Zingiber officinale and Panax ginseng ameliorate ulcerative colitis in mice via modulating gut microbiota and its metabolites
Introduction
Ulcerative colitis (UC), a chronic non-specific inflammatory disease, is characterized by the damage of the colonic mucosa and its symptoms contain unintentional weight loss, abdominal pain, and bloody diarrhea [1]. Because of its recurrence and long course, UC has been considered one of the hardest diseases to control and treat [2]. Even worse, the global incidence of UC is rising rapidly, and it has become a major public health problem worldwide. Currently, the aminosalicylic acid preparations, corticosteroids and immunosuppressants are conventionally used for the treatment of UC [3]. Yet, they have severe side effects and bring a huge economic burden on both patients and their families. Recently, traditional Chinese medicines (TCMs), as alternative medicines for the treatment of UC, are increasingly favored by the general public owing to their safety, low toxicity, and effectiveness [4].
The combination of Zingiber officinale and Panax ginseng has been used as a classic herb pair in TCM prescriptions for thousands of years. Importantly, the herb pair consisting of Zingiber officinale and Panax ginseng (ZP) was widely utilized in the traditional Chinese formulae such as Lizhong Decoction, Banxia Xiexin Decoction, and Wumei Pill for the prevention and treatment of UC in the clinical practices [5], [6], [7]. As the basic complicated unit of Chinese herbal formulas, herb pairs are much simpler than complex multi-herb prescriptions, while retaining basic therapeutic features [8]. Hence, the research on herb pairs will contribute to reveal the synergistic mechanism and scientific connotation of the clinical efficacy in complicated pharmacological formulas. Zingiber officinale Ros. (ZO), which belongs to the family of Zingiberaceae, is a native plant in Southeast Asia. Notably, ZO is often used as spice and medicine owing to the effect of warm-up [9]. Modern medical research show that ZO has the potential to ameliorate gastrointestinal conditions, cardiovascular disorders, vomiting and cancer, which is mainly due to its multiple pharmacological activities such as anti-inflammation, antitumor, antioxidation, and antibiosis [10]. Furthermore, Panax ginseng C. A. Mey. (PG) is one of the most famous medicinal plants worldwide, which has powerful properties including anti-inflammation, antiulcer, antioxidation and immunity enhancement [11]. Indeed, the combination of ZO and PG is widely used in the clinical treatment of gastrointestinal diseases. Previous studies indicated that the active ingredients in ZO and PG could significantly alleviate dextran sulfate sodium (DSS) induced colitis in mice [12], [13]. However, the potential mechanism of ZO-PG herb pair on the therapy of UC has not been fully revealed.
Thus far, the pathogenesis of UC remains poorly understood, various studies suggest that the dysbiosis of symbiotic flora and disorder of metabolism contribute to the development of UC [14]. It is well known that the gastrointestinal tract is the habitat of the largest bacterial population [15]. The homeostasis of gut microflora is essential for maintaining gastrointestinal health. Previous studies reported that the composition of the gut microbiome was notably altered in patients with UC and experimental colitis mice (such as the increased level of Bacteroidetes and decreased level of Firmicutes) [16], [17]. Nonetheless, to fully realize the function of gut flora, it is not enough to understand the composition of the microbial community. The metabolic activity of gut flora is also a key factor in maintaining host-microbial homeostasis [18]. Especially, the disturbance of the intestinal microbiota can lead to the dysregulation of numerous microbiota-derived metabolites and secreted proteins (such as bile acids, short-chain fatty acids and tryptophan derivatives). These metabolites are considered to prevent or promote the pathogenesis and progression of UC [19]. Thus, it is suggested that the regulation of gut microbiota and its metabolism provides a new perspective for the treatment of UC.
With the reduction of sequencing cost and the maturity of data analysis methods, 16S rRNA sequencing is gradually becoming an important method for the study of gut microbiome due to its advantages of obtaining more information, but it cannot describe metabolic potential or activity of the microbial community [20]. However, ultra-high-performance liquid chromatography coupled with quadrupole time-of-flight mass spectrometry (UPLC-Q-TOF-MS/MS) based untargeted metabolomics can sensitively monitor changes of small molecule metabolites to make up for a deficiency in 16S rRNA sequencing [21]. Therefore, through the integrated analysis of microbiome and metabolomics, this study would provide a scientific basis for further clarifying the synergistic mechanism of ZP herb pair in the clinical treatment of UC.
Section snippets
Chemicals and reagents
Zingiber officinale Ros. (Batch NO. 200821) and Panax ginseng C. A. Mey. (Batch NO. 200901) were purchased from Nanjing Yifeng Pharm. Co., Ltd. (Nanjing, China), which complied with Chinese Pharmacopoeia Commission (2015). DSS was bought from MP Biomedicals (molecular mass 36,000–50,000 Da, Santa Ana, CA, USA). Sulfasalazine (SASP) was supplied by Xinyi Pharmaceutical, Ltd. (Shanghai, China). Acetonitrile, methanol and formic acid (Merck, Germany) were of HPLC-grade; ultrapure water was
Amelioration of combined herbs on DSS-induced colitis
In this study, DSS-induced UC mouse model was established and successfully applied to investigate the respective and combined therapeutic effects of ZO and PG. The typical clinical features of colitis in mice were observed during the induction process of UC, including weak movements, lost weight, and diarrhea. Moreover, after giving DSS aqueous solution, slight hematochezia appeared on the 4th day and severe hematochezia was present in the 7th day from feces of mice, while oral administration
Discussion
Ulcerative colitis is a complex intestinal inflammation characterized by persistent, relapsing, and non-specific ulceration of the bowel, which almost affects the population-health of approximate 4 million people worldwide [31]. However, there are no effective drugs to cure the disease due to the diversity of pathogenesis and the complexity of pathological process of UC. Fortunately, TCMs, which are widely used in China and many other Asian countries, may provide another option for the patients
Conclusions
Taken together, ZO and PG are usually used in combination to treat UC, but the potential mechanism of treatment with UC remains ambiguous. Our findings suggested that ZO, PG and ZP exhibited a protective effect against DSS-induced UC through alleviating mucosal damage and colonic inflammation in mice. Majorly, gut microbiota and its metabolic activities of UC mice were analyzed by using 16S rRNA gene sequencing combined with UPLC-Q-TOF-MS/MS metabolomics technology, which showed that ZO, PG and
Declaration of Competing Interest
The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper.
Acknowledgements
This work was financially supported by Jiangsu Collaborative Innovation Center of Chinese Medicinal Resources Industrialization (No.ZDXM-3-9).
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