Perspective: Alpha-Bugs, Their Microbial Partners, and the Link to Colon Cancer
Open accessAbstract
A dramatic intersection between the infectious diseases and oncology fields has emerged from the appreciation that many cancers arise in the setting of chronic infection. For certain viral-induced cancers, such as human papilloma virus (HPV)–associated cervical cancer, the integrated virus encodes oncogenes that directly drive the transformation of infected cells. However, the vast majority of infection-associated cancers arise from chronic immune responses that, although ineffective in eliminating the inciting microbe, collaborate with microbial products to drive carcinogenesis. As many as one-third of cancers worldwide, particularly epithelial cancers, are associated with identified single microbial infections, leading to the conceptual paradigm that chronic infection with specific microbes causes these cancers, independent of other components of the ambient microbial community. In addition to cervical cancer and HPV, other well-established examples include gastric cancer and Helicobacter pylori, liver cancer and hepatitis B and C viruses, urinary bladder cancer and Schistosoma hematobium, and biliary tree cancer, Clonorchis sinensis, and Opisthorchis viverrini. A contrasting view of microbial carcinogenesis has been applied to colon cancer, the second leading cause of death due to cancer among adults in the United States. On the basis of increasingly high through put methods, we now understand that the colon is home to one of the most dense and diverse communities of bacteria in the body and that, although clustering of the colon microbiome sequences may occur in families or under similar close-contact conditions, we are all remarkably unique in our bacterial make up [1–2]. Indeed, beginning in the 1960s, investigators postulated and pursued links between the complex colon commensal flora and colon cancer [3]. Our recent work demonstrating the capacity of a specific human colonic bacterium, enterotoxigenic Bacteroides fragilis (ETBF), to induce colon tumors in multiple intestinal neoplasia (Min) mice [4] leads us to propose the “Alpha-bug hypothesis,” which integrates the single microbe and microbiome community views of microbial carcinogenesis. While we focus on colon carcinogenesis as an example, we propose that the Alpha-bug hypothesis might apply to other cancer types as well as other chronic immune-based pathology such as inflammatory bowel disease (IBD). Understanding how our colon bacterial communities contribute to the pathogenesis of colon cancer will require understanding the tripartite relationship depicted in Figure 1. This tripartite relationship positions members of the colon microbiome at its apex to suggest that bacteria are the key drivers of the mucosal immune response and subsequent changes in epithelial cell function and genetics that underpin oncogenic transformation. Colonic epithelial cells (CEC) possessing genetic or epigenetic mutations that disorder cell signaling and function are the cells of origin for colon cancer. It is estimated that clinical colon cancer emerges after a 20- to 40-year span in which sufficient CEC mutations accumulate to permit oncogenic transformation. Mucosal inflammation is integral to understanding colon cancer pathogenesis based on the strong clinical link of intestinal neoplasia and IBD such as Crohn’s disease and ulcerative colitis together with the recent demonstration of key molecular links between innate and adaptive immune responses and epithelial cancers. Further microbiome studies in IBD patients serve to well illustrate that microbiome dysbiosis is usual with chronic intestinal inflammation [5]. Tripartite relationship contributing to colon cancer pathogenesis. The microbiome, colonic mucosal immune balance, and colonic epithelial cell (CEC) responses (to the microbiome and mucosal immune responses) and CEC genetics are proposed to collectively contribute to the pathogenesis of colon cancer. Colon cancer has not yet been epidemiologically linked to a single microbe, raising the alternative idea that it is driven by multiple members of the complex colonic microbial community [6–8 ]. So how might the microbiota play a role in colon oncogenesis? One hypothesis might be that the colonic bacterial species act collectively to induce colon cancer in specific hosts (with possibly host gene polymorphisms leading to subtle pro-tumor mucosal immune responses), particularly if the host is ingesting a cancer-prone diet. This builds on the often-cited epidemiologic data indicating that the colon cancer risk of a migrating population will assume that of their resident country [7]. The more conventional hypothesis is that select microbiome members are sufficiently dominant that they alone define the oncogenic risk. This is, in essence, our clinical construct for diarrheal disease pathogenesis. If an individual develops diarrhea and a Shigella spp. is isolated from his or her feces, the person is designated as a case of shigellosis. While numerous organisms ha
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The keystone-pathogen hypothesis and the α-bug hypothesis both state that certain low abundance microbiota members, such as enterotoxigenic B. fragilis, possess unique virulence traits that are pro-oncogenic and remodel the microbiome, promoting mucosal immune responses and colonic epithelial cell changes.
“The keystone-pathogen hypothesis88 and the α-bug hypothesis both state that certain, low abundance microbiota members (such as enterotoxigenic B. fragilis) possess unique virulence traits, which are pro-oncogenic and remodel the microbiome and in turn promote mucosal immune responses and colonic epithelial cell changes.89”
From The gut microbiota and host health: a new clinical frontier (2016) · cites this paper as [89]
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- Authors
- Sears, C. L., & Pardoll, D. M.
- Affiliations
- Johns Hopkins University (US)
- Venue
- The Journal of Infectious Diseases
- Publisher
- Oxford University Press (OUP)
- Published
- 2011-02-01
- Volume
- 203
- Issue
- 3
- Pages
- 306-311
- ISSN
- 0022-1899 (ISSN-L)
- 1537-6613
- PMC
- PMC3071114
- OpenAlex
- W2096233985
- Cited by
- 259
- References
- 29
- Citations by year
- 2026: 22 · 2025: 13 · 2024: 25 · 2023: 23 · 2022: 18 · 2021: 23 · 2020: 21 · 2019: 19 · 2018: 17 · 2017: 13 · 2016: 15 · 2015: 7 · 2014: 12 · 2013: 16 · 2012: 11
- FWCI
- 4.01
- Type
- journal article
- Language
- en
- Open access
- bronze
- doi.org
- Locations
- The Journal of Infectious Diseases (publishedVersion)
- PubMed Central (publishedVersion)
- PubMed (publishedVersion)
- Funders
- Johns Hopkins University
- National Cancer Institute (R01CA151325, R01CA151393)
- National Institute of Diabetes and Digestive and Kidney Diseases (R01DK045496, R01DK080817, R01DK059655)
- Topics
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Gut microbiota and health
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Biotechnology › Cancer Research and Treatments
- Health Sciences › Dentistry › Periodontics › Oral microbiology and periodontitis research
- Keywords
- colon cancer, colon microbiome, enterotoxigenic Bacteroides fragilis, microbial carcinogenesis, chronic infection, mucosal immune response, oncogenic transformation, ApcMin/+ mice, inflammatory bowel disease
- MeSH terms
- Bacteria, Colon, Colonic Neoplasms, Humans
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