br Due to its high mortality and
. Due to its high mortality and significant regional disparity in its dis-tribution, GC remains an important public health burden in China.
GC is a multifactorial disease, and alterations of the tumor microen-vironment are required for GC initiation, progression and metastasis. As part of the tumor microenvironment, gastric microbiota has attracted increasing attention, as it can affect cancer growth and spread in many ways. However, gastric microbiota has been relatively understudied compared to the gut microbiota. Due to acidic conditions and other an-timicrobial factors, the human stomach is thought to be exclusively inhabited by Helicobacter pylori (HP) and viewed as an inhospitable en-vironment for microorganisms. However, recent advances in sequenc-ing technologies have provided a broader picture of the gastric microbiota [4–11]. The tremendous complexity of the gastric microbiota shows significant differences with the microbiota described in the mouth and oesophagus, indicating that the stomach may be home to a
Research in context
Evidence before this study
Gastric microbiota were one of the important elements of the tumor microenvironment, which participated in gastric cancer (GC) initiation, progression and metastasis. Previous studies have investigated the characteristics of the gastric microbiota in different gastric diseases, from superficial gastritis, atrophic gas-tritis, intestinal metaplasia to intestinal-type GC. Recently, several studies found that the gastric mucosal microbiota dysbiosis changed across stages of gastric carcinogenesis and several spe-cific bacterial markers had been identified that could distinguish GC from other gastric diseases. However, most of these studies had always considered the whole stomach as one habitat, the dif-ferences of gastric microbiota among different stomach microhab-itats in patients with GC were still unclear.
The value of this study
Stomach microhabitats are not always uniform; instead, they vary considerably across sites within the stomach, at the same site over time, and with the health status. The specific changes among different stomach microhabitats might help to reveal the real role of the gastric bacteria on gastric carcinogenesis. With a larger cohort of GC patients without preoperative chemotherapy enrollment, we firstly demonstrated that GC-specific stomach mi-crohabitats determine the composition and Lipo2000 of the gastric microbiota. The most important bacterial carcinogen, Helicobacter pylori (HP), were significantly decreased in tumoral microhabitat, while the higher relative abundance of HP influenced the overall structure of the gastric microbiota in normal and peritumoral mi-crohabitats. Inconsistent with previous studies, we found that bacteria from different stomach microhabitats showed different correlation network and functions.
Implications of all the available evidence
We report novel findings on the relationship between gastric mi-crobiota and GC. Stomach microhabitats determine the overall structure and composition of the gastric microbiota, which pro-vide new insights into the roles of gastric microbiota in different stomach microhabitats on gastric carcinogenesis, especially the pathogenesis of HP.
distinct microbial ecosystem. The high number and immense diversity of bacteria within the stomach can influence metabolism, tissue devel-opment, inflammation, and immunity [12,13], and gastric dysbiosis has been linked to various pathological conditions, including GC . Aviles-Jimenez et al. demonstrated a gradual shift in the gastric microbi-ota profiles from non-atrophic gastritis (NAG) to intestinal metaplasia (IM) to intestinal-type GC , and Tseng et al. reported changes in the gastric microbiota before and after surgical treatment (subtotal gastrec-tomy) of GC . Recently, Coker et al. demonstrated that the microbial composition changes with GC progression and they identified the differ-ences in bacterial interactions across the different stages of gastric carci-nogenesis .
The various habitats throughout the body contribute to the diversity and composition of the microbiota and are in a dynamic state of change according to their distinct atmospheric and nutritional compositions that provide a setting for symbiotic interactions among the various mi-crobes within that ecosystem and the host. However, the gastric micro-biota shows remarkable heterogeneity at different sites within the
stomach and at the same site at different physiological and pathophys-iological states . Distinct pH, oxygen, nutrients, ions, and chemicals may vary considerably in tumor tissues and adjacent tumor-free tissues, which can be considered as different microhabitats that preferentially support the colonisation of certain bacterial strains. Previous studies have found that tumor-inciting microbes, such as HP, are gradually eliminated by changes in the tumor microenvironment. These changes result in an environment that is no longer hospitable to the microbe [17,18]. As different bacterial species preferentially inhabit tumor mi-croenvironments, changes in a particular microbial species may modify the gastric microbiota towards a more carcinogenic bacterial commu-nity. To establish the role of the gastric microbiota in GC, it is important to determine the differences in the colonisation of gastric microbiota in tumors compared to tumor-free tissues.