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    2022-05-13

    r> that occur in stomach microhabitats during GC development. Previous studies on colorectal cancer have suggested that different bacterial spe-cies preferentially inhabit the tumor sites but not tumor-free sites [41,42]. The altered gastric microbiota influences inflammation and im-munity both locally at the mucosal level and systemically. Our previous study demonstrated that patients with GC had increased regulatory T Artesunate (Tregs) in peripheral blood and carcinoma tissue [43]. Disorders of the intimate interactions between the gastric microbiota in the tumor microenvironment and immune system may contribute to GC development by eliciting tumor-promoting immune responses.
    To our knowledge, this is the first large-scale trial to explore specific changes of the gastric microbiota in GC stomach microhabitats using high-throughput sequencing techniques. Previous studies have found changes in the gastric microbiota across stages of gastric carcinogenesis in patients with NAG, IM and GC [8,16,44]. A Chinese pilot study re-ported Artesunate that gastric microbiota features are associated with cancer risk factors and clinical outcomes in patients with gastric cardia cancer [5]. Consistent with the previous studies, we also found altered diversity and composition of the gastric microbiota in stomach microhabitats. Specifically, the bacterial richness showed a marked decreasing trend from normal to peritumoral to tumoral tissues, demonstrating that the altered microenvironment of the tumoral sites is not suitable for specific bacterial colonisation. The GC stomach microhabitat, but not GC stage, type, or cell differentiation, determined the overall structure of the gas-tric microbiota. Interestingly, our present study also found that the cor-relation network in the tumoral microhabitat became much simpler.
    As a class I carcinogen of GC, HP in the tumoral sites is classically be-lieved to contribute to GC tumorigenesis, and mass eradication of HPI significantly decreases the risk of developing cancer in infected individ-uals without pre-malignant lesions [45–47], reinforcing the theory that HP influences early stages in gastric carcinogenesis. HP is the strongest known risk factor for both diffuse-type and intestinal-type GC, and it uses various mechanisms to dampen host immune responses and per-sist in the stomach [48]. In fact, HP acts by a “hit and run” mechanism for GC and is no longer present in the intratumoral microhabitat at the time when GC is identified [17]. Our present findings confirmed that HP was significantly decreased in the tumoral microhabitat. The altered tumoral microhabitat with loss of specialized glandular tissue and de-creased acid secretion might lead to the decrease of HP [5]. We also demonstrated that the presence or absence of HP led to significantly dif-ferent population structures in normal and peritumoral microhabitats [49], correlating with the relative abundance of HP. A previous study found that persistent HPI of the gastric mucosa influences gastric in-flammatory gene expression resulting in AG, a condition associated with a reduced capacity for gastric acid secretion and an increased risk of GC [49]. The high prevalence of HPI with reduced gastric acid secre-tion in peritumoral and normal microhabitats might allow for the sur-vival and proliferation of other microbes, such as Halomonas, Prevotella and Streptococcus, which are normally killed by the acidic environment, resulting in the initiation of gastric carcinogenesis [50]. As a carcino-genic pathogen, HP might actively participate in GC by changing the gastric mucosal immunity, especially the imbalance of Treg/Th17. How-ever, HP colonisation in the stomach alone is not sufficient to induce gastric carcinogenesis. Lofgren et al. demonstrated that HP-induced GC is promoted by the presence of a complex microbiota, as HP mono-associated mice developed fewer tumors than their specific pathogen-free counterparts in a hypergastrinaemic transgenic mouse model [51]. This may be explained by increased conversion of dietary nitrates, such as N-nitrosamines and N-nitrosamides, that might be attributed to