Gastric De Novo Muc13 Expression and Spasmolytic Polypeptide-Expressing Metaplasia during Helicobacter heilmannii Infection

Abstract

bHelicobacter heilmannii is a zoonotic bacterium that has been associated with gastric disease in humans. In this study, the mRNA expression of mucins in the stomach of BALB/c mice was analyzed at several time points during a 1-year infection with this bacterium, during which gastric disease progressed in severity. Markers for acid production by parietal cells and mucous metaplasia were also examined. In the first 9 weeks postinfection, the mRNA expression of Muc6 was clearly upregulated in both the antrum and fundus of the stomach of H. heilmannii-infected mice. Interestingly, Muc13 was upregulated already at 1 day postinfection in the fundus of the stomach. Its expression level remained high in the stomach over the course of the infection. This mucin is, however, not expressed in a healthy stomach, and high expression of this mucin has so far only been described in gastric cancer. In the later stages of infection, mRNA expression of H ؉ /K ؉ -ATPase ␣/␤ and KCNQ1 decreased, whereas the expression of Muc4, Tff2, Dmbt1, and polymeric immunoglobulin receptor (pIgR) increased starting at 16 weeks postinfection onwards, suggesting the existence of spasmolytic polypeptide-expressing metaplasia in the fundus of the stomach. Mucous metaplasia present in the mucosa surrounding low-grade mucosa-associated lymphoid tissue (MALT) lymphoma-like lesions was also histologically confirmed. Our findings indicate that H. heilmannii infection causes severe gastric pathologies and alterations in the expression pattern of gastric mucins, such as Muc6 and Muc13, as well as disrupting gastric homeostasis by inducing the loss of parietal cells, resulting in the development of mucous metaplasia.

Divergence between the Highly Virulent Zoonotic Pathogen Helicobacter heilmannii and Its Closest Relative, the Low-Virulence “Helicobacter ailurogastricus” sp. nov

“…A recent study also highlighted the potential role of the gland mucin MUC6 in the early colonization process of H. heilmannii (46). In contrast, the binding of H. ailurogastricus to the surface epithelium is more pronounced, like that of H. pylori (56).…”

“…In contrast, genes encoding homologs of IceA1 and HrgA and a putative jhp0562-like glycosyltransferase are present in the H. heilmannii genomes. H. heilmannii has been associated with a number of different gastric disorders in humans, and the risk of developing mucosa-associated lymphoid tissue (MALT) lymphoma is higher after infection with H. heilmannii than after infection with H. pylori (1,46,47). The biological function of these putative virulence-associated proteins and their exact role in the disease outcome of H. heilmannii infection remain to be investigated.…”

Transmembrane Mucins: Signaling Receptors at the Intersection of Inflammation and Cancer

“…Besides inhibition of apoptosis, MUC13 can influence cell proliferation in the stomach. While MUC13 is normally not expressed in the stomach, it is rapidly upregulated in the stomach of mice infected with the zoonotic bacterium Helicobacter heilmannii [84]. This MUC13 upregulation is associated with the development of gastric cancer.…”

“…This MUC13 upregulation is associated with the development of gastric cancer. H. heilmannii also leads to upregulation of MUC4 and the mucin-like protein DMBT1 in the stomach, and both proteins are considered to be metaplastic markers [84]. Contrary to MUC13 knockout mice, MUC4 knockout mice are less susceptible to the induction of colitis, show reduced infiltration of inflammatory cells, and reduced inflammation-induced carcinogenesis in the colon [85].…”

Splice variants and regulatory networks associated with host resistance to the intestinal worm Cooperia oncophora in cattle

“…Furthermore, multiple exon skipping events were detected (Table 3). The overexpression of MUC13 is known to have a significant impact on tumor progression (Gupta et al, 2014) and is implicated in bacterial infection (Liu et al, 2014). MUC13 and MUC1…”