5. Microbiome Alterations in IM
Different profiles of the microbiome have been identified in most parts of the human body. However, the richest microbiome is found in the gastrointestinal tract, and its alterations have been associated with various diseases
[84][85][86]. The gut microbiome plays an important role in maintaining a mucosal immune response, and dysbiosis could lead to gastric inflammation
[87][88][89]. It has been reported that
H. pylori infection alters gastric microbiome structure
[90][91][92][93].
H. pylori is the most important gastric microbiome member, and it displays the highest relative abundance when present, but the stomach has a diverse microbiota when it is absent. The most abundant phyla in HP-positive and HP-negative patients are
Proteobacteria,
Firmicutes,
Actinobacteria,
Bacteroidetes, and
Fusobacteria [94]. The microbiota changes gradually in the process of gastric carcinogenesis
[95][96]. Therefore, it could be used as one of the biomarkers to determine premalignant gastric lesions, including IM.
A study with a very small cohort (10 subjects with IM and 10 healthy controls) investigated the gastric and duodenal microbiome differences between the two groups. The study concluded that the diversity of the duodenal microbiota in the control group was higher than that of IM group. Moreover, a significant difference in the duodenal microbiota structure was observed between the two groups.
Lactococcus,
Flavobacterium,
Psychrobacter,
Mysroides,
Enhydrobacter,
Streptococcus, and
Leuconostoc were enriched in patients with IM. Interestingly, the status of
H. pylori infection did not influence the structure of duodenal microbiota. Still, a statistically significant difference in gastric mucosal microbiota structure was observed between HP-positive and HP-negative patients in both groups
[97].
Another study observed a decreasing gastric microbiota diversity (ranging from 8 to 57 bacterial genus) trend from non-atrophic gastritis (NAG) to intestinal metaplasia to gastric cancer (statistically significant difference was observed between NAG and GC groups). Moreover, the most abundant phyla in all three groups were Firmicutes (
Lachnospiraceae and
Streptococcaceae representing over 20%) and Proteobacteria, representing almost 70% of all phyla. The study showed five taxa with a decreasing trend from NAG to IM to GC (two
Saccharibacteria, two
Porphyromonas, and one
Neisseria). Meanwhile, two taxa increased from NAG to IM to GC (
Lactobacillus and
Lachnospiraceae)
[98].
A study by Sung et al. analyzed the alteration of the gastric microbiome after
H. pylori eradication. Firstly, a significant reduction of gastric mucosal inflammation was observed one year after
H. pylori eradication with OAC (omeprazole, amoxicillin, and clarithromycin) regimen compared to the placebo group. Even though IM changes were similar between the OAC-treated and placebo groups, the enrichment of
Peptostreptococcus and depletion of
Lachnospira in patients with IM before OAC treatment was observed. Among subjects with IM at baseline,
Pseudomonas,
Peptostreptococcus,
Halomonas, and
Parvimonas were enriched in those with progressed or persisted IM, and
Peptostreptococcus was consistently positively associated with IM, before and after OAC treatment. It was observed that different sets of bacteria were associated with IM before and after
H. pylori eradication. Among subjects with no IM at baseline,
Mesorhizobium and
Cupriavidus were enriched while
Actinomyces were depleted in those with IM following
H. pylori eradication
[99].
Interestingly, research by Korean scientists showed that the evenness and diversity of gastric microbiota in GC group were increased compared to chronic gastritis (CG) and intestinal metaplasia groups. The GC group showed a significant decrease in the relative abundances of
Epsilonproteobacteria class compared to the CG and IM groups. In contrast, the relative abundance of
Helicobacteraceae family was significantly higher in the CG and IM groups
[100].
Another Korean study analyzed the gastric microbiome of 138 patients based on the disease (CG, IM, and GC) and
H. pylori infection status. Cyanobacteria were significantly reduced in the
H. pylori negative IM group (4 %) compared to the
H. pylori negative CG group (14%). Moreover, a statistically significant relative abundance of Rhizobiales was observed in the
H. pylori negative IM group (15%) compared to the HP negative CG and HP negative GC groups (2% and 3 %, respectively). Interestingly, the study concluded that after a successful
H. pylori eradication, the gastric microbiome resembled that in the HP-negative IM group
[101].
Another study also investigated the changes of the gastric microbiome in the progression from healthy individuals to gastric cancer. The results revealed that the microbiota profile of intestinal metaplasia and chronic gastritis patients was quite similar—Acidobacteria, Gemmatimonadetes, Proteobacteria, and Verrucomicrobia were enriched in these groups. At the genus level, the abundance of
Halomonas,
Shewanella,
Aquincola, and
Sphingomonas was significantly higher in IM and CG groups. After analyzing each disease stage separately, the authors concluded that IM was featured by a higher abundance of
Aquincola tertiaricarbonis and a taxon of
Sphingomonas genus. What is even more important, the study investigated the possibility of using gastric microbiota as a predictive indicator for stages of gastric carcinogenesis. The constructed predictive model was able to identify the gastric histological type accurately. However, the calculated error rate was higher in CG and IM groups compared to the other disease stages, which further indicated microbiome similarity between these two groups
[102].
A Chinese study investigated the associations between
H. pylori status, its eradication, fecal microbiota and
H. pylori-related gastric lesions, including IM. It was found that the abundance of Bacteroidetes was significantly higher in the
H. pylori negative group compared to past HP infection group (66% compared to 33% respectively). The same trend was observed when comparing normal gastric mucosa to intestinal metaplasia group (76% compared to 47% respectively). It was also observed that the abundance of Firmicutes and Proteobacteria was significantly higher not only in the IM group (32% and 20%, respectively) compared to normal mucosa (18% and 5% respectively) but also in the past
H. pylori infection group compared to HP-negative group. The findings suggest that alterations of fecal microbiota, including the previously mentioned phyla, may be involved in
H. pylori related gastric lesion progression
[103].
In conclusion, most of the previously mentioned studies identified microbiome alterations in IM that may be involved in gastric tumorigenesis. They laid a foundation for future studies using bacterial markers for diagnosing premalignant gastric conditions, including intestinal metaplasia. However, larger-scale studies and significant efforts are still needed to standardize the process of microbiome analysis and the interpretation of the result to apply these findings to clinical practice.
6. Conclusions
In conclusion, the latest progress in novel diagnostic methods allows scientists to identify various molecular alterations in gastric intestinal metaplasia, such as polymorphisms in various genes, changes in the expression of miRNAs and lncRNAs, and altered microbiome profile. Some of these alterations have strong associations with intestinal metaplasia and a potential to be used as one of the tools for the screening, treatment, and prognostic purposes; however, the use of current findings in real-life clinical practice is still very limited. One of the most important limiting factors is the inhomogeneity of the studies, such as the lack of data on concomitant H. pylori infection, lack of risk modification by HP CagA status, heterogeneous methods used to assess preneoplastic gastric lesions, uneven or small cohorts, etc. Therefore, further large-scale studies and clinical trials with standardized methods designed by multicenter consortiums are needed. As of today, various molecular alterations in intestinal metaplasia could become a part of personalized medicine, which would help us deliver a personalized approach for each patient and identify those at risk of progression to gastric cancer.