Vaginal microbiota and the pathobiosis path: its role in the evolution of HPV cervical intraepithelial neoplasia and cancer

Human microbiome study has become pivotal during the last years; eubiosis, pathobiosis, and balanced ecosystem are now leading terms in comprehension of Health and Disease in humans. Vaginal ecosystem is a balance system in which microbiome is in constant dynamic profile in relation to the symbiotic equilibrium from different species and cells (human cells, lactobacilli and other bacteria, virus or fungi. Previous experiences demonstrated how it is possible to restore human vaginal ecosystem by using a long-time course of a selected population of vaginal symbiotic containing lactobacillus rhamnosus BMX 54 plus lactose. Taking into account the leading role of lactobaciili in human vaginal microbiota and the pathobiosis pathway from eubiosis to pathology until cancer (eubiosis derangement versus a more aggressive and dangerous pathobiosis), the authors hypothesized that exogenously manipulation of vaginal microbiome by a selected symbiotic could stop the pathobiosis pathway leading to a new health system. Surprisingly a recent published clinical trial showed a consistent percentage of clearance of PAP-smear abnormalities and HPV-DNA clearance obtained in women affected by concomitant vaginitis/bacterial vaginosis and HPV infections treated for long-term course with vaginal tabs of lactobacillus rhamnosus BMX 54 plus lactose. Since exogenous vaginal manipulation of microbiome could be a new and promising tool for eubiosis restoration in vaginal ecosystem, and since “pathobiosis pathway” could be interrupted by long-term use of vaginal probiotics, it seems possible to confirm the hypothesis that eubiosis replacement in vaginal microbiome could lead to counter infections such as HPV and its detrimental-related pathologies in women. Vaginal probiotics application could represent a safe, less expensive, and effective treatment to control HPV infections.

Vaginal microbiota; Pathobiosis path; HPV; Cancer; Cervical intraepithelial neoplasia

[1] Palma E., Recine N., Domenici L., Giorgini M., Pierangeli A., Benedetti Panici P.: “Long-term Lactobacillus rhamnosus BMX 54 application to restore a balanced vaginal ecosystem: a promising solution against HPV-infection”. BMC Infect. Dis., 2018, 18, 1.

[2] Parolin C., Foschi C., Laghi L., Zhu C., Banzola N., Gaspari V., et al.: “Insight into vaginal bacterial communities and metabolic profiles of Chlamydia trachomatis infection: positioning between eubiosis and dysbiosis”. Front. Microbiol., 2018, 9, 600.

[3] Bukharin O.V., Sgibnev A.V., Chercasov S.V.: “The role of pro-and antioxidants of microorganisms in regulation of symbiosis homeostasis mechanisms (on the model of human vaginal biotope”. Zh. Mikrobiol. Epidemiol. Immunobiol., 2014, 3, 9.

[4] Crucitti T.: “Eve’s garden: myths, legends and secrets unmasked”. Res. Microbiol., 2017, 168, 773.

[5] Aroutcheva A., Gariti D., Simon M., Shott S., Faro J., Simoes J.A., et al.: “Defense factors of vaginal lactobacilli”. Am. J. Obstet. Gynecol., 2001, 185, 375.

[6] Conti C., Malacrino C., Mastromarino P.: “Inhibition of herpes simplex virus type 2 by vaginal lactobacilli”. J. Physiol. Pharmacol., 2009, 60, 19.

[7] Matu M.N., Orinda G.O., Njagi E.N., Cohen C.R., Bukusi E.A.: “In vitro inhibitory activity of human vaginal lactobacilli against pathogenic bacteria associated with bacterial vaginosis in Kenyan women”. Anaerobe, 2010, 16, 210.

[8] Bultman S.J.: “Emerging roles of the microbiome in cancer”. Carcinogenesis, 2014, 35, 249.

[9] Schiffman M., Castle P.E., Jeronimo J., Rodriguez A.C., Wacholder S.: “Human papillomavirus and cervical cancer”. Lancet, 2007, 370, 890.

[10] Clarke M.A., Rodriguez A.C., Gage J.C., Herrero R., Hildersheim A., Wacholder S., et al.: “A large, population-based study of age-related associations between vaginal pH and human papillomavirus infection”. BMC Infect. Dis., 2012, 12, 33.

[11] Turner J.R.: “Intestinal mucosal barrier function in health and disease”. Nat. Rev. Imm., 2009, 9, 799.

[12] Taha T.E., Hoover D.R., Dallabetta G.A., Kumwenda N.I., Mtimavalye L.A.R., Yang L.P., et al.: “Bacterial vaginosis and disturbances of vaginal flora: association with increased acquisition of HIV”. AIDS, 1998, 12, 1699.

[13] Solomon D., Davey D., Kurman R., Moriarty A., O’Connor D., Prey M., et al.: “The 2001 Bethesda system: terminology for reporting results of cervical cytology”. JAMA, 2002, 287, 2114.

[14] Lee J.E., Lee S., Lee H., Song Y.M., Lee K., Han M.J., et al.: “Association of the vaginal microbiota with human papillomavirus infection in a Korean twin cohort”. PLoS One, 2013, 8, e63514.

[15] Holst E.: “Bacterial vaginosis microbiological and clinical findings”. Eur. J. Clin. Microbiol., 1987, 6, 536.

[16] Bornstein J., Bentley J., Bösze P., Girardi F., Haefner H., Menton M., et al.: “2011 colposcopic terminology of the International Federation for Cervical Pathology and Colposcopy”. Obstet. Gynecol., 2012, 120, 166.

[17] Amsel R., Totten P.A., Spiegel C.A., Chen K.C.S., Eschenbach D., Holmes K.K.: “Nonspecific vaginitis. Diagnostic criteria and microbial and epidemiologic associations”. Am. J. Med., 1983, 74, 14.

[18] Mitra A., MacIntyre D.A., Marchesi J.R., Lee Y.S., Bennett P.R., Kyrgiou M.: “The vaginal microbiota, human papillomavirus infection and cervical intraepithelial neoplasia: what do we know and where are we going next?” Microbiome, 2016, 4, 58.

[19] Song D., Kong W.M., Zhang T.Q., Jiao S.M., Chen J., Han C., et al.: “The negative conversion of high-risk human papillomavirus and its performance in surveillance of cervical cancer after treatment: a retrospective study”. Arch. Gynecol. Obstet., 2017, 295, 197.

[20] Gillet E., Meys J.F.A., Verstraelen H., Verhelst H., De Sutter P., Temmerman M., et al.: “Association between bacterial vaginosis and cervical intraepithelial neoplasia: systematic review and meta-analysis”. PLoS One, 2012, 7, e45201.

[21] Nam K.H., Kim Y.T., Kim S.R., Kim S.W., Kim J.W., Lee M.K., et al.: “Association between bacterial vaginosis and cervical intraepithelial neoplasia”. J. Gynecol. Oncol., 2009, 20, 39.

[22] Bosch F.X., Lorincz A., Muñoz N., Shah K.: “The causal relation between human papillomavirus and cervical cancer”. J. Clin. Pathol., 2002, 55, 244.

[23] Motevaseli E., Shirzad M., Akrami S.M., Mousavi A.S., Mirsalehian A., Modarressi M.H.: “Normal and tumour cervical cells respond differently to vaginal lactobacilli, independent of pH and lactate”. J. Med. Microbiol., 2013, 62, 1065.

[24] Bertini M.: “Is time for thinking to vaginal microbiome to prevent sexually transmitted diseases?” Int. J. Fam. Comm. Med., 2018, 2, 1.

[25] Pendharkar S., Magopane T., Larsson P.G., De Bruyn G., Gray G.E., Hammarström L., et al.: “Identification and characterisation of vaginal lactobacilli from south African women”. BMC Infect. Dis., 2013, 13, 43.

[26] Jespers V., van de Wijgert J., Cools P., Verhelst R., Verstraelen H., Delany-Moretlwe S., et al.: “Vaginal biomarkers study group. The significance of lactobacillus crispatus and L. Vaginalis for vaginal health and the negative effect of recent sex: a cross-sectional descriptive study across groups of African women”. BMC Infect. Dis., 2015, 15, 115.

[27] De Backer E., Verhelst R., Verstraelen H., Alqumber M.A., Burton J.P., Tagg J.R., et al.: “Quantitative determination by real-time PCR of four vaginal lactobacillus species, Gardnerella vaginalis and Atopobium vaginae indicates an inverse relationship between L. Gasseri and L. Iners”. BMC Microbiol., 2007, 7, 115.

[28] Spurbeck R.R., Arvidson C.G.: “Lactobacilli at the front line of defense against vaginally acquired infections”. Future Microbiol., 2011, 6, 567.

[29] Iyer C., Kosters A., Sethi G., Kunnumakkara A.B., Aggarwal B.B., Versalovic J.: “Probiotic lactobacillus reuteri promotes TNF-induced apoptosis in human myeloid leukemia-derived cells by modulation of NF-kappaB and MAPK signalling”. Cell. Microbiol., 2008, 10, 1442.

[30] Hemarajata P., Versalovic J.: “Effects of probiotics on gut microbiota: mechanisms of intestinal immunomodulation and neuromodulation”. Therap. Adv. Gastroenterol., 2013, 6, 39.

[31] Orlando A., Messa C., Linsalata M., Cavallini A, Russo F.: “Effects of lactobacillus rhamnosus GG on proliferation and polyamine metabolism in HGC-27 human gastric and DLD-1 colonic cancer cell lines”. Immunopharmacol. Immunotoxicol., 2009, 31, 108.

[32] Orlando A., Refolo M.G., Messa C, Amati L., Lavermicocca P., Guerra V, et al.: “Antiproliferative and proapoptotic effects of viable or heat-killed lactobacillus paracasei IMPC2.1 and Lactobacillus rhamnosus GG in HGC-27 gastric and DLD-1 colon cell lines”. Nutr. Cancer, 2012, 64, 1103.

[33] Sharma S., Singh R.L., Kakkar P.: “Modulation of Bax/Bcl-2 and caspases by probiotics during acetaminophen induced apoptosis in primary hepatocytes”. Food Chem. Toxicol., 2011, 49, 770.

[34] Tamrakar R., Yamada T., Furuta I., Cho K., Morikawa M., Yamada H., et al.: “Association between lactobacillus species and bacterial vaginosis-related bacteria, and bacterial vaginosis scores in pregnant Japanese women”. BMC Infect. Dis., 2007, 7, 128.

[35] Boccardo E., Lepique A.P., Villa L.L.: “The role of inflammation in HPV carcinogenesis”. Carcinogenesis, 2010, 31, 1905.

[36] Reid G.K., Mills A.P., Bruce A.W.: “Implantation of lactobacilli Casei var-rhamnosus into the vagina”. Lancet, 1994, 344, 1229.

[37] Recine N., Palma E., Domenici L., Giorgini M., Imperiale L., Sassu C., et al.: “Restoring vaginal microbiota: biological control of bacterial vaginosis. A prospective case-control study using Lactobacillus rhamnosus BMX 54 as adjuvant treatment against bacterial vaginosis”. Arch. Gynecol. Obstet., 2016, 293, 101.