Colorectal cancer is one of the third most common types of cancer in the world and it is also the main cause of cancer death (Cao et al., 2021; Sung et al., 2021; Xie et al., 2021). Colorectal cancer is a complex disease influenced by genetics, diet, chronic inflammation, and environmental factors (Dekker et al., 2019; Nguyen et al., 2020; Parmar and Easwaran, 2022). Moreover, advanced polyps are closely related to the occurrence of colorectal cancer (Leslie et al., 2002; He et al., 2018). Therefore, early diagnosis such as screening for polyps is very important to prevent the occurrence and development of colorectal cancer.

Colorectal polyps are caused by the interruption of the normal proliferation and apoptosis cycle of the colon epithelium. Tubular adenomatous polyps and serrated polyps are two common types of precancerous lesions with high malignant potential (He et al., 2020). However, little is known about the composition and role of the microbiome associated with precancerous polyps. Kordahi et al. (2021) revealed the occurrence of colorectal adenoma is closely related to Bacteroides fragilis. The gut microbiota is related to human health and can affect human physiological function through immune function and inflammation inhibition, food breakdown and nutrient absorption (Korecka and Arulampalam, 2012; The Human Microbiome Project Consortium, 2012). Pieces of evidence indicated that the dysregulation of human intestinal flora is closely related to the development of a variety of gastrointestinal diseases (Feng et al., 2015; Flemer et al., 2017; Sepich-Poore et al., 2021). However, the gut microbiota varies greatly from individual to individual and the complicative variation limits our understanding of this relationship (Yatsunenko et al., 2012). The presentation of enterotypes is one way to reduce the complexity of these analyzes. Through the analysis of human microbiome genome, Arumugam et al. first introduced the concept of “Enterotypes,” and they found three bacterial groups in human: Bacteroides enterotype, Prevotella enterotype, and Ruminococcus enterotype (Arumugam et al., 2011). Enterotypes is a classification of the gut microbiota of different populations, indicating that variation in gut microbiota is stratified among individuals. Enterotypes is stable, which is mainly affected by long-term dietary habits. It has no direct relationship with gender, age, geography and cultural background. The enterotypes is characterized by different digestive functions. Prevotella enterotype can hydrolyze fiber effectively and has the potential of low fat and low protein fermentation. In contrast, Bacteroides enterotype has specific digestive enzymes and is associated with the digestion of animal protein and fat (Christensen et al., 2018). Several associations between enterotypes and disease phenotypes in humans have been reported. Yang et al. (2019) reported that the intestinal microbiome that develops into colorectal cancer in the adenoma-carcinoma sequence can be influenced by its enterotypes. The abnormal biological features of colorectal cancer vary among various intestinal types, especially those dominated by Escherichia. The increased abundance of Bacteroides is closely related to the occurrence of colorectal cancer, which can be used as an indicator of risk or susceptibility to certain diseases (Zeller et al., 2014; Costea et al., 2018). Based on the various models available, enterotypes could in some cases provide some important indications. The integration of enterotypes into various models can be a tool to better understand the presence of an individual’s susceptibility to certain diseases (Di Pierro, 2021).

For the risk factors of adenoma development, most studies are still carried out on specific microflora (Kordahi et al., 2021). Due to the complex diversity of intestinal microflora, it is difficult to coordinate the differences among different individuals through one or several types of bacteria. In contrast, enterotypes is an emerging classification method to express the characteristics of human intestinal flora. However, few studies have directly investigated the association between enterotypes and adenoma. Therefore, we aim to systematically study the microbial composition of human fecal samples at various points based on enterotypes. Taxonomic and enterotypes data were used to investigate whether there was a difference in enterotypes between intestinal adenoma and control patients, and whether there was an association between enterotypes and intestinal adenoma.

Our study showed that the Prevotella enterotype exists in patients with colorectal adenoma, and is considered to be a characteristic enterotype in colorectal adenoma. Most colorectal cancer patients develop through colorectal polyps. Colorectal polyps can develop into highly dysplasia through sufficient mutations and eventually invade the submucosa (Shaukat et al., 2020). Intestinal flora has been reported to play an important role in promoting the development of colorectal adenomatous polyps to colorectal cancer (Tjalsma et al., 2012). It has been reported that a significant increase in Fusobacterium_mortiferum is closely related to the development of colorectal polyps (Liang et al., 2020). The relationship between intestinal flora and colorectal polyps is limited due to the great variation of intestinal flora among individuals.

Methods involving metagenomic sequencing in our study. Compared to assembly-based species annotation, metagenomic species annotation methods may be more comprehensive and accurate for reads-based methods. However, metagenomic analysis also has a disadvantage, It is based on existing databases and cannot detect new genes in samples, so assembly-based analysis and read-based analysis each have advantages and disadvantages.

Enterotypes as a new concept to characterize human intestinal flora, has been widely used in various research in recent years. Arumugam et al. (2011) proposed that human intestinal microbial community can be divided into three different types “enterotypes”. The enterotypes of an individual can be highly variable, and the concept of enterotypes has important implications for how disease studies related to the microbiome are conducted (Knights et al., 2014). At present, more and more studies show that intestinal pattern is related to the occurrence of various diseases. Studies have shown that Bacteroides enterotype may be associated with the development of anxiety and depression syndrome (Valles-Colomer et al., 2019). Sobhani et al. (2011) found that the significant elevation of Bacteroides/Prevotella populations in colorectal cancer patients seemed to be related to the elevation of IL17-producing cells in the mucosa of cancer patients. In addition, studies have indicated that Bacteroides can affect the metabolism of nutrients in the body through dietary habits in patients with inflammatory bowel disease (Weng et al., 2019). However, few studies have been conducted on the correlation between enterotypes and colorectal adenoma. In our study, the incidence of colorectal adenomas was independent of age by univariate baseline characteristics analysis (p = 0.271). But in previous studies, it is considered that the occurrence of adenoma is correlated with the age (Wong et al., 2020). However, when Arumugam et al. first proposed enterotypes, they proposed that enterotypes are independent of ethnicity, sex, age, and BMI, but are driven by populations together and dominated by dominant bacteria. After the overall classification of the samples, the samples were first divided into two groups, but this rough classification obviously lacked the characteristics to judge the subsequent adenoma. Therefore, after the enterotypes analysis of the control group and the adenoma group, we found that the control group could be divided into three enterotypes: Escherichia enterotype, Bacteroides enterotype and Veroniella enterotype. The adenoma group was divided into Bacteroides enterotype and Prevotella enterotype. In the previous study, Arumugam et al. (2011) proposed three dominant bacteria for enterotypes: Bacteroides enterotype, Prevotella enterotype and Ruminococcus enterotype. As for the possible classification of other enterotypes, Liang et al. (2017) found that Enterobacteriaceae could be a new subtype of enterotypes in the Asian population. In a study based on a Chinese population, Lu et al. (2021) identified four enterotypes in 2678 healthy Chinese people, three of which were enriched in Prevotella, Bacteroides and Escherichia coli, while the fourth was a mixed type with no dominant genus. In this study, the three enterotypes were consistent with those seen in previous studies. Our results showed that the Bacteroides enterotypes included adenoma patients and control people, the Prevotella enterotypes was only present in the adenoma group, and the Escherichia enterotypes type was only present in control people. The differences in the distribution and formation of enterotypes in different regions may be related to geographical environment, altitude, local urbanization process, diet and other factors (Lu et al., 2021). This also indicates that the research on enterotypes may be different with different sample ranges, and people in each region may have enterotypes distribution with corresponding regional characteristics.

In this study, we also identified a new enterotypes in the control group, the Veillonella enterotype. Because we only found it in control people, we wanted to know if Veillonella enterotype had an inhibitory effect on adenoma, or if it had a protective effect on the human gut. A study based in Japan found that Veillonella is commonly found and studied as a human oral colonizer (Mashima et al., 2021). Veillonella is commonly found in the natural cavities of animals and humans, and is found in the mouth, pharynx, respiratory tract and digestive tract. Its ability to adhere to surfaces or interact with other bacteria and form biofilms is critical to the composition and function of the gut and oral microbiome, particularly in the oropharynx and gut (Mashima et al., 2021). In addition, it has also been suggested that Veillonella may play a protective and beneficial role in early childhood immune system development (Hasegawa et al., 2016). Veillonella can be metabolized in the human body by using short-chain organic acids as a carbon source and energy source (van den Bogert et al., 2013). The interaction between Veillonella and the host has been implicated in the pathogenesis of gastrointestinal diseases and chronic inflammation. The presence of typical oral microorganisms (including Veillonella) in the intestinal mucosa has been associated with a variety of pathologies, including colorectal cancer and inflammatory bowel disease (Geng et al., 2014; Flemer et al., 2018). Nitrate is a signature metabolite of inflammation, and Veillonella has respiratory nitrate reductase, which is capable of anaerobic respiration. Nitrate respiration promotes Veillonella’s growth on organic acids and regulates its metabolic pool, enabling it to use amino acids and peptides as carbon sources. The growth of Veillonella is dependent on nitrate during intestinal inflammation, which is the primary factor determining the ability of extrenteral microorganisms to colonize the intestine. Veillonella utilizes the respiratory action of nitrate to ectopic colonize the intestine. Veillonella may promote colorectal cancer by aggregating inflammation in the gut (Rojas-Tapias et al., 2022). There was a study that showed the abundance of Veillonella was significantly increased in colorectal cancer by terminal restriction fragment length polymorphism and next-generation sequencing analysis and may act as an opportunistic pathogen and/or a driver of inflammation (Kasai et al., 2016). In addition, a metagenomic analysis of the gut microbiome based on an Indian population showed an abundance of Veillonella in colorectal cancer patients, significantly different from the normal population. Genetic and epigenetic changes in cancer may result from genotoxic stress to the gut microbiome or metabolites in the gut environment (Bamola et al., 2022). This contradicts our findings of Veillonella in healthy people, and further studies are needed to confirm the role of Veillonella in the gut.

Colorectal cancer occurs mostly through the adenomato-cancer pathway, but colorectal polyps do not have typical clinical features in the early stage of the disease. Therefore, early screening of polyps plays a key role in the prevention of colorectal cancer. The correlation between polyps and microbial characteristics can provide new ideas for early diagnosis. The occurrence and development of colorectal adenoma are closely related to the increase of Prevotella abundance. Increased Prevotella abundance is associated with increased T-assisted type 17 (Th17) mediated mucosal inflammation, promoting mucosal T immune response and neutrophil recruitment. Moreover, Prevotella can mediate mucosal inflammation leading to the systemic spread of inflammatory mediators, bacteria and bacterial products. In turn, it can exhibit more inflammatory properties, which are involved in the occurrence and development of diseases in the body (Larsen, 2017; Iljazovic et al., 2021). The influence of the gut microbiota on health and disease regulation is primarily through their metabolites. Prevotella possesses the enzymes and gene clusters necessary for the fermentation and utilization of complex polysaccharides and can produce major dominant metabolites such as acetate and propionic acid by fermentation (Di Pierro, 2021). Prevotella can efficiently hydrolyze plant fiber and has a low-fat, low-protein fermentation potential. Prevotella was highly sensitive to bile salts and highly dependent on bicarbonate. The main metabolic pathway of Prevotella is based on fumarate glycolysis and succinate production. Pyruvate can be degraded to acetate and formate (Franke and Deppenmeier, 2018). The diversity of Prevotella species is related to diet, lifestyle and geography (Tett et al., 2021). In our study, the abundance of Prevotella in the adenoma group was significantly increased compared with the control group by LEfSe analysis (Figure 3). Clinically, the occurrence of colorectal polyps and adenomas is closely related to dietary habits. Colorectal adenomas occur in patients with relatively control diets or vegetarians, and these patients have a reduced risk of colorectal adenomas (Guo et al., 2021; Nguyen et al., 2021). Studies have indicated that enterotypes is related to long-term diet, and the intestinal microbes that cause colorectal adenomas may be different among different enterotypes (Wu et al., 2011). Therefore, we speculate that the occurrence of colorectal polyps and adenomas is related to the promotion of inflammation and the change of long-term dietary habits.

Our study found that Prevotella enterotype was positively correlated with the occurrence of adenoma. This suggests that fecal flora is a potentially beneficial tool for colorectal cancer detection. Our study suggests that Prevotella may increase the incidence of colorectal adenoma, and that people classified as enteric Prevotella have a greater risk of adenoma. We provide a risk prediction model for colorectal adenoma based on Prevotella enterotype. Enterotypes differentiation may be helpful for precision medicine. There are some limitations to our study. First of all, the small sample size of the analysis means that the representativeness of our study is not ideal. Second, we only used one method to cluster fecal samples, and we did not identify the microbiome structure of other populations. Third, pathological and genetic heterogeneity of gut microbiome among different enrolled participants may be confounding factors in our study. Fourthly, our study lacks the validation of external cohort samples, which makes our study have certain limitations. In conclusion, the exact effect of enterotypes on colorectal adenoma needs to be further verified by large prospective studies and also confirmed in animal models. Nevertheless, our results provide a new direction for exploring the relationship between gut flora and colorectal adenoma.

For coastal people, Prevotella enterotype has a high risk of adenoma in high-risk population of colorectal cancer. Prevotella enterotype prompts people to make early diagnosis of adenoma, so as to warn such people to pay attention to the occurrence of adenoma, early diagnosis and treatment, and prevent the evolution of colorectal cancer. Further research is needed to determine whether Vellonella enterotype has a protective effect on the human gastrointestinal tract.

The datasets presented in this study can be found in online repositories. The names of the repository/repositories and accession number(s) can be found at: BioProject, PRJNA911829.

The studies involving human participants were reviewed and approved by the study was approved by institutional ethics board of the Sixth Affiliated Hospital, Sun Yat-sen University (NO. 2022ZSLYEC-121). The patients/participants provided their written informed consent to participate in this study.

XG and JL study conception and design. JH, QZ, and DL administrative support. TX and XB acquisition of data. MS, ML, JZ, and JD analysis and interpretation of data. All authors contributed to the article and approved the submitted version.

This work was supported by National Key Clinical Discipline, Natural Science Foundation of Tibet Autonomous Region, China (2031021016). Data analysis service were provided by Wekemo Tech Group Co, Ltd. Shenzhen China.

The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest.

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