Published online Sep 29, 2018. doi: 10.4291/wjgp.v9.i2.47
Peer-review started: May 11, 2018
First decision: July 10, 2018
Revised: August 8, 2018
Accepted: August 26, 2018
Article in press: August 26, 2018
Published online: September 29, 2018
Processing time: 140 Days and 8.5 Hours
The incidence of colorectal cancer (CRC), the third most common malignancy, is not only higher among African Americans (AAs), but is also associated with higher mortality. In addition, AAs tend to be diagnosed with CRC at a younger age than Caucasian Americans (CAs) and exhibit worse prognoses than their CA counterparts. Despite this grim outlook, neither the extrinsic/intrinsic factor(s) nor the underlying molecular and/or biochemical mechanisms are fully understood. We hypothesize that imbalance in the gut microbiome between AAs and CAs results in alterations of metabolites, which changes symbiotic relationships and enhance gastrointestinal diseases, including CRC. A number of bacteria are known to promote carcinogenesis in the colon by altering gut microbial composition, which may play a major role in colorectal carcinogenesis.
CRC is the third leading malignancy world-wide, affecting both males and females equally. It represents one of the most common cancers in the United States and is estimated to be the second and third leading cause of cancer-related deaths in men and women, respectively, in the United States. Several studies have also demonstrated that AAs have the highest rate of CRC than any other racial group in the USA, and also AA men are even more likely to die from CRC than AA women. With these grim statistics, it is important to gain a better understanding of the underlying mechanism(s), particularly the role of gut microbiota, in regulating racial disparity in colorectal carcinogenesis.
The current investigation was aimed at studying microbial dysbiosis in the gut between AAs and CAs. The primary endpoint of this investigation was to determine whether the increased incidence of CRC in AAs could be attributed to alterations in gut microbiota. In this pilot study, we investigated the diversity and abundance of specific gut microbial communities in colonic effluents using 16S rRNA gene profiling in AAs and CAs and their possible role in the increased incidence of CRC in AAs.
Male and female AA and CA patients, aged between 40 and 80 years, undergoing routine colonoscopy at the John D. Dingell VA Medical Center in Detroit were asked to participate. To determine the microbial diversity and the microbial richness in AAs and CAs, colonic effluent from each patient was used for DNA extraction and 16s RNA gene-based microbial community profiling which was performed and analyzed by LC Sciences (Houston, Texas, United States). The composition of OTU and alpha diversity was measured by Venn diagram and Rarefaction measurement method. The relative abundance of phylum and classes was depicted by bar and pie chart. The phylogenic tree was plotted for AA and CA to determine the relative abundance of family in microbial community. Several inflammatory and probiotic bacterial marker candidates such as Enterobacteria, Bifidobacteria, Lactobacillus, Fusobacterium and/or Clostridium genus and species-specific bacteria were identified by real-time qPCR using specific primers designed on the basis of conserved and variable region in bacterial 16S rRNA genes according to our standard protocol. Statistical analysis was performed for each experiment accordingly.
The relative abundance of Fusobacterium nucleatum, which has been associated with the development and progression of CRC, was found to be significantly higher in AAs than CAs, indicating a greater risk for the development of CRC in AAs. Clostridium IV, a known mediator of anti-inflammatory effects, was found to be higher in CAs than AAs.
The human colon harbors a complex microbial flora. Bacterial density in the human colon is among the highest found in nature, approaching 1012 bacteria/gm wet weight of feces. These bacteria are in a symbiotic relationship with the intestine, utilizing undigested nutrients as substrates and in return, produce various vitamins, amino acids, transform bile salts and assist in the maintenance of the intestinal barrier, and the appropriate immune response against pathogens. This homeostasis is altered in a state of dysbiosis, which is overgrowth of pathogenic bacteria that are normally inhibited by commensal bacteria. Our current investigation, for the first time, demonstrates microbial dysbiosis between AAs and CAs. This imbalance, we believe, is partially responsible for the racial disparity in CRC observed between AAs and CAs.
Although numerous studies have demonstrated that the incidence of CRC is higher in AAs than CAs, the reasons for this racial disparity are not fully understood. Data generated from this investigation reveal a role for the gut microbiome in racial disparity. The precise mechanisms by which changes in gut microbiota would lead to an increase CRC in AAs remain unexplored. However, it is tempting to speculate that this dysbiosis or overgrowth of certain bacteria in the gut of AAs resulting in alterations in microbial metabolites, specifically deoxycholic acid and lithocholic acid, which are known for their co-carcinogenic activity, could induce the process(es) of carcinogenesis in the colon of AAs. However, the levels of microbial metabolites, including bile acids in AAs and CAs with and without adenomas have not determined. Moreover, no information is available whether the observed dysbiosis in AAs is due to changes in diet and/or lifestyle. Undoubtedly, further investigations are needed to gain a better and fuller understanding of the intrinsic and extrinsic factors that are critically involved in regulating racial disparity in CRC.