Helicobacter pylori Dampens Gut Epithelial Self-Renewal by Inhibiting Apoptosis, a Bacterial Strategy to Enhance Colonization of the Stomach

Abstract

Colonization of the gastric pits in the stomach by Helicobacter pylori (Hp) is a major risk factor for gastritis, gastric ulcers, and cancer. Normally, rapid self-renewal of gut epithelia, which occurs by a balance of progenitor proliferation and pit cell apoptosis, serves as a host defense mechanism to limit bacterial colonization. To investigate how Hp overcomes this host defense, we use the Mongolian gerbil model of Hp infection. Apoptotic loss of pit cells induced by a proapoptotic agent is suppressed by Hp. The ability of Hp to suppress apoptosis contributed to pit hyperplasia and persistent bacterial colonization of the stomach. Infection with WT Hp but not with a mutant in the virulence effector cagA increased levels of the prosurvival factor phospho-ERK and antiapoptotic protein MCL1 in the gastric pits. Thus, CagA activates host cell survival and antiapoptotic pathways to overcome self-renewal of the gastric epithelium and help sustain Hp infection.

Suppressed Gastric Mucosal TGF-β1 Increases Susceptibility to H. pylori-Induced Gastric Inflammation and Ulceration: A Stupid Host Defense Response

“…The presence of H. pylori in gastric mucosa is associated with chronic active gastritis and implicated in more severe gastric diseases, such as chronic atrophic gastritis and intestinal metaplasia (a precursor of gastric carcinogenesis), peptic ulcer, mucosa-associated lymphoid tissue lymphoma, and gastric cancer. However, the fact that peptic ulcer disease and gastric carcinoma occur in only a small portion of individuals chronically infected with H. pylori stressed that the role of the host defense factor is postulated to be an important determinant in the clinical outcome of H. pylori infection, 2 further supported with outstanding publication of Mimuro H et al 3 that H. pylori dampens gut epithelial self-renewal by inhibiting apoptosis, a bacterial strategy to enhance colonization of the stomach.…”

“…3B), iii) dependence of H. pylori attachment on TGF-β signaling status (Fig. 4A), iv) reverse association between TGF-β levels and gastric inflammation (Table 1), v) transactivation of TGF-β signaling with H. pylori and TGF-β ligand, and vi) publication 3 showing that H.…”

Immunohistopathological Role of Bcl2 and P53 Gene Expression in Helicobacter Pylori Cytotoxin-Associated Gene a Positive Versus Cytotoxin-Associated Gene a Negative Antral Predominant Non-Atrophic Gastritis in Iraqi Patients

“…p53 can directly disrupt the Bcl2/Bax complex by binding to a novel regulatory region of Bcl2's flexible loop domain (aa 32-68) which known as a "negative" regulatory domain in Bcl2 [45]. The consequence of this interaction is the release of proapoptotic Bax that is "peripherally" associated with mitochondria to become integrally associated in the outer mitochondrial membrane leading to cytochrome c release, it binds together with dATP and apoptosis activity factor-1 to procaspase-9, resulting in the activation of downstream caspases that induces proteolytic processing and activation of cell death [47], which explain the current finding of the positive correlation of p53 expression with increase of gastric apoptotic index % in CagA positive patients. This explanation comes in accordance with other studies [19,[48][49][50][51], stated a significant association between HP infection and the expression of Bax which leads to gastric epithelium apoptosis through upregulation of Bax and downregulation of Bcl2.…”

Echoes of a Distant Past: The cag Pathogenicity Island of Helicobacter pylori

“…However, in H. pylori infected cells, CagA promotes the interaction between p53 and ASPP2, leading to an enhanced degradation of p53, and therefore inhibition of its transcriptional activity. CagA inhibits apoptosis by binding the tumor suppressor ASPP2 and through this interaction p53 is degraded and its apoptotic function inhibited (Mimuro et al 2007;Buti et al 2011).…”