Hydrolyzed wheat gluten alleviates deoxynivalenol-induced intestinal injury by promoting intestinal stem cell proliferation and differentiation via upregulation of Wnt/β-catenin signaling in mice
Graphical abstract
Proposed mechanism by which HWG regulates ISCs during intestinal epithelium repair postinjury induced by DON.DON-induced the disruption of the intestinal epithelial integrity by reducing Wnt/β-catenin signaling activity, which leads to the inhibition of proliferation and differentiation of ISCs, thereby impairing the intestinal structure and function. HWG blocks this process, leading to a reduction in ISC injury and preservation of intestinal homeostasis.
Introduction
The integrity of intestinal epithelium is a crucial defense against bacteria and viruses living in the environment, as well as natural toxins occurring in food and feed (Sartor and Wu, 2017; Vignal et al., 2018). The maintenance of intestinal homeostasis depends on the continuous proliferation and differentiation of Lgr5-positive intestinal stem cells (ISCs), which are interspersed between terminally differentiated Paneth cells and located at the lower third of the crypts with a highly dynamic niche (Snippert et al., 2010). The Paneth cell-derived niche supplies ISCs with essential pro-proliferative and differentiative factors that include Wnts; thus, the activity of ISCs is tightly controlled by the Wnt/β-catenin pathway (Krausova and Korinek, 2012; Sato et al., 2011). Additionally, β-catenin accumulates in the cell cytoplasm and enters the nucleus, where it displaces the Groucho from TCF/LEF transcription factors, and TCF/LEF-β-catenin complexes thus act as bipartite transcriptional activators of specific target genes such as Lgr5 (Kretzschmar and Clevers, 2017).
Deoxynivalenol (DON), a Fusarium metabolite, mainly contaminates cereal-based food and feed worldwide (Rodríguez-Carrasco et al., 2014). DON is considered an important food safety issue since it is an extremely prevalent mycotoxin (Streit et al., 2013). Since DON mainly enters the body via the oral route, the intestinal epithelium is one of the primary targets following dietary DON exposure, which can cause the destruction of intestinal architecture, a decrease in trans-epithelial electrical resistance, modulation of the opening of tight junctions, an increase in intestinal permeability and bacterial translocation, reduced goblet cell density and β-defensin production, and alteration in the intestinal cell proliferative and apoptotic index (Akbari et al., 2014; Cheat et al., 2016; Gerez et al., 2015; Ghareeb et al., 2015; Li et al., 2019; Park et al., 2017; Springler et al., 2016; Wang et al., 2014). In addition, DON exposure may be associated with allergies (Akbari et al., 2017). However, whether DON exposure causes disintegration of intestinal epithelial integrity by changing the fate of ISC proliferation and differentiation in a Wnt/β-catenin-dependent manner remains unclear. Therefore, it will be of great significance to conduct further investigations into the mechanism of DON-induced intestinal toxicity.
Nutritional intervention for intestinal injury is emphasized by the enormous harm of DON to human and animal health. Hydrolyzed wheat gluten (HWG), obtained by enzymatic hydrolysis of wheat gluten and purified by molecular size or electric charge, exhibits immunity-strengthening properties in healthy human subjects, prevents diarrhea and promotes growth (Han et al., 2017; Horiguchi et al., 2005; Wang et al., 2011). Consequently, HWG is widely used as a practical, natural, functional food to improve the health of humans due to its glutamate, glutamine and a variety of biologically active-wheat peptides (Wang et al., 2007).
Considering the beneficial effects of HWG as a nutritional fortifier and its role in the protection of the anti-diarrhea function, we hypothesized that HWG could prevent DON-induced disruption of intestinal integrity. This is the first study to find the that the preventive effects of HWG against DON-induced intestinal epithelial injury in mice depend on promoting the proliferation and differentiation of ISCs by activating Wnt/β-catenin signaling and enhancing intestinal barrier function.
Section snippets
Chemicals and reagents
HWG was provided by Zhengzhou Newwill Nutrition Technology Co., Ltd. (China) and the ingredient composition of the HWG (Table 1) was described by Wang et al. (2011). Physiological saline was used to dissolve the HWG, and the final concentration used was equivalent to a gavage administration of 1000 and 2000 mg/kg body weight (BW).
The purified DON (MW: 296.32) was purchased from Sigma-Aldrich (St. Louis, MO, USA) and dissolved in physiological saline, the final concentration was 2 mg/kg BW. In
HWG increases the weight gain and water intake of mice exposed to DON
To investigate the effect of HWG on mice with DON poisoning, weight gain, feed intake and water intake were monitored during the experiment. The experimental procedure is shown in Fig. 1a, compared with the CON group, the average daily gain (ADG) of mice in DON group was decreased significantly; however, compared with the DON group, HWG significantly increased the ADG and average water intake (ADWI) of mice (P < 0.05) (Fig. 1b and c) but had no effect on the average daily feed intake (ADFI)
Discussion
An important function of the intestinal epithelium is to digest and absorb nutrients to provide the necessary energy for the body. Dietary exposure to DON has been shown to reduce feed intake and weight gain (Dänicke et al., 2012; Pestka and Smolinski, 2005). In the present study, The ADG, not the ADFI, was negatively affected by the given dose of DON; thus, it is not difficult to suggest that DON might decrease the absorption and utilization of nutrients in the intestine. Marc et al. (2002)
Acknowledgments
The authors are thankful to Zhengzhou Newwill Nutrition Technology Co., Ltd. for providing us with hydrolyzed wheat gluten, and Nikon for providing us with laser confocal for free.
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Present/permanent address:College of Animal Science, South China Agricultural University.