Archives

  • 2019-10
  • 2019-11
  • 2020-03
  • 2020-07
  • 2020-08
  • 2021-03
  • br To our knowledge this is the first large scale

    2020-07-25


    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 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 Z-VAD-FMK 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
    HPI-associated gastric microbiota alterations, which would ultimately promote GC development [52,53]. Compared with the tumoral micro-habitat, the inferred function of the gastric microbiota by PiCRUSt changed significantly in normal and peritumoral microhabitats with or without HP colonisation, and this may contribute to the initiation of gas-tric carcinogenesis. In contrast to the roles of HP in the promotion of gastric carcinogenesis, HP colonisation in the stomach has been sug-gested to protect against oesophageal adenocarcinoma. This is due to down-modulation of gastric acid secretion [54], which emphasizes the organ-specific effects of bacterially driven carcinogenesis.
    Interestingly, P. melaninogenica, S. anginosus and P. acnes were enriched in tumoral microhabitat and P. copri and B. uniformis decreased significantly, whereas B. fragilis and A. muciniphila showed a similar changing pattern between peritumoral and tumoral tissues. P. acnes, a classic skin bacterium, has recently been identified as a member of the gastric microbiota, which is a microhabitat-preferred bacterium that is found only in mucosal specimens but not in the gastric fluid [4,55,56]. In this study, the tumoral microhabitat was characterized by overabun-dance of Propionibacterium acnes, which is an important participant in GC tumorigenesis. P. acnes and its products, mainly short-chain fatty acids, trigger a possible corpus-dominant lymphocytic gastritis [57]. Tu-moral microhabitat-enriched oral-originated S. anginosus, which was significantly decreased in the normal and peritumoral microhabitats, has been found to be associated with GC, and has significant centralities in the GC ecological network [16]. In combination with other bio-markers, such as Peptostreptococcus stomatis, Parvimonas micra, Slackia exigua and Dialister pneumosintes, S. anginosus distinguished GC from AG with an AUC of 0.81 [16]. Andersson et al. also demonstrated that Streptococcus was the most dominant genus in the stomach in the ab-sence of HPI [58]. P. melaninogenica, an oral and respiratory pathogen, was also observed to be increased in the tumoral microhabitat. Dong et al. found that P. melaninogenica was the dominant species of the genus Prevotella in the stomach microbiota, making up an average of 9.17% for the NAG group and 6.95% for the chronic AG group [59]. How-ever, unlike S. anginosus and P. melaninogenica, P. copri was significantly decreased in peritumoral and tumoral microhabitats. Hollister et al. re-ported that P. copri was detected in stool specimens but rarely observed in samples from other body sites [60], while our present study showed that P. copri was one of the dominant species in the gastric mucosal mi-crobiota. Using 454 pyrosequencing, Scher et al. demonstrated that the presence of P. copri in fecal microbiota was strongly correlated with disease in new-onset untreated rheumatoid arthritis patients [61]. However, the role of P. melaninogenica and P. copri in the tumor micro-environment in GC pathogenesis requires further investigation. In addi-tion, B. cereus, a food-borne pathogen that causes diarrhoeal disease in human, was found to be significantly decreased in the peritumoral mi-crohabitat. A previous study showed that spores or vegetative B. cereus cells can survive the pH barrier and pepsin of the stomach and reach to the small intestine where they produce toxins in sufficient amounts [62]. As an opportunistic human pathogen, B. fragilis enterotoxin may have the potential to contribute to oncogenic transformation in the colon [63]. As a common member of the colonic microbiota, mucin-degrading A. muciniphila could increase the number of intestinal tumors, the thickness of the intestinal mucus layer, and the density of mucin-producing goblet cells, which are prime candidates for microbiota-borne modulation of intestinal tumorigenesis [64,65]. Con-sistent with previous studies, both B. fragilis and A. muciniphila were enriched in peritumoral and tumoral tissues, and might participate in the process of gastric carcinogenesis. Further mechanistic studies are