Probiotic-drug co-delivery system enhances sulfasalazine activation for inflammatory bowel disease therapy

Sep 29, 2026

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Inflammatory bowel disease (IBD) affects millions and involves mucosal inflammation alongside gut microbiota dysbiosis. Sulfasalazine (SSZ), a prodrug of 5-aminosalicylic acid (5-ASA), is used clinically but shows limited efficacy because azo-bond cleavage is inefficient, mainly due to insufficient intestinal azo reductase activity. Clostridium butyricum (CB) possesses azo reductase activity and can convert SSZ into 5-ASA. A dual pH/enzyme responsive system (CBs/SSZ/CS/EudS-100) encapsulates SSZ-loaded CB spores with chitosan and Eudragit S100 for colonic release. CB germination drives 5-ASA generation to reduce inflammation, repairs the intestinal barrier, and also reshapes gut microbiota to provide combined probiotic-pharmacotherapy for IBD.

LanguageEnglish

CategoryHealthcare

FormatPDF

Pages14

Reading Time35 min

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Introduction

Inflammatory bowel disease and associated dysbiosis

Sulfasalazine activation and limitations of azo reductase

Rationale for a colon-targeted co-delivery strategy

Clostridium butyricum as an azo reductase-active probiotic

Materials Today Bio 36 (2026) 102669 Contents lists available at ScienceDirect Materials Today Bio journal [homepage:](homepage: www.journals.elsevier.com/materials-today-bio)[ www.journals.elsevier.com/materials-today-bio](homepage: www.journals.elsevier.com/materials-today-bio) | Probiotic-drug co-delivery system enhances sulfasalazine activation for inflammatory bowel disease therapy
Luo Zhao a,b,1, Xinxin Liu a,b,1, Fangfang Wang a,b, Mengya Niua,b, Zilin Maa,b, Ziqing Wang a,b, Yange Du a,b, Shuang Gong a,b, Yuanyuan Li c, Qingling Song a,b,*, Yun Zhang a,b,** , Lei Wang a,b,c,d,***
a School of Pharmaceutical Sciences, Zhengzhou University, Zhengzhou, 450001, China
b Henan Key Laboratory of Nanomedicine for Targeting Diagnosis and Treatment, Zhengzhou, 450001, China c Tumor Immunity and Biomaterials Advanced Medical Center, Zhengzhou University, Luoyang, 471009, China d Tianjian Laboratory of Advanced Biomedical Sciences, Zhengzhou University, 450001, China | | | | --- | --- | --- | | A R T I C L E I N F O | | A B S T R A C T | | Keywords:
Inflammatory bowel disease Sulfasalazine Azo reductase
Clostridium butyricum Gut microbiota | | Inflammatory bowel disease (IBD), affecting millions of patients worldwide, is associated with mucosal inflammation and gut microbiota dysbiosis. As a prodrug of 5-aminosalicylic acid (5-ASA), sulfasalazine (SSZ) is a first-line medication for IBD. However, SSZ exhibits limited clinical efficacy due to its nonspecific systemic distribution and the inefficient cleavage of the azo bond, which results from inadequate azo reductase (AR) activity. Intriguingly, we found that Clostridium butyricum (CB) possess AR activity and can metabolize SSZ into 5-ASA. Here, we develop a pH and enzyme dual-responsive drug delivery system CBs/SSZ/CS/EudS-100 by encapsulating the SSZ-loaded Clostridium butyricum spore (CBs) with chitosan (CS) and Eudragit S100 (EudS- 100). After oral administration, it is identified that the CS and EudS-100 coating enables the colonic release of SSZ. On the one hand, CBs germinates into CB, which facilitates the conversion of SSZ to 5-ASA, relieving inflammation and repairing intestinal barrier. On the other hand, CB modulates the disordered gut microbiota. This provides a new strategy for integrating probiotic therapy with pharmacological treatment in the management of IBD. | 1. Introduction Inflammatory bowel disease (IBD), including ulcerative colitis (UC) and Crohn’s disease (CD), is a chronic relapsing autoimmune disorder characterized by diffuse mucosal inflammation, epithelial barrier dysfunction, and dysbiosis [1]. This persistent inflammatory response not only profoundly impairs patients’ quality of life but also substantially elevates the risk of colorectal cancer development [2]. Sulfasalazine (SSZ), a prodrug of 5-aminosalicylic acid (5-ASA) with sound anti-inflammatory effects, is a first-line medication for IBD [3]. This kind of azo-linked 5-ASA prodrugs exerts its therapeutic activity primarily through the reductive cleavage of the azo bond by colonic azo reductase (AR), thereby releasing active 5-ASA at the target site [4,5]. The efficient functioning ofSSZ depends on the shear ofAR produced by the gut microbiota as well as on the contact duration with microbiota. However, the AR within the intestinal microbiota is functionally diverse but generally present at low levels, which limits their capacity to efficiently cleave SSZ [6]. Previous studies have demonstrated that sequential oral administration of a probiotic mixture and SSZ significantly increased the AR activity in the intestinal contents, but did not prolong the residence time of SSZ in the colon [7]. Zhang et al. further loaded the 5-ASA azo prodrug balsalazide onto the surface of Lactobacillus rhamnosus GG (LGG), which facilitated enhanced colonic delivery and prolonged retention of balsalazide. However, the delivery of LGG did not lead to an increase in intestinal AR a

FAQs

Why is sulfasalazine activation limited in inflammatory bowel disease therapy?

Sulfasalazine is a prodrug that requires colonic azo reductase to cleave its azo bond into 5-ASA. Limited clinical efficacy arises from nonspecific systemic distribution and inefficient azo-bond cleavage caused by inadequate azo reductase activity in the gut.

How does Clostridium butyricum contribute to sulfasalazine conversion?

Clostridium butyricum is reported to possess azo reductase activity and can metabolize sulfasalazine into 5-ASA, thereby supporting anti-inflammatory effects and intestinal barrier repair.

What is the role of the dual-responsive CBs/SSZ/CS/EudS-100 delivery system?

The CS and EudS-100 coatings enable colonic release after oral administration. The system then supports CB spore germination, promoting SSZ-to-5-ASA conversion while CB also modulates dysordered gut microbiota for improved IBD management.

Sep 29, 2026

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