Association of Lactobacillus, Firmicutes, Bifidobacterium, Clostridium, and Enterococcus with colorectal cancer in Iranian patients.
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Abstract
Background
Colorectal cancer (CRC) is one of the primary causes of cancer-associated deaths worldwide, and growing evidence shows that alteration in the gut microbiota may be a contributing factor to the development and progression of the disease. This study investigates the correlation between CRC and specific intestinal microbiota abundance, including Firmicutes, Lactobacillus, Enterococcus, Clostridium, and Bifidobacterium.Material and methods
In this study, 100 CRC samples and adjacent normal tissues were obtained from Iranian patients. Afterward, we assessed the abundance of the mentioned bacteria in matched tumor and normal tissue samples from 100 CRC patients, by TaqMan quantitative real-time polymerase chain reaction (qPCR).Results
Most of the patients (55 %) had grade II cancer (moderately differentiated), followed by grade III (poorly Differentiated) in 19 %, and the distribution of the tumor location was 65 % in the colon and 35 % in the rectum. Our research showed a substantial difference in the relative abundance of specific bacteria in tumors and healthy tissues. To this end, four genera of bacteria, including Bifidobacterium, Lactobacillus, Clostridium, and Firmicutes, exhibited statistically significant reductions in tumor tissues compared to adjacent normal tissue (p < 0.05). Conversely, Enterococcus demonstrated a statistically significant increase in tumor tissue samples (p < 0.05). Noteworthy, statistical analysis revealed a significant relationship between Enterococcus and prior cancer (p < 0.05).Conclusions
These findings provide significant insight into the complex association between the gut microbiota and CRC and may pave the way for future research on novel screening methods, preventive measures, and therapeutic strategies targeting the gut microbiota in CRC patients.Free full text
Association of Lactobacillus, Firmicutes, Bifidobacterium, Clostridium, and Enterococcus with colorectal cancer in Iranian patients
Associated Data
Abstract
Background
Colorectal cancer (CRC) is one of the primary causes of cancer-associated deaths worldwide, and growing evidence shows that alteration in the gut microbiota may be a contributing factor to the development and progression of the disease. This study investigates the correlation between CRC and specific intestinal microbiota abundance, including Firmicutes, Lactobacillus, Enterococcus, Clostridium, and Bifidobacterium.
Material and methods
In this study, 100 CRC samples and adjacent normal tissues were obtained from Iranian patients. Afterward, we assessed the abundance of the mentioned bacteria in matched tumor and normal tissue samples from 100 CRC patients, by TaqMan quantitative real-time polymerase chain reaction (qPCR).
Results
Most of the patients (55 %) had grade II cancer (moderately differentiated), followed by grade III (poorly Differentiated) in 19 %, and the distribution of the tumor location was 65 % in the colon and 35 % in the rectum. Our research showed a substantial difference in the relative abundance of specific bacteria in tumors and healthy tissues. To this end, four genera of bacteria, including Bifidobacterium, Lactobacillus, Clostridium, and Firmicutes, exhibited statistically significant reductions in tumor tissues compared to adjacent normal tissue (p < 0.05). Conversely, Enterococcus demonstrated a statistically significant increase in tumor tissue samples (p < 0.05). Noteworthy, statistical analysis revealed a significant relationship between Enterococcus and prior cancer (p < 0.05).
Conclusions
These findings provide significant insight into the complex association between the gut microbiota and CRC and may pave the way for future research on novel screening methods, preventive measures, and therapeutic strategies targeting the gut microbiota in CRC patients.
1. Introduction
Colon, bowel, and rectal cancer, commonly known as colorectal cancer (CRC), is the second deadliest cancer and the third leading cause of cancer-related deaths worldwide. This critical health problem, which accounts for approximately 9.4 % of cancer-associated deaths in 2020, includes signs and symptoms such as weight loss, changes in bowel movements, fatigue, and the presence of blood in the stool [1,2]. The incidence of CRC is very different in various parts of the world. The highest rate of this cancer occurrence is in Australia, North America, Western Europe, New Zealand, and China. Additionally, the prevalence of CRC in Iran has been steadily rising in recent years. This cancer ranks fourth among cancers affecting Iranians, women are most commonly affected after breast cancer, and men after lung, and prostate cancer [[3], [4], [5]].
CRC is a multifactor disease that is affected by both genetic and environmental factors, most of which are non-hereditary and sporadic, such as obesity, the Western diet, and high alcohol consumption. However, less than 5 % of CRCs are hereditary, such as Hereditary Non-Polyposis Colon Cancers (HNPCC or Lynch syndrome) and Familial Adenomatous Polyposis (FAP) [[6], [7], [8], [9]].
The human gut microbiota, primarily colonized by three phyla (Actinobacteria, Bacteroides, and Firmicutes), not only contributes to the natural physiological environment by supporting the gut barrier system, enhancing epithelial cell survival, and regulating energy metabolism but also plays an essential role in protecting the body from opportunistic or external pathogens. Nevertheless, when dysbiosis occurs, the intestinal microbiota may contribute to the pathogenesis of various diseases, including CRC [[10], [11], [12]].
Considering the carcinogenic role of numerous microorganisms in CRC in recent studies, the recognition of the gut microbiota as an important and key factor in the process of carcinogenesis and metastasis, as well as its effect on the effectiveness of CRC treatment, has become particularly important. On the other hand, the intestinal microbiota can be a promising yet important biomarker for early screening [[13], [14], [15], [16]].
Studies showed the high and low prevalence of some bacterial species and their function in the pathogenesis of CRC by examining stool or tissue samples from CRC patients [6]. For example, it is thought that the probiotic strains of Bifidobacterium and Lactobacillus have a protective function through the secretion of antibacterial peptides and competing for adhesion sites; therefore, the levels of these bacteria are decreasing in colorectal carcinoma [16,17]. In contrast, several investigations have revealed higher levels of Firmicutes, Clostridium, and Enterococcus in CRC samples in comparison to healthy tissues [6,18].
Therefore, further examination of patients in different regions is essential to understand the association between the early diagnosis of CRC through screening and modification of the intestinal microbiota [19,20]. Recently published research has evaluated the association between different bacteria and CRC in Iranian patients. Nevertheless, the authors of these research employed low-quality detection techniques, including basic PCR, and a small number of tissues or feces as samples [13,21,22]. In this context, we aimed to investigate the prevalence of four genera and a bacterial phylum including Lactobacillus, Bifidobacterium, Clostridium, Enterococcus, and Firmicutes, in 100 tumor and adjacent non-tumor tissues by TaqMan quantitative Real-Time Polymerase Chain Reaction (qPCR). Moreover, the correlation between the clinicopathological characteristics of CRC patients and the bacteria was examined.
2. Materials and methods
2.1. Participants and sample collection
Between February 2019 and January 2021, 100 CRC tissue samples and adjacent healthy tissues with a distance of 10–15 cm from the tumor were collected from recently diagnosed CRC patients referred the Iran National Tumor Bank, which is founded by the Cancer Institute of Tehran University of Medical Sciences. Eligible participants in this study were enrolled before surgery and filled out the informed consent form. Each of the participants who were not able to register for this research met at least one of the exclusion criteria (Table 1). All the required information and data, including histopathological parameters, gender, and age, were extracted from the case report forms and patients' records. Before starting each treatment regime, all biopsies were collected, and all samples were transferred after surgery to the pathology unit for evaluation by the center's pathologist, who was blind to the molecular and clinical information. After confirming the samples, a part of the tumor tissue and a part of the adjacent normal tissue were selected and then transferred to RNAlater Reagent (Qiagen, Germany) and stored at −70 °C until the DNA extraction process. Of note, the present cross-sectional study protocols and informed consent were approved by the Ethics Committee of the Iran University of Medical Sciences.
Table 1
Exclusion and inclusion criteria of the individuals in the study.
| Inclusion criteria (CRC patients) | |
|---|---|
| Exclusion criteria (CRC patients) |
2.2. DNA extraction
For genomic DNA extraction, 25 mg of each tissue sample was weighed, and total bacterial DNA was extracted directly from all samples using FavorPrepTM DNA Mini Kit (Favorgen, Taiwan) according to the manufacturer's protocol. Upon extraction, DNA concentration, and quality were determined at OD (260 nm) by a Nanodrop spectrophotometer (Nanodrop Technologies, USA) and on an agarose gel electrophoresis. Then, the whole verified extracted DNAs were immediately preserved at - 20 °C.
2.3. Real-time PCR
The five genera were identified by using the 16S rDNA gene sequence by real-time TaqMan qPCR in a Rotor-Gene 6000 real-time PCR cycler (Qiagen Corbett, Germany) (Table 2). As in a prior study, SLCO2A1, the reference gene, was utilized to normalize each bacterium's cycle threshold (CT) values [23]. NCBI BLAST databases were used to assess the specificities of the primers and probes. All the reported data were carried out in duplicate, and the mean values of duplicate qPCR analyses were used for analysis and calculation.
Table 2
Utilized TaqMan probes and primers in the present study.
| Target bacteria | Primer/Probe | Oligonucleotide sequence (50e30) | Product size (bp) | Reference |
|---|---|---|---|---|
| Lactobacillus | Primer F Primer R Probe | GTCTGATGTGAAAGCCYTCG CCAGGGTATCTAATCCTGTTYG YCACCGCTACACATGRAGTTCCACT | 204 | [24] |
| Bifidobacterium | Primer F Primer R Probe | GGTTAACTCGGAGGAAGG GTACCGGCCATTGTAGCA CGTCAGATCATCATGCCCCTTACG | 85 | [24] |
| Clostridium | Primer F Primer R Probe | CGTCAGATCATCATGCCCCTTACG GTATGTCRCAAGCGTTATCC CCTAGACGCGCTTTACGCCCAAT | 157 | [25] |
| Enterococcus | Primer F Primer R Probe | TAGAGAAGAACAAGGABGAKAGT GGGCTTTCACATCAGACTTA AAACGATGGATGCCCGC | 171 | [26] |
| Firmicutes | Primer F Primer R Probe | GCGTGAGTGAAGAAGT CTACGCTCCCTTTACAC ACTTCCAACTTGTCTTCCCGCCTG | 160 | [27] |
| SLCO2A1 | Primer F Primer R Probe | GAGAGATTTGAATGTTGGACAAAGC ACACTTCTGTGGTCACTCGTC TCCTACTGCCATCCTTCTACCTGCCA | 89 | [13] |
Each reaction mixture with a total volume of 20 μl was made up of 9 μl of Universal Probe Ex Taq PCR Master Mix (Ampliqon, Denmark), 20 ng of extracted DNA, 0.25 μM of the probe, 0.5 μM of each primer. qPCR was performed by the following cycle parameters: an initial holding at 95 °C for 15 min, followed by 40 cycles of denaturation at 95 °C for 15 s, and annealing/extension at 58–62 °C for 30 s. Negative controls, in every analysis, included all the ingredients of the reaction mixture except genomic DNA. In CRC patients with detectable bacteria (r2 > 0.99), CT values in the qPCR for each bacterium and SLCO2A1 decreased linearly in proportion to the amount of input DNA (on a log scale). The prevalence of four bacteria was determined in each sample as a relative unitless value normalized to SLCO2A1 using the 2−ΔCT technique (where ΔCT is the difference between the average CT value of each bacterium and the reference gene), as previously reported [23,28].
2.4. Statistical analysis
Statistical analysis was performed with SPSS version SPSS v.20.0 software and GraphPad Prism v.8.3.0. P-value <0.05 was considered statistically significant. We used the Chi-squared test on a sample of tissues to compare the relative amounts of each bacterium between adjacent normal mucosa and tumor. A Fisher exact test was also used to analyze the association between the ordinal (negative or positive) categories of the numbers of bacteria and categorical data.
3. Results
3.1. Demographic, clinical, and pathological variables
We analyzed the histopathological and demographic features of 100 Iranian patients who were diagnosed with CRC. The sample included 55 men and 45 women, with a mean age of 57 years (SD ± 11.04, range 17–93). Most of the patients (55 %) had grade II cancer (moderately differentiated), followed by grade I (well differentiated) in 17 %, grade III (poorly differentiated) in 19 %, and grade IV (undifferentiated) in 9 % (Table 3). The distribution of the tumor location was 65 % in the colon and 35 % in the rectum. Finally, only 8 % of the patients reported alcohol consumption, and 10 % reported smoking habits.
Table 3
General and clinicopathological characteristics of Iranian patients with CRC (N = 100).
General Characteristics of CRC Patients | Pathological T | ||
|---|---|---|---|
| Male/Female (n (%)) | 55(55 %)/45(45 %) | Tx | 1 % |
| Age: Mean ± SD | (56.69 ± 11.04) | T2 | 11 % |
| T3 | 74 % | ||
| Age of death (Mean ± SD) | 57.6 ± 17.25 (age range: 20–83 years) | T4 | 13 % |
| Tumor size (Mean ± SD) | 6.02 ± 2.41ranging from (2–12 cm) | N/A | 1 % |
| Site of primary | Pathological N | ||
| Cecum Ascending colon Transverse Colon Splenic Flexure Descending Colon Sigmoid Colon Rectosigmoid Rectum Colon, NOS | 16 % 7 % 3 % 1 % 2 % 15 % 10 % 35 % 11 % | Nx N0 N1 N2 NA | 1 % 37 % 34 % 27 % 1 % |
| Tumor size (Mean ± SD) | Clinical metastasis | ||
| Size ≤ 5 Size >5 | 45 % 55 % | Mx M0 M1 | 6 % 85 % 9 % |
| Invasion, Nodal status, and Tumor deposit | Histology | ||
| Lymphatic Vascular Perineural Perineal Extramural Blood Vessel Extra-Nodal Extension Perforation Peritoneal Seeding | 54 % 59 % 37 % 1 % 2 % 11 % 9 % 10 % | Adenocarcinoma Mucinous (colloid) adenocarcinoma Mucinous Carcinoid Signet-ring cell adenocarcinoma Other | 83 % 12 % 1 % 2 % 2 % |
| Grade | TNM staging | ||
| I: (Well Differentiated) II: Moderately Differentiated III: Poorly Differentiated IV: Undifferentiated | 17 % 55 % 19 % 9 % | Stage I Stage IIA Stage IIIA Stage IIB Stage IIIB Stage IIIC Stage IV | 7 % 22 % 4 % 4 % 30 % 24 % 9 % |
| Alcohol | Smoking status | ||
| Non-drinker Social drinker | 92 % 8 % | Non-smoker DX-Smoker at Diagnosis but Discontinued Smoker Ex-smoker | 81 % 7 % 10 % 2 % |
3.2. Bacterial quantification
In this study, we evaluated the bacterial levels of tumor tissue and adjacent normal mucosa tissues in CRC patients to investigate microbiota alteration in Iranian patients with CRC. According to our findings, the relative abundance of various bacterial taxa differed significantly between tumor and healthy tissue samples. To this end, four genera of bacteria, including Bifidobacterium, Lactobacillus, Clostridium, and Firmicutes, exhibited statistically significant reductions in tumor tissues compared to adjacent normal tissue (p < 0.05). Conversely, Enterococcus demonstrated a statistically significant increase in tumor tissue samples (p < 0.05). In detail, the findings of our study demonstrate that Enterococcus comprised 55 % of the bacterial population in the tumor tissue, whereas it was present in only 45 % of the healthy tissue samples. On the other hand, the Firmicutes phylum exhibited a higher prevalence in normal tissue (60 %) compared to cancerous tissue (40 %). Additionally, we observed distinct patterns in the distribution of individual bacterial genera Lactobacillus displayed a higher abundance in the adjacent normal tissue (64 %) compared to the tumor tissue (36 %). Similarly, Bifidobacterium exhibited a higher prevalence (70 %) in normal tissue and a reduced presence (30 %) in tumor samples. We also examined the presence of Clostridium in both tumor and adjacent normal samples, with an occurrence rate of 48 % and 52 %, respectively (Fig. 1). Our statistical analysis using Fisher's test revealed a significant relationship between Bifidobacterium and smoking (p < 0.05). Additionally, we observed a relationship between Clostridium and perforation and pathological T. However, there was no correlation between bacteria and other clinicopathological characteristics of patients (p > 0.05).
The analysis is visualized using scatter plots with accompanying bars on the left and the relative abundance of each bacterium in the tumor and adjacent healthy samples on the right. The relative quantity of Bifidobacterium, Lactobacillus, Clostridium, and Firmicutes (n = 100, p < 0.05) was significantly lower in CRC samples than in adjacent normal tissues obtained 10–15 cm beyond cancer margins. Furthermore, the abundance of Enterococcus was shown to be substantially higher in tissue samples from the control group compared to the tumor group. (*p value < 0.05).
4. Discussion
Intestinal microbes interact with hosts through metabolic exchange, converting dietary components into active forms, and modulating the host's metabolism and immunity [29,30]. Culture-independent methods have provided insight into the potential contribution of microbial compositions in the colorectal region toward the pathogenesis of CRC, although the causation of CRC remains multifactorial and intricate. Nevertheless, it is evident that a comprehensive understanding of the role of gut microbiota in this cancer remains an elusive goal, despite significant progress made thus far [[31], [32], [33]].
This study investigates the abundance of five genera and phylum of bacteria related to CRC in cancerous and normal tissues from 100 Iranian CRC patients. In this research, we use fresh frozen biopsies, which are preferred due to their similarity and proximity to the lumen microbiota, to address the knowledge gap in Microbiome research on CRC in developing countries like Iran [[34], [35], [36]].
Our findings revealed a considerable difference in the abundance of opportunistic pathogens between CRC tissue and adjacent healthy tissue. CRC samples exhibited a higher proportion of Enterococcus genus compared to healthy tissue samples (p-value <0.05). In line with our results, in another study, the authors used 16S rRNA gene sequencing and reported that the frequency of pathogenic Enterococcus was more common in CRC patients than in the healthy control group [37]. Furthermore, in research by Chen et al., the microbial communities of individuals with ColoRectal Adenoma (CRA) were compared to healthy controls using fecal samples and high-throughput 454 pyrosequencing. The study included 47 individuals matched for sex, age, and lifestyle. Results showed that the Enterococcus genus was dominant in the CRA group compared to the healthy control group. These findings are consistent with our own study, which suggests a correlation between the frequency of Enterococcus and the early grades of cancer [38].
Previous research has highlighted the various roles of intestinal microbiota in producing Nitric Oxide Synthase (NOS), activating macrophages, and damaging intestinal epithelial cell DNA through inflammatory responses [32]. In this concept, Enterococcus has been demonstrated to release NOS, activate macrophages, and trigger inflammatory responses that could lead to DNA damage and consequent destruction of colon epithelial cells [37]. Therefore, it is postulated that the increased presence of Enterococcus in CRC may be a contributing factor in the pathogenesis and development of the disease by releasing extracellular inflammatory compounds that harm the DNA of colon epithelial cells [39]. These findings suggest that the abundance of Enterococcus may act as a potential biomarker for diagnosing CRC; however, the role of this bacterium in CRC pathogenesis should be evaluated in future studies and animal models.
Firmicutes is one of the predominant phyla of the intestinal microbiota, and it has been reported that it has the capacity to enhance energy harvest from diet, which includes butyrate-producing genera such as Faecalibacterium, Roseburia, Eubacterium, and Clostridium [40,41]. Butyrate, a source of energy for colonocytes, could lead to the prevention of CRC by increasing colon regulatory T cells (Treg) and decreasing inflammatory cytokines [15,[40], [41], [42]]. In this study we found that Firmicutes, primarily involved in butyrate production, are expected to decrease in the microbiota of CRC patients. Zhang et al. comprehensively analyzed the microbiota composition and gene expression in CRC using tissue samples from healthy volunteers. It was determined that the frequency of Firmicutes decreased in CRC patients [43]. On the other hand, Zhiguang et al. also investigated the distribution of intestinal microbiota in cancerous tissues and adjacent non-cancerous samples. The researchers utilized pyrosequencing-based analysis of the 16S rRNA gene V3 region to analyze the microbial communities. Their results revealed a notable increase in the abundance of this phylum [18].
Therefore, we estimate that this discrepancy in the results is due to the possible roles of race, geographic region, obesity, high-fiber dietary pattern, mealtime, and alcohol consumption in different patients. Additionally, since the maintenance of antitumor effects of butyrate is concentration-dependent and this short-chain fatty acid in high concentrations causes chronic inflammation in CRC. It is possible that the high concentration of butyrate, in turn, may be the reason for the increase of Firmicutes in their study [44,45].
Clostridium is one of the important genera of Firmicutes bacteria linked to CRC. Our study has shown that Clostridium has a negative correlation with colorectal neoplasms, like other epidemiological studies [46,47]. This indicates their role in producing Short-Chain Fatty Acids (SCFAs), especially butyrate, from dietary fibers [29,48]. An examination of the enrichment of the Clostridia class using stool samples (94 control participants and 47 CRC case subjects) showed their relative reduction [30]. Similarly, a recent report by 454 pyrosequencing based on 16S rRNA found a decrease in this genus in advanced colorectal adenoma [38]. Our study supports hypotheses suggesting that butyrate-producing bacteria may aid host defense and contribute to structural imbalance in the intestinal microbiota of CRC patients [49,50]. However, according to the study of Fang et al. (2021), Clostridium has been found to promote CRC growth [51]. Considering that this genus of bacteria consists of harmful species such as Clostridium difficile and probiotics such as Clostridium butyricum [6,52]. The discrepancy between these results may be attributed to the differential abundance of carcinogenic Clostridium, which may vary depending on dietary factors and the molecular methods used for the detection and quantification of bacteria [45,53].
Probiotic microorganisms, particularly Bifidobacterium and Lactobacillus, have anticancer activity [54]. Kosumi et al. investigated the potential relationship between Bifidobacterium abundance, immune response, and tumor differentiation in CRC tissue. The team employed a qPCR on a large cohort of more than 1000 human CRC cases to evaluate their hypothesis. Their results showed a significant decline in the levels of this specific genus of probiotics in the CRC tissue compared to the control [55]. In addition, other researchers reported a reduction in Bifidobacterium probiotics in CRC patients based on 16S rRNA gene sequencing of tissue samples [18,56,57].
The outcomes mentioned above agreed with the findings of our study. Our findings, in line with previous investigations, underscore the critical role of Bifidobacterium in maintaining a healthy gut ecosystem, particularly in regulating immune and inflammatory responses and modulating inter-microbial communication. Consequently, our findings support the proposal that Bifidobacterium could serve as a promising biomarker for evaluating gut homeostasis and detecting dysbiosis-associated pathologies, including CRC. Also, further studies could elucidate the mechanisms underlying the relationship between Bifidobacterium and CRC and could potentially lead to the development of novel therapeutic and diagnostic strategies for this disease [32,45,58].
Finally, our data revealed statistically significant reductions in the abundance of Lactobacillus within tumor tissues versus adjacent non-tumor tissues. Other studies also observed a decline in the abundance of Lactobacillus in CRC patients compared to healthy controls, which agrees with our findings [32,59]. However, some studies have reported contradictory results, suggesting a complex and context-dependent relationship between intestinal microbiota dysbiosis and CRC [60]. For instance, Aindelis et al. (2020) found that Lactobacillus abundance was substantially higher in patients with CRC than in healthy controls [61]. Such discrepancies may reflect variations in study design, sample size, and patient characteristics, highlighting the need for more research to clarify the role of gut microbiota dysbiosis in CRC development [62].
5. Limitations
There are some limitations to this study that should be mentioned. First, we were unable to measure the bacterial density or count in the healthy colorectal tissue of normal subjects because ethical concerns prevented us from using healthy individuals for biopsy. This limits our ability to compare the microbiota profiles of CRC patients and healthy controls and to identify potential biomarkers for CRC diagnosis or prevention. Second, we used a cross-sectional design that does not allow us to determine the time order of variables or demonstrate causal relationships between alteration in intestinal microbiota and CRC development. It is possible that alterations in the gut microbiota are a consequence rather than a cause of CRC. Therefore, longitudinal research is needed to clarify the temporal dynamics and causal mechanisms of the microbiota-CRC association. Third, we utilized real-time PCR to quantify the abundance of specific bacterial groups, but this method does not provide information about the metabolic activities or functional roles of each bacterium in the context of CRC. Future studies should employ metagenomics or metatranscriptomic approaches to elucidate the functional implications of microbiota changes in CRC pathogenesis and therapy.
6. Conclusion
The present study evaluated the frequency of five genera of bacteria, including Lactobacillus, Firmicutes, Enterococcus, Bifidobacterium, and Clostridium, in CRC patients. We observed that the abundance of Lactobacillus and Bifidobacterium was considerably lower in CRC samples, while that of Enterococcus was higher in cancerous tissue in comparison to normal tissues. These findings suggest this bacterial genus may be associated with CRC development and progression. Additionally, our analysis showed that Firmicutes and Clostridium frequencies varied between the two groups, suggesting that a decline in these two types of bacteria may contribute to the formation of CRC. Our research adds to the growing evidence that gut microbiota is associated with the development of CRC and may be a valuable target for CRC prevention and therapy. Future studies should explore the mechanisms by which these bacteria influence CRC and evaluate their utility as biomarkers or therapeutic agents for CRC.
Ethical approval
The study protocol and ethical issue were approved by the Ethics Committee of Iran University of Medical science (IR.IUMS.FMD.REC.1401.057). All participants were informed of the objectives of this study and signed a written consent form prior to their participation.
Funding
This research was supported by grant No: 1400-3-99-22219 from Iran University of Medical Sciences.
Availability of data and materials
Data will be made available on request.
CRediT authorship contribution statement
Zahra Elahi: Writing – original draft, Project administration, Investigation. Aref Shariati: Writing – review & editing, Supervision, Methodology, Formal analysis, Conceptualization. Narjess Bostanghadiri: Supervision. Leila Dadgar-Zankbar: Investigation. Shabnam Razavi: Writing – review & editing. Samira Norzaee: Formal analysis. Saba Vazirbani Arasi: Investigation. Davood Darban-Sarokhalil: Writing – review & editing, Resources, Project administration, Conceptualization.
Declaration of competing interest
The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper.
Acknowledgements
Not applicable.
References
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Grant ID: 1400-3-99-22219