Andrographolide Exerts Antihyperglycemic Effect through Strengthening Intestinal Barrier Function and Increasing Microbial Composition of Akkermansia muciniphila

Abstract

Accumulating evidence indicates that type 2 diabetes (T2D) is associated with intestinal barrier dysfunction and dysbiosis, implying the potential targets for T2D therapeutics. Andrographolide was reported to have several beneficial effects on diabetes and its associated complications. However, the protective role of andrographolide, as well as its underlying mechanism against T2D, remains elusive. Herein, we reported that andrographolide enhanced intestinal barrier integrity in LPS-induced Caco-2 cells as indicated by the improvement of cell monolayer barrier permeability and upregulation of tight junction protein expression. In addition, andrographolide alleviated LPS-induced oxidative stress by preventing ROS and superoxide anion radical overproduction and reversing glutathione depletion. In line with the in vitro results, andrographolide reduced metabolic endotoxemia and strengthened gut barrier integrity in db/db diabetic mice. We also found that andrographolide appeared to ameliorate glucose intolerance and insulin resistance and attenuated diabetes-associated redox disturbance and inflammation. Furthermore, our results indicated that andrographolide modified gut microbiota composition as indicated by elevated Bacteroidetes/Firmicutes ratio, enriched microbial species of Akkermansia muciniphila, and increased SCFAs level. Taken together, this study demonstrated that andrographolide exerted a glucose-lowering effect through strengthening intestinal barrier function and increasing the microbial species of A. muciniphila, which illuminates a plausible approach to prevent T2D by regulating gut barrier integrity and shaping intestinal microbiota composition.

Protein quality and quantity influence the effect of dietary fat on weight gain and tissue partitioning via host-microbiota changes

“…Moreover, many other metabolites linked to ROS production and apoptosis (Chao et al, 2019) (3,5-DMA [3,5-Dimethylaniline]), and liver cirrhosis (pipecolinic acid, a metabolite of lysine) (Kawasaki et al, 1988), were reduced (Figure S6D), whereas the levels of medium-chain dicarboxylic acids (MCDAs) were increased in WPI relative to CAS (Figure S6D). Azelaic acid possesses anti-in-flammatory properties, suberic and sebacic acids are microbial metabolites formed from breakdown of oleic and linoleic FAs, and andrographolide is a known promoter of growth of A. muciniphila (Su et al, 2020), as seen in WPI-fed animals. Along with upregulation of microbial FA biosynthesis pathways, 30% WPI groups, with their potential to bind dietary fat, had increased fecal TAGs relative to CAS at 55% fat (Figure S6E).…”

Dietary sophorolipid accelerates growth by modulation of gut microbiota population and intestinal environments in broiler chickens

“…At species level, Akkermansia muciniphila, has received attention because of its specific biological properties including immune modulation, wound healing, and SCFA production [32]. Moreover, various studies have demonstrated that A. muciniphila has the potential to act as a probiotic because it could exert a glucose-lowering effect by regulating gut barrier integrity through increased expression levels of tight junction proteins [33,34]. Similar to the results of these studies, we also found an increased population of A. muciniphila and strengthened gut epithelial integrity and mucus secretion capacity.…”

Andrographolide: A review of its pharmacology, pharmacokinetics, toxicity and clinical trials and pharmaceutical researches

“…As an extremely interesting multitarget diterpenoid lactones, in recent years, andrographolide has attracted considerable number of interests in the medicinal chemistry society with its potential multiple pharmacological activities such as antiinflammatory (Ding et al, 2017), antioxidant (Mussard et al, 2019; Zhang et al, 2020), anticancer (Farooqi et al, 2020; Sato et al, 2018; Zhang et al, 2017), antimicrobial (Gupta, Mishra, & Ganju, 2017; Panraksa, Ramphan, Khongwichit, & Smith, 2017; Shi et al, 2020; Srivastava, Garg, Srivastava, & Seth, 2021), antihyperglycemic (Su et al, 2020) and regulating blood lipid (Lin et al, 2018), immunoregulation (Zhang, Yang, Du, & Guo, 2020), improving memory impairment (Das, Mishra, Ganju, & Singh, 2017), as well as mitigating cartilage damage (Chen, Luo, & Chen, 2020) and so on (Figure 2). In view of the increasing awareness of the side effects of chemotherapy drugs, this medicinal ingredient may serve as one of the backbones for the treatment of related diseases in the future.…”