Does Active Oral Sex Contribute to Female Infertility?

We hypothesize that Chlamydia trachomatis evolved as a commensal of the gastrointestinal tract; oral inoculation of the pathogen, previously reduced/eliminated by sanitation, is significantly contributed by increased oral sex practices, upon which reproductive tract contamination/infection may occur via rectovaginal transmission.

Abstract

Based on recent, historical, and circumstantial evidence, we present a multifactorial hypothesis that has potential direct implications on the epidemiology and management of chlamydial infection and disease in humans. We propose that (1) like its veterinary relatives, the oculogenital pathogen Chlamydia trachomatis evolved as a commensal organism of the human gastrointestinal (GI) tract primarily transmissible via the fecal-oral route; (2) in the modern era, C. trachomatis causes “opportunistic” infection at non-GI sites under conditions driven by improved sanitation/hygiene and reduced fecal-oral transmission; and (3) the rise in the practice of oral sex is contributing to the increased prevalence of C. trachomatis in the human GI tract. Infectious organisms produced in the GI tract and reaching the rectum may then chronically contaminate and infect the female urogenital tract, thereby potentially contributing to the most serious sequelae of chlamydial infection in women: pelvic inflammatory disease, ectopic pregnancy, and tubal factor infertility.

(See the major article by Carlson et al, on pages 990–9.)

We hypothesize that:

1. All members of the Chlamydiaceae have evolved primarily as commensals of the digestive tract of their host(s) with fecal-oral transmission (FOT) as the principal route of dissemination to new hosts. In communities where FOT is reduced, the occurrence of chlamydiae in the digestive tract is reduced.

2. Chlamydia trachomatis, a commensal microorganism of the human gastrointestinal tract (GIT), is an opportunistic pathogen in the genital and respiratory tracts and the conjunctiva. Under conditions of reduced FOT, direct contact is the primary mode of transmission.

3. Chlamydia trachomatis is efficiently transmitted to the GIT of new hosts via oral sex. The increasing practice of oral sex is contributing to the increased prevalence of C. trachomatis in the human GIT in communities where FOT was previously reduced.

Tenets 1–2 imply a paradigm shift in the study of C. trachomatis infection reflecting its revised status from principal pathogen to commensal organism causing opportunistic infection at mucosal epithelia other than its evolutionarily preferred gastrointestinal (GI) site. For instance, the ability of these organisms to vary antigenically [1], the odd structures and properties of chlamydial peptidoglycan [2] and lipo-oligosaccharide [3, 4], and the extrusion of plasma membrane–bound inclusions or inclusion fragments [5] may have evolved to facilitate chlamydial survival and colonization of the GIT.

Tenet 3 implies that orally inoculated chlamydiae that survive in and colonize the GIT may reach the rectum and, chronically or episodically, contaminate and/or infect the female genital tract, eventually progressing to cause or contribute to tubal pathology. The global hypothesis therefore raises the question: Does active oral sex contribute to female infertility?

ALL CHLAMYDIA SPECIES HAVE EVOLVED TO COLONIZE THE GIT

An indirect but compelling argument that supports the idea that C. trachomatis colonizes the GIT without clinical disease is that most, if not all, other Chlamydia species are first and foremost innocuous gut commensals. This was previously suggested [6–8], and Supplementary Data 1 briefly documents supportive evidence for each species. Infectious chlamydiae that colonize the digestive tract of animals may be disseminated to new hosts via FOT, and may behave as opportunistic pathogens when contaminating a non-GI site in the same host or another susceptible host of the same species. Alternatively, FOT may occur to a different animal species or zoonotically to humans (eg, psittacosis). Confirmed or suspected colonization of the digestive tract of their host by veterinary Chlamydia species therefore begs the question: Is C. trachomatis also an innocuous, unsuspected commensal colonizer of the human GIT? If so, can it also be transmitted via FOT? Are ingested chlamydiae able to survive host defenses and reach the rectum? From there, can they contaminate and infect the female genital tract?

CHLAMYDIA TRACHOMATIS CAUSES OPPORTUNISTIC INFECTIONS AT GENITAL, OCULAR, AND RESPIRATORY MUCOSAL EPITHELIA

The proposed revision of C. trachomatis’ status as a gut commensal organism complements but does not challenge the well-documented evidence of C. trachomatis infections at urogenital, ocular, and respiratory sites and transmission via sexual activity or direct contact. Opportunity for feces-borne transmission of veterinary chlamydiae to nonenteric sites abounds in natural and domestic environments and is facilitated by the ability of chlamydial elementary bodies to remain infectious for some time outside their hosts. In addition, dissemination from the GIT to distant sites may also occur via circulating infected cells such as macrophages or dendritic cells, thus allowing access to different sites in the host. In humans, such mechanisms are proposed to contribute to the dissemination of Chlamydia pneumoniae from infected lungs to atherosclerotic plaques [9, 10] and of C. trachomatis from the infected genital tract to synovial cells and synovial membrane of arthritic joints [11, 12]. Conversely, infectious chlamydiae may target the GIT from distant sites by similar mechanisms as suggested by recent experiments using the mouse/Chlamydia muridarum model system [13]. In humans, in addition to oral inoculation, infectious chlamydiae may also occur at the rectum via genital-rectal autoinoculation or via rectal intercourse with an infected partner. Overall, this suggests that infectious chlamydiae have multiple ways to access the GIT, from where they have ample, nonmutually exclusive opportunities to access non-GI sites from endogenous or environmental feces-contaminated sources and via circulating monocytic cells of the immune system.

MODERN SANITATION AND ENHANCED PERSONAL HYGIENE HAVE CURTAILED TRANSMISSION OF C. TRACHOMATIS VIA THE FECAL ORAL ROUTE

Modern sanitation consists of an array of measures aimed at globally eliminating or minimizing contact between humans and waste from humans and animals. Enteric bacteria including Escherichia coli pathotypes (eg, E. coli O157:H7) [14] and environmental microorganisms such as Vibrio cholerae [15] may be harmless in animal hosts but are capable of causing severe disease in humans. Global sanitation measures that have historically reduced FOT of enteric pathogens to humans, together with enhanced personal hygiene [16], have dramatically altered the composition and diversity of the human gut microbiota. We propose that, in the pre–sexual revolution/human immunodeficiency virus (HIV)/AIDS pandemic period, when oral sex was not as commonly practiced as it is today, this included a significant reduction of commensal C. trachomatis from the gut microbiota in humans. In support of this hypothesis, we review historical and epidemiological evidence (Supplementary Data 2) that suggests the existence of a missing reservoir of infectious chlamydiae for trachoma, the other notorious disease caused by C. trachomatis, in regions of the world that have poor to no sanitation.

ACTIVE ORAL SEX “REINTRODUCES” C. TRACHOMATIS IN THE GIT

Seventy five percent of women report they have ever engaged in oral sex [17]. The popular belief that oral sex is “not sex” [18] and the search for safer sex in the face of the HIV epidemic have fueled the notion that oral sex is relatively safe and does not require physical protection such as a condom or dam. Indirect evidence [19–21] suggests that oral sex is a frequent recreational activity of young sexually active high-school or college-age adolescents/young adults who think that the risk-to-benefit ratio of oral sex is relatively small. Reality is different: although the probability of transmitting HIV via oral sex is lower than via vaginal or anal sex, the practice is still associated with many diverse risks [22]. Oral sex is known to transmit a variety of viral and bacterial sexually transmitted infections, including herpes, syphilis, gonorrhea, human papillomavirus (HPV), and hepatitis A/B infection [23, 24], and the association with HPV-related oropharyngeal cancer is a growing concern [25].

Orally inoculated C. trachomatis colonizing the GIT of its host may, however, systematically elude detection through a combination of factors. No reason a priori exists for an apparently healthy woman or her physician to suspect oral or rectal chlamydia when a nucleic acid amplification diagnostic test from a cervical swab is negative. Oral, rectal, or fecal samples are not routinely tested for C. trachomatis. Perhaps most importantly, orally acquired chlamydiae may elude the unsuspecting woman’s own immune system as it fails to recognize or respond to a microbe that is quietly colonizing the GIT.

We hypothesize that infectious chlamydiae are transmitted to the female genital tract via active oral sex and colonization of unidentified GIT site(s). We further hypothesize that all Chlamydia species have evolved conserved mechanisms to evade innate and immune host defenses in the GIT, and that orally inoculated chlamydiae will contaminate and infect not only the rectum but also the lower genital tract in women. GIT colonization may allow the organism to “persist” undetected by the human host and tolerated by the immune system for extended periods of time. Evidence from murine models of chlamydial genital infection strongly supports this hypothesis (Supplementary Data 3). Repeated, unsuspected exposure of the reproductive tract to even low levels of infectious chlamydiae may cause chronic inflammation, low-level infection, and/or disturbance of the vaginal microbiota that, individually or together, may facilitate ascending infection to the upper genital tract. The outcome is that, having made the relatively short, final journey from the rectum to the vagina and cervix, orally acquired chlamydia may contribute to chronic chlamydial infection of the female reproductive tract and its most serious sequelae: pelvic inflammatory disease, tubal factor infertility, and life-threatening ectopic pregnancies.

Conclusions

The proposed relationship between oral sex, GIT colonization, repeated exposure/infection of the female lower genital tract, ascending infection, tubal disease, and its sequelae raises many more questions that can be listed here, some of which may be testable experimentally. For instance, if sanitation facilitated the establishment of C. trachomatis as a sexually transmitted pathogen, then the reverse should be true in areas where FOT is still ever-present, eg, cholera-endemic areas. If oral sex is significantly contributing to the inoculation of C. trachomatis into the GIT, where along the 9-m length does colonization occur? In developed, sanitized regions of the world, sexual transmission remains the major route by which C. trachomatis disseminates among men and women. GIT colonization may, however, be making a comeback with the help of increasing oral sex practices. A sobering thought is that with oral sex and GIT colonization, C. trachomatis may have “evolved” yet another, most unsophisticated way to elude the clinician, the infected patient, and the patient’s own immune system.

Supplementary Data

Supplementary materials are available at The Journal of Infectious Diseases online. Consisting of data provided by the authors to benefit the reader, the posted materials are not copyedited and are the sole responsibility of the authors, so questions or comments should be addressed to the corresponding author.

Notes

Acknowledgments. The authors acknowledge the significant contribution to the development of the “gut hypothesis” of chlamydial persistence made by members of the National Institute of Allergy and Infectious Diseases, National Institutes of Health Sexually Transmitted Infection Cooperative Research Center (NIH-NIAID-STI Maryland CRC) during biweekly teleconference discussions over the past 7 years. P. B. acknowledges Dr Karine Laroucau (ANSES, Maison-Alfort, France) for her insistence that there must be an “environmental” source of chlamydiae that accounts for the ease and frequency of transmission of veterinary Chlamydia species. The authors are also indebted to Drs Lee Ann Campbell (University of Washington Medical Center, Seattle), Khalil Ghanem and Sheila West (Johns Hopkins University School of Medicine, Baltimore, Maryland), Gary Entrican and David Longbottom (Moredun Research Institute, Midlothian, United Kingdom), Robin Bailey and David Mabey, (London School of Hygiene and Tropical Medicine, United Kingdom), Henry de Vries (University of Amsterdam, the Netherlands), Konrad Sachse (University of Jena, Germany), and Cosette Wheeler (University of New Mexico, Albuquerque) for their useful comments and suggestions.

Disclaimer. The content is solely the responsibility of the authors and does not necessarily represent the official views of the National Institutes of Health.

Financial support. This work was supported by the NIH-NIAID-STI CRC (grant number U19 AI084044).

Potential conflicts of interest. All authors: No reported conflicts of interest. All authors have submitted the ICMJE Form for Disclosure of Potential Conflicts of Interest. Conflicts that the editors consider relevant to the content of the manuscript have been disclosed.

Presented in part: German Chlamydia Workshop, Jena, Germany, 23 February 2017; Eighth Meeting of the Chlamydia Basic Research Society, Charlotte, North Carolina, 10 April 2017; Annual Meeting of the NIH-NIAID-STI Cooperative Research Center, Santa Fe, New Mexico, 24 May 2017; and FEMS Congress, Valencia, Spain, 10 July 2017.