The Bacteroides fragilis toxin (bft) Gene: Its Role in Virulence, Regulation, and Disease
Main Article Content
Authors
A. Bekbayeva
National Center for Biotechnology, 13/5, Kurgalzhynskoye road, Astana,Kazakhstan, 010000
L.N. Gumilyov Eurasian National University, 2 Satbaev st., Astana, Kazakhstan, 010000
B.S. Kongyr
Al-Farabi Kazakh National University, 71 Al-Farabi Ave., Almaty, Kazakhstan, 050040
E.V. Zholdybayeva
National Center for Biotechnology, 13/5, Kurgalzhynskoye road, Astana,Kazakhstan, 010000
S.S. Kozhakhmetova
National Center for Biotechnology, 13/5, Kurgalzhynskoye road, Astana,Kazakhstan, 010000
Abstract
Bacteroides fragilis can be divided into two different groups of strains: an enterotoxigenic strain (ETBF) that has a pathogenicity island and the Bacteroides fragilis toxin gene (bft) and a non-toxigenic strain (NTBF) that does not have a pathogenicity island and the bft gene. Recent studies have shown that there is a correlation between the presence of the bft gene in enterotoxigenic Bacteroides fragilis (ETBF) strains and various gastrointestinal disorders, including colorectal cancer and inflammatory bowel disease. Due to its ability to disrupt the intestinal epithelial barrier, promote chronic inflammation, and affect carcinogenesis, the presence and expression of bft significantly contribute to the pathogenicity of ETBF. This review provides an analysis of the genetic structure, allelic variants, and regulatory mechanisms of bft. A membrane protein vital to cell adhesion, E-cadherin, is disrupted by Bacteroides fragilis toxin, resulting in disruption of epithelial integrity and facilitating bacterial entry. BFT also stimulates important intracellular signaling pathways, including mitogen-activated protein kinase (MAPK) and nuclear factor kappa-light chain enhancer of activated B cells (NF-kB). These signaling pathways significantly influence both cellular transformation and inflammatory responses. This review also highlights advances in diagnostic methods and innovative therapeutic approaches, such as the development of allosteric inhibitors that can block BFT activity. Although much has been learned about the regulation and function of the bft gene, there are significant gaps in understanding the environmental factors that lead to gene upregulation and its molecular interactions. Future research should aim to elucidate these mechanisms to facilitate the development of targeted therapies.
Keywords
Bacteroides fragilis toxin (bft);, enterotoxigenic Bacteroides fragilis (ETBF);, epithelial barrier disruption;, MAPK pathway;, NF-kB pathway;, colorectal cancer;, allosteric inhibitors;, therapeutic strategies
Article Details
References
Kierzkowska M., Majewska A., Szymanek-Majchrzak K., Sawicka-Grzelak A., Mlynarczyk A., Mlynarczyk G. The presence of antibiotic resistance genes and bft genes as well as antibiotic susceptibility testing of Bacteroides fragilis strains isolated from inpatients of the Infant Jesus Teaching Hospital, Warsaw during 2007–2012. Anaerobe. 2019;56:109-115. DOI:10.1016/j.anaerobe.2019.03.003
Yekani M., Rezaee M.A., Beheshtirouy S., Baghi H.B., Bazmani A., Farzinazar A., Memar M.Y., Sóki J. Carbapenem resistance in Bacteroides fragilis: a review of molecular mechanisms. Anaerobe. 2022;76:102606. DOI:10.1016/j.anaerobe.2022.102606
Kierzkowska M., Majewska A., Karłowicz K., Pituch H. Phenotypic and genotypic identification of carbapenem resistance in Bacteroides fragilis clinical strains. Medical Microbiology and Immunology. 2023;212(3):231-240. DOI:10.1007/s00430-023-00765-w
Cao Y., Rocha E.R., Smith C.J. Efficient utilization of complex N-linked glycans is a selective advantage for Bacteroides fragilis in extraintestinal infections. Proc Natl Acad Sci USA. 2014;111(35):12901-12906. DOI:10.1073/pnas.1407344111
Ma W., Zhang L., Chen W., Chang Z., Tu J., Qin Y., Yao Y., Dong M., Ding J., Li S. Microbiota enterotoxigenic Bacteroides fragilis-secreted BFT-1 promotes breast cancer cell stemness and chemoresistance through its functional receptor NOD1. Protein & Cell. 2024;15(6):419-440. DOI: Crossref
Jasemi S., Emaneini M., Ahmadinejad Z., Fazeli M.S., Sechi L.A., Sadeghpour Heravi F., Feizabadi M.M. Antibiotic resistance pattern of Bacteroides fragilis isolated from clinical and colorectal specimens. Annals of Clinical Microbiology and Antimicrobials. 2021;20:1-8. DOI: Crossref
Guo Y., Ouyang Z., He W., Zhang J., Qin Q., Jiao M., Muyldermans S., Zheng F., Wen Y. Screening and epitope characterization of diagnostic nanobody against total and activated Bacteroides fragilis toxin. Frontiers in Immunology. 2023;14:1065274. DOI: Crossref
Spigaglia P., Barbanti F., Germinario E.A.P., Criscuolo E.M., Bruno G., Sanchez-Mete L., Porowska B., Stigliano V., Accarpio F., Oddi A. Comparison of microbiological profile of enterotoxigenic Bacteroides fragilis isolates from subjects with colorectal cancer or intestinal pre-cancerous lesions versus healthy individuals and evaluation of environmental factors involved in intestinal dysbiosis. Anaerobe. 2023;82:102757. DOI: Crossref
Kangaba A.A., Saglam F.Y., Tokman H.B., Torun M., Torun M.M. The prevalence of enterotoxin and antibiotic resistance genes in clinical and intestinal Bacteroides fragilis isolates in Turkey. Anaerobe. 2015;35:72-76. DOI: Crossref
Ghotaslou R., Yekani M., Memar M.Y. The role of efflux pumps in Bacteroides fragilis resistance to antibiotics. Microbiological Research. 2018;210:1-5. DOI: Crossref
Lee C.G., Hwang S., Gwon S.Y., Park C., Jo M., Hong J.E., Rhee K.J. Bacteroides fragilis toxin induces intestinal epithelial cell secretion of interleukin-8 by the E-cadherin/β-catenin/NF-κB dependent pathway. Biomedicines. 2022;10(4):827. DOI: Crossref
Sears C.L. Enterotoxigenic Bacteroides fragilis: a rogue among symbiotes. Clinical Microbiology Reviews. 2009;22(2):349-369. DOI: Crossref
Wexler H.M. Bacteroides: the good, the bad, and the nitty-gritty. Clinical Microbiology Reviews. 2007;20(4):593-621. DOI: Crossref
Sears C.L., Geis A.L., Housseau F. Bacteroides fragilis subverts mucosal biology: from symbiont to colon carcinogenesis. Journal of Clinical Investigation. 2014;124(10):4166-4172. DOI: Crossref
Carrow H.C., Batachari L.E., Chu H. Strain diversity in the microbiome: lessons from Bacteroides fragilis. PLoS Pathogens. 2020;16(12):e1009056. DOI: Crossref
NCBI Nucleotide Database. National Center for Biotechnology Information. 2024. Available from: URL (accessed 05 Feb 2024).
Sears C.L., Buckwold S.L., Shin J.W., Franco A.A. The C-terminal region of Bacteroides fragilis toxin is essential to its biological activity. Infection and Immunity. 2006;74(10):5595-5601. DOI: Crossref
Dadgar-Zankbar L., Shariati A., Bostanghadiri N., Elahi Z., Mirkalantari S., Razavi S., Kamali F., Darban-Sarokhalil D. Evaluation of enterotoxigenic Bacteroides fragilis correlation with the expression of cellular signaling pathway genes in Iranian patients with colorectal cancer. Infectious Agents and Cancer. 2023;18(1):48. DOI: Crossref
Paradis T., Bègue H., Basmaciyan L., Dalle F., Bon F. Tight junctions as a key for pathogens invasion in intestinal epithelial cells. International Journal of Molecular Sciences. 2021;22(5):2506. DOI: Crossref
Jimenez-Alesanco A., Eckhard U., Asencio del Rio M., Vega S., Guevara T., Velazquez-Campoy A., Gomis-Rüth F.X., Abian O. Repositioning small molecule drugs as allosteric inhibitors of the BFT-3 toxin from enterotoxigenic Bacteroides fragilis. Protein Science. 2022;31(10):e4427. DOI: Crossref
Purcell R.V., Pearson J., Aitchison A., Dixon L., Frizelle F.A., Keenan J.I. Colonization with enterotoxigenic Bacteroides fragilis is associated with early-stage colorectal neoplasia. PLoS ONE. 2017;12(2):e0171602. DOI: Crossref
Zafar H., Saier M.H. Gut Bacteroides species in health and disease. Gut Microbes. 2021;13(1):1848158. DOI: Crossref
Amiri R., Norouzbabaei Z., Kalali N., Ghourchian S., Yaseri M., Abdollahi A., Douraghi M. Identification of enterotoxigenic Bacteroides fragilis in patients with diarrhea: a study targeting 16S rRNA, gyrB and nanH genes. Anaerobe. 2022;75:102546. DOI: Crossref
Kato N., Liu C.X., Kato H., Watanabe K., Tanaka Y., Yamamoto T., Suzuki K., Ueno K. A new subtype of the metalloprotease toxin gene and the incidence of the three bft subtypes among Bacteroides fragilis isolates in Japan. FEMS Microbiology Letters. 2000;182(1):171-176. DOI: Crossref
Franco A.A., Cheng R.K., Goodman A., Sears C.L. Modulation of bft expression by the Bacteroides fragilis pathogenicity island and its flanking region. Molecular Microbiology. 2002;45(4):1067-1077. DOI: Crossref
Choi V.M., Herrou J., Hecht A.L., Teoh W.P., Turner J.R., Crosson S., Wardenburg J.B. Activation of Bacteroides fragilis toxin by a novel bacterial protease contributes to anaerobic sepsis in mice. Nature Medicine. 2016;22(5):563-567. DOI: Crossref
Zamani S., Besharat S., Behnampour N., Behnam A., Asgari N., Mortazavi N. Bacteroides fragilis in saliva: investigating links with ulcerative colitis. Brazilian Journal of Microbiology. 2024;55(4):3691-3698. DOI: Crossref
Patrick S. A tale of two habitats: Bacteroides fragilis, a lethal pathogen and resident in the human gastrointestinal microbiome. Microbiology. 2022;168(4):001156. DOI: Crossref
Cao Y., Wang Z., Yan Y., Ji L., He J., Xuan B., Shen C., Ma Y., Jiang S., Ma D. Enterotoxigenic Bacteroides fragilis promotes intestinal inflammation and malignancy by inhibiting exosome-packaged miR-149-3p. Gastroenterology. 2021;161(5):1552-1566.e12. DOI: Crossref
Quaglio A.E.V., Grillo T.G., De Oliveira E.C.S., Di Stasi L.C., Sassaki L.Y. Gut microbiota, inflammatory bowel disease and colorectal cancer. World Journal of Gastroenterology. 2022;28(30):4053-4063. DOI: Crossref
Jamal W., Khodakhast F., Rotimi V. Antimicrobial susceptibility and prevalence of extra-intestinal enterotoxigenic Bacteroides fragilis among a 5-year collection of isolates causing sepsis in Kuwait. Open Forum Infectious Diseases. 2018;5(Suppl_1):S237. DOI: Crossref
Franco A.A., Mundy L.M., Trucksis M., Wu S., Kaper J.B., Sears C.L. Cloning and characterization of the Bacteroides fragilis metalloprotease toxin gene. Infection and Immunity. 1997;65(3):1007-1013. DOI: Crossref
Avila-Campos M.J., Liu C., Song Y., Rowlinson M.C., Finegold S.M. Determination of bft gene subtypes in Bacteroides fragilis clinical isolates. Journal of Clinical Microbiology. 2007;45(4):1336-1338. DOI: Crossref
Merino V.R.C., Nakano V., Liu C., Song Y., Finegold S., Avila-Campos M.J. Quantitative detection of enterotoxigenic Bacteroides fragilis subtypes isolated from children with and without diarrhea. Journal of Clinical Microbiology. 2011;49(1):416-418. DOI: Crossref
Purcell R.V., Pearson J., Frizelle F.A., Keenan J.I. Comparison of standard, quantitative and digital PCR in the detection of enterotoxigenic Bacteroides fragilis. Scientific Reports. 2016;6:34554. DOI: Crossref
Allen J., Hao S., Sears C.L., Timp W. Epigenetic changes induced by Bacteroides fragilis toxin. Infection and Immunity. 2019;87(6):e00447-18. DOI: Crossref
Ladaycia A., Loretz B., Passirani C., Lehr C.M., Lepeltier E. Microbiota and cancer: in vitro and in vivo models to evaluate nanomedicines. Advanced Drug Delivery Reviews. 2021;170:44-70. DOI: Crossref
Hill C.A., Casterline B.W., Valguarnera E., Hecht A.L., Shepherd E.S., Sonnenburg J.L., Bubeck Wardenburg J. Bacteroides fragilis toxin expression enables lamina propria niche acquisition in the developing mouse gut. Nature Microbiology. 2024;9(1):85-94. DOI: Crossref
Valles-Colomer M., Blanco-Míguez A., Manghi P., Asnicar F., Dubois L., Golzato D., Armanini F., Cumbo F., Huang K.D., Manara S., Masetti G., Pinto F., Piperni E., Punčochář M., Ricci L., Zolfo M., Farrant O., Goncalves A., Selma-Royo M., Binetti A.G., Becerra J.E., Han B., Lusingu J., Amuasi J., Amoroso L., Visconti A., Steves C.M., Falchi M., Filosi M., Tett A., Last A., Xu Q., Qin N., Qin H., May J., Eibach D., Corrias M.V., Ponzoni M., Pasolli E., Spector T.D., Domenici E., Collado M.C., Segata N. The person-to-person transmission landscape of the gut and oral microbiomes. Nature. 2023;614(7946):125-135. DOI: Crossref
Ko S.H., Choi J.H., Kim J.M. Bacteroides fragilis enterotoxin induces autophagy through an AMPK and FoxO3 pathway, leading to the inhibition of apoptosis in intestinal epithelial cells. Toxins. 2023;15(9):544. DOI: Crossref