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312 Songtanin et al. | Journal of Clinical and Translational Research 2023; 9(5): 308-316
et al. reported that 16 patients out of 1873 patients with acute With the novel concept of gut biofilm and dysbiosis in
appendicitis were found to have colon cancer [28]. The median association with both benign and colorectal cancer due to ongoing
time interval before diagnosis was 5.8 months. The odds ratios of colonic inflammation, alteration of intestinal biofilms after
having an increase in cancer incidence were 38.5-fold in patients appendectomy has been proposed as a possible pathophysiology
older than 40 with acute appendicitis. Consequently, older patients underlying colorectal cancer [33]. Dejea identified polymicrobial
with acute appendicitis should be evaluated for colon cancer. bacterial biofilms in 89% of proximal tumors but in only 12%
Since the proximal colon and distal colon have different of the distal tumors [35]. Bacterial biofilms were associated
embryological origins, this could contribute to differences in the with increased epithelial permeability and activation of IL-6 and
prevalence and prognosis in colon cancers in these two regions. Stat3 [35]. In the normal colon mucosa, biofilms were associated
Furthermore, there are differences in the carcinogenic pathway and with increased crypt epithelial cell proliferation and possibly
gene expression in proximal and distal colon cancers; proximal initiate pro-carcinogenic tissue inflammation. In addition, IL-6 and
tumors more often have a microsatellite instable pathway and Stat3 have been associated with increased epithelial proliferation,
hypermutated DNA, whereas distal colon tumors often have apoptosis, and/or angiogenesis. These authors suggest that the
large chromosomal alterations [29,30]. Proximal colon tumors have presence and organization of biofilm are important factors in
low chromosomal instability, whereas distal colon tumors have high the pathogenesis of colorectal cancer pathogenesis and this
chromosomal instability. These proximal cancers are associated process may not depend on the types of bacteria in biofilm. Dejea
with older age, higher tumor grade, mucinous differentiation, reported that biofilms found in colorectal cancer patients had
and dense infiltration of lymphocytes [29]. The genes that are bacterial invasion into the tumor mass and this possibly changes
overexpressed in these tumors include genes associated with tissue biology by enhancing cellular proliferation and oncogenic
inflammatory reactions and drug metabolism. Genetic alterations transformation. This feature was not detected in biofilm-
include microsatellite instability, hypermethylation, mutations in negative tumors [35]. Shi and coinvestigators also analyzed the
key tumor genic pathways, and BRAF mutants. These pathways gut microbiome in 157 appendectomy cases and 157 normal
may be stimulated by bacterial toxins and mutagenic metabolites controls using metagenomic sequencing [27]. The patients with
and lead to tumor development. appendectomy had a significant increase in the Fusobacterium
The association of appendectomy with the development of phylum. Patients with appendectomy had lower microbiota
proximal colon cancer requires consideration of the function diversity, and these changes persisted over a 2-year follow-up
of the appendix and the potential changes in colonic health period. These changes were more pronounced in older patients
associated with appendectomy. The mucosa in the appendix (>50 years). Patients with appendectomy had an enrichment of
contains plasma cells which secrete IgA and IgG; it is the colorectal cancer-associated species in the gut. There were 11
primary site for IgA production. The submucosa contains enriched species, and seven of them have been associated with
aggregates of lymphocytes, and the morphology is similar to colorectal cancer. Five possibly protective bacteria were depleted
the concentrated lymphoid tissue in Peyer’s patch in the ileum. in these samples. Microbial genes were analyzed to determine
The appendix is a repository for commensal gut bacteria, such the metabolic pathways in these microbiomes. In appendectomy
as Firmicutes, Proteobacteria, Bacteroidetes, Fusobacteria, and cases, the pathways for the biosynthesis of deoxyribonucleotides,
Actinobacteria [31,32]. Its immune function probably depends peptidoglycan, L-glutamine, L glutamate, and pyrimidine
in part on these commensal organisms [6]. The existence of deoxyribonucleotides were increased; these pathways have been
biofilm in the appendix has beneficial effects on the entire reported as cancer promoting. The biosynthesis L-proline was
digestive system [6] and is thought to act as a sanctuary for decreased, and this compound is thought to be protective. Overall,
commensal bacteria and to facilitate their reinoculation of the this study demonstrates that appendectomy causes microbial
gut after a gastrointestinal infections and possibly episodes of dysbiosis with increases in colorectal cancer-promoting bacteria
antibiotic treatment. The changes in commensal bacteria and the and depletion of possibly beneficial microbes [27].
development of “abnormal” biofilms could lead to alterations in In summary, the association between appendectomy and the
colonic health and function [33]. proximal colon cancer has several possible explanations. First, the
The development of colorectal cancer is explained in part by proximal colon has higher levels of microbial biofilms (89%) than
alterations in genetic factors. However, environmental factors, the distal colon (18%). The appendix is located on the cecum and
such as local inflammation and microbiota, may also have an the appendectomy can alter the microbiome and result in dysbiosis
important role [24]. A study of the appendiceal tissue revealed and bacterial invasion which stimulates tumor formation. Second,
increased numbers of natural killer (NK) T cells that can produce the loss of immune function after appendectomy leads to changes
cytokines following activation [6]. The evidence of immune in the interaction between microbiota and colonic mucosa. Clinical
cells in appendiceal tissue is also supported by another study by investigations need to determine if there is a consistent alteration
Yaun-Kun which demonstrated that patients with appendiceal in colonic flora associated with pathogenic biofilms. This might
inflammation have lower NK cells; patients with colorectal lead to prospective studies on the development of colon cancer in
cancer and a normal appendix have low NK cells [34]. The cells patients with these changes in flora and eventually to determine
have a suppressor function and could limit the development and whether or not strategies to replace pathogenic flora with normal
proliferation of malignant cells. flora have potential benefit [36].
DOI: http://dx.doi.org/10.18053/jctres.09.202305.23-00090