Ulcerative colitis (UC) is a chronic inflammatory bowel disease in which recurrent intestinal inflammation can be difficult to control over the long term. Current treatments include 5-aminosalicylic acid (5-ASA), corticosteroids, immunomodulators, biologics, and small-molecule therapies, but drug resistance and adverse effects remain important clinical concerns. A key feature of UC is disrupted cluster of differentiation 4-positive (CD4+) T-cell homeostasis, including excessive T helper 1 (Th1) and T helper 17 (Th17) responses and insufficient regulatory activity. Hudi enteric-coated capsule (HDEC) has been used for gastrointestinal disorders, while polydatin has shown anti-inflammatory potential, yet earlier work relied mainly on chemically induced acute colitis models and left its immune mechanism unresolved. Based on these challenges, deeper investigation is needed into how HDEC and polydatin regulate intestinal T-cell immunity in chronic colitis.

Researchers from the First Affiliated Hospital of Henan Medical University, Affiliated Suzhou Hospital of Nanjing Medical University, Dongfang Hospital of Beijing University of Chinese Medicine, Shanghai Tenth People's Hospital, Tongji University School of Medicine, and collaborating institutions reported (DOI: 10.1093/pcmedi/pbag018) the study in Precision Clinical Medicine on July 3, 2026. The team investigated HDEC and polydatin using immune-driven mouse colitis models, mouse and human CD4+ T cells, UC mucosal samples, transcriptomic and protein analyses, and molecular interaction assays, aiming to explain how the treatment suppresses pathogenic T-cell inflammation and restores intestinal immune balance.

The researchers first established chronic colitis by transferring CD45RBhigh CD4+ T (Treg) cells into immunodeficient mice, then treated animals with HDEC or polydatin. Both interventions eased weight loss, disease activity, colon shortening, and histological damage, while reducing inflammatory Th1- and Th17-associated responses. Screening major HDEC constituents identified polydatin as the strongest inhibitor of Th1 and Th17 differentiation. A dose-ranging experiment showed that 45 mg/kg achieved efficacy comparable to 90 mg/kg, with no liver-toxicity signal in serum enzyme measurements. RNA sequencing then pointed to NFE2L2 signaling: polydatin increased NFE2L2-associated antioxidant activity and lowered intracellular reactive oxygen species (ROS). When NFE2L2 was blocked pharmacologically with ML385 or reduced using ribonucleic acid interference (RNAi), polydatin largely lost its ability to suppress Th1 and Th17 cells, promote Treg differentiation, and control oxidative stress, showing that the pathway is functionally required. The mechanism was then carried into human systems. Polydatin increased NFE2L2 nuclear accumulation in CD4+ T cells from healthy donors and patients with active UC, as well as in UC intestinal mucosal samples. Finally, surface plasmon resonance (SPR), molecular docking, and molecular dynamics simulations supported direct, stable binding between polydatin and Kelch-like ECH-associated protein 1 (KEAP1), providing a molecular explanation for NFE2L2 activation.

The authors said the findings connect a defined natural compound with a specific molecular target and an immune pathway that is central to intestinal inflammation. Rather than showing only that HDEC or polydatin can reduce colitis, they said the study explains how polydatin may release NFE2L2 from KEAP1 control, reduce oxidative stress, and shift CD4+ T-cell differentiation away from inflammatory Th1 and Th17 states toward a more regulatory profile. This mechanistic link, they said, helps clarify the pharmacological basis of HDEC and gives polydatin a clearer path for further translational evaluation.

The findings position polydatin as a candidate for further development as a KEAP1-targeting approach to UC, while also offering a mechanistic framework for evaluating HDEC beyond traditional use. Because the work combines chronic immune-driven colitis models with human peripheral and intestinal immune cells, it provides a stronger translational bridge than acute chemical models alone. However, the study remains preclinical. The authors report that clinical sample sizes were limited, Treg stability and possible Th17-to-Treg conversion require further study, and key pharmacokinetic questions—including oral bioavailability, intestinal distribution, in vivo stability, and dose-response relationships—remain unresolved. Larger human studies and rigorous clinical trials will be needed to establish long-term safety, dosing, and therapeutic efficacy.

Source:

Journal reference:

Wu, X., et al. (2026). Hudi enteric-coated capsule and its active constituent polydatin suppress Th1/Th17-mediated intestinal inflammation by modulating the KEAP1-NFE2L2 signaling pathway. Precision Clinical Medicine. DOI: 10.1093/pcmedi/pbag018. https://academic.oup.com/pcm/article/9/3/pbag018/8724111