.1038/s41598-020-76175-2

Toshiharu Sakurai, Hiroshi Kashida + Show 10 more

Open Access

https://doi.org/10.1038/s41598-020-76175-2

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Abstract

Given that sustained remission is the ultimate treatment goal in the management of patients with ulcerative colitis (UC), the decision to stop anti-tumor necrosis factor (anti-TNF) treatment in UC patients is difficult. The aim of this study was to evaluate mucosal microbiota and gene expression profiles associated with long-term remission after discontinuation of anti-TNF therapy. In nine UC patients who received anti-TNF therapy for 6 months, microbiota isolated from uninflamed mucosae and gene expression in inflamed and uninflamed mucosae were investigated at week 0 and at week 24. At treatment initiation, Fusobacterium sp. and Veillonella dispar were over-represented in the relapse group compared with the non-relapse group. After treatment, Dorea sp. and Lachnospira sp. were over-represented in the non-relapse group. In the relapse group only, a significant shift in gut bacterial community composition was found between week 0 and week 24. Gene expression of ALIX (PDCD6IP) and SLC9A3 was significantly higher in the non-relapse group than in the relapse group. Lastly, we used machine learning methods to identify relevant gene signatures associated with sustained remission. Statistical analyses of microbiota and expression profiles revealed differences between UC patients who did or did not keep remission after the discontinuation of TNF inhibitors.Trial registration: UMIN000020785: Evaluation of adalimumab therapy in mesalazine-resistant or -intolerant ulcerative colitis; an observational study (EARLY study).

Highlights

Given that sustained remission is the ultimate treatment goal in the management of patients with ulcerative colitis (UC), the decision to stop anti-tumor necrosis factor treatment in UC patients is difficult
Factors associated with risk of relapse after discontinuation of anti-TNF therapy include the absence of mucosal healing, the lack of immunosuppressant maintenance treatment after anti-TNF is stopped, younger age, and the discontinuation of anti-TNF inhibitors due to adverse events[9,17]
Two out of the three operational taxonomic units (OTUs) that were over-represented in the relapse group at treatment baseline (Fig. 2A) were potentially pro-inflammatory: Fusobacterium sp. and Veillonella dispar

Summary

Introduction

Given that sustained remission is the ultimate treatment goal in the management of patients with ulcerative colitis (UC), the decision to stop anti-tumor necrosis factor (anti-TNF) treatment in UC patients is difficult. The aim of this study was to evaluate mucosal microbiota and gene expression profiles associated with long-term remission after discontinuation of anti-TNF therapy. Patients who achieve remission with anti-TNF agents are often treated for many years if they are able tolerate the treatment. A major burden experienced by IBD patients is that the disease follows a relapsing–remitting course over many years In this pilot study, we treated mesalazine-resistant or -intolerant UC patients with TNF inhibitors for 6 months and examined the gut mucosal microbiota and gene expression levels at week 0 and week 24 of anti-TNF therapy to explore factors related to long-term remission after withdrawal of TNF inhibitors. We applied machine learning to whole transcriptome data to develop a proof of concept model that could identify UC patients with long-term remission after discontinuation of anti-TNF therapy

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