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Therapeutic effects and mechanisms of isoxanthohumol on DSS-induced colitis: regulating T cell development, restoring gut microbiota, and improving metabolic disorders

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Abstract

Ulcerative colitis (UC) is a severe hazard to human health. Since pathogenesis of UC is still unclear, current therapy for UC treatment is far from optimal. Isoxanthohumol (IXN), a prenylflavonoid from hops and beer, possesses anti-microbial, anti-oxidant, anti-inflammatory, and anti-angiogenic properties. However, the potential effects of IXN on the alleviation of colitis and the action of the mechanism is rarely studied. Here, we found that administration of IXN (60 mg/kg/day, gavage) significantly attenuated dextran sodium sulfate (DSS)-induced colitis, evidenced by reduced DAI scores and histological improvements, as well as suppressed the pro-inflammatory Th17/Th1 cells but promoted the anti-inflammatory Treg cells. Mechanically, oral IXN regulated T cell development, including inhibiting CD4+ T cell proliferation, promoting apoptosis, and regulating Treg/Th17 balance. Furthermore, IXN relieved colitis by restoring gut microbiota disorder and increasing gut microbiota diversity, which was manifested by maintaining the ratio of Firmicutes/Bacteroidetes balance, promoting abundance of Bacteroidetes and Ruminococcus, and suppressing abundance of proteobacteria. At the same time, the untargeted metabolic analysis of serum samples showed that IXN promoted the upregulation of D-( +)-mannose and L-threonine and regulated pyruvate metabolic pathway. Collectively, our findings revealed that IXN could be applied as a functional food component and served as a therapeutic agent for the treatment of UC.

Graphical abstract

Model of IXN ameliorated DSS-induced colitis via regulating T cell development and restoring gut microbiota. Oral IXN could effectively alleviate DSS-induced colitis. Mechanically, IXN restored gut microbiota disorder, increased gut microbiota diversity, altered serum metabolic profile, and regulated Treg/Th17 balance.

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Data availability

The data used and analyzed during the current study are available from the corresponding author upon reasonable request.

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Funding

This study was supported by the Chinese National Natural Science Foundation (Grant Nos. 92268118, 82071396, 82271199), the Fundamental Research Funds for the Central Universities (Grant Nos. GK202201013, GK202305001, GK202202006), the Tian Jia bing Scholar Program, and Graduate pilot training program of Shaanxi Normal University (LHRCCX23171, LHRCYB23003, LHRCCX23194).

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  1. Ya-Na Yang and Bing Han contribute equally to this work.

Authors and Affiliations

  1. Key Laboratory of Medicinal Resources and Natural Pharmaceutical Chemistry (Shaanxi Normal University), The Ministry of Education, College of Life Sciences, Shaanxi Normal University, Xi’an, 710119, Shaanxi, China

    Ya-Na Yang, Bing Han, Mao-Qing Zhang, Na-Nan Chai, Feng-Lin Yu, Wen-Hui Qi, Meng-Yuan Tian, Dong-Zhi Sun, Ying Huang, Qing-Xin Song, Yan Li, Mao-Cui Zhu, Yuan Zhang & Xing Li

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  1. Ya-Na Yang
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Contributions

YZ and XL conceived and designed the experiments. YNY and BH carried out the experiments, analyzed data and wrote the manuscript. MQZ, NNC, FLY, WHQ, MYT, DZS, YH, QXS, YL, and MCZ verified data and proofed the manuscript. All authors read and approved the final manuscript.

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Correspondence to Yuan Zhang or Xing Li.

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The authors declare no conflicts of interest.

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All experimental procedures on mice were carried out in accordance with the standardized guidelines and specifications (No. ECES-2015–0247), which were approved and supported by the Institutional Animal Ethics Committee of Shaanxi Normal University and strict accordance with the guidelines of ARRIVE (https://arriveguidelines.org/).

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Yang, YN., Han, B., Zhang, MQ. et al. Therapeutic effects and mechanisms of isoxanthohumol on DSS-induced colitis: regulating T cell development, restoring gut microbiota, and improving metabolic disorders. Inflammopharmacol 32, 1983–1998 (2024). https://doi.org/10.1007/s10787-024-01472-5

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