Chlamydia and the Gastrointestinal System

Abstract

Chlamydiae are intracellular, gram-negative, and prokaryotic microorganisms. Capable of causing disease in many mammalian and avian species, there are three types that cause disease in humans: Chlamydia trachomatis, Chlamydia pneumoniae, and Chlamydia psittaci. Among the chlamydia species, C. trachomatis is the most studied and encountered type because it is a leading cause of trachoma and sexually transmitted diseases. C. trachomatis, a known pathogen of the genital tract, can also be routinely detected in the human gastrointestinal tract. It can infect the enteroendocrine cells of the gastrointestinal tract. The best-known manner for C. trachomatis to enter the gastrointestinal tract is through oral and anal sex. Most of them are dormant, without causing any infection in the infected person. Chlamydia proctitis is the most well-known disease caused by C. trachomatis in the gastrointestinal tract. In this section, we evaluated the often-overlooked Chlamydia and the gastrointestinal system findings within the gastroenterology practice, the diseases it causes, and the treatments for these diseases.

1. Introduction

Among the diseases caused by chlamydia, trachoma is the most widely known. The earliest known information about trachoma is found in Egyptian papyrus and Ancient Chinese inscriptions [1, 2, 3]. Intracytoplasmic inclusion bodies of Chlamydia trachomatis were first demonstrated by the researchers Halberstaedter and Von Prowazek [4]. In 1907, Halberstaedter and Von Prowazek applied a sample from a patient with trachoma to the conjunctiva of a monkey and, after the infection emerged, were able to show the intracytoplasmic inclusion bodies by staining the mucopurulent exudate sample with Giemsa. They defined these bodies as protozoa and named them Chlamidozoa [5]. The role of C. trachomatis in genital infections was evidenced by the same researchers in 1909 when they showed inclusion bodies in the conjunctival cells of babies with non-gonococcal ophthalmia neonatorum, in the cervical epithelial cells of the mothers of babies, and in the urethral epithelial cells of male patients with non-gonococcal urethritis. In 1910, Lindner showed how the mother and father of a baby with inclusion conjunctivitis showed inclusion bodies in the mother’s cervical and father’s urethral specimens [5]. Lymphogranuloma venereum (LGV) was first described in the late 1700s [3] and was reported by Durand, Nicolas, and Favre in 1913. Gamma and Favre showed inclusion bodies in the cytoplasm of mononuclear cells in an infected lymph node in 1924 [5]. Psittacosis was first described in humans by Ritter in 1879. Later, outbreaks were reported in many European countries. In the 1950s, attention was drawn to contamination, especially from poultry [3]. Chlamydia pneumonia was first isolated in 1965 during trachoma vaccine studies in Taiwan. It was later isolated from throat cultures of children with pharyngitis in the United States in 1983 [3, 6]. C. trachomatis was produced in the yolk sac of embryonated eggs by T’ang et al. in 1957 and isolated from cell culture by Gordon and Quan in 1965. In 1970, the microimmunofluorescence technique started being used in diagnosis, and Direct Fluorescent Antibody (DFA) and Enzyme Immunoassay (EIA) tests were developed in the 1980s [3, 7]. After the 1990s, polymerase chain reaction (PCR), ligase chain reaction (LCR), and nucleic acid amplification tests (NAAT) have been used in diagnosis [8, 9].

Chlamydiae are gram-negative, cocci-shaped, immobile, and obligate intracellular microorganisms that cause many diseases in humans. Although they have many enzymes and limited metabolic activities, they have been studied among viruses for many years due to their lack of mechanisms for providing metabolic energy and their inability to generate their own energy (Adenosine Triphosphate). However, they are distinguished from viruses by the fact that they contain both DNA and RNA, reproduce by dividing in the middle, have a similar cell wall structure to gram-negative bacteria, have ribosomes, have various enzymes that provide metabolic activity, and are sensitive to various antibiotics [1]. Unlike other bacteria, chlamydia has a biphasic life cycle. During their life cycles, they appear in two forms, which are called elementary bodies and reticular bodies, with different metabolic activity characteristics, sizes, and morphological appearances. Elementary body is the infective form that is resistant to environmental conditions and is not metabolically active. Reticular body, on the other hand, is the metabolically active form that has no infective properties but has the ability to proliferate within the host cell. Because chlamydia are compulsory intracellular parasites, they cannot be grown in artificial media [10]. They require live cell environments for their reproduction [2].

Chlamydias belong to the Chlamydiaceae family, which is under the order Chlamydiales. In the taxonomic classification according to their phenotypic characteristics, there are four species in the genus Chlamydia, namely C. trachomatis, C. psittaci, C. pneumoniae, and C. pecorum. Among these four species, only C. pecorum does not cause disease in humans [5]. Apart from this classification, two different genera were proposed based on 16S rRNA and 23S rRNA sequence analyses. There are three species within the genus Chlamydia, C. trachomatis, C. suis, and Chlamydia muridarum, and six species within the genus Chlamydophila, C. pneumonia, C. psittaci, C. pecorum, C. felis, Chlamydophila caviae, and C. abortus. However, since this classification is not accepted by many researchers, both classifications are used in the literature today [1, 8, 11, 12]. There are three biovars within the species C. trachomatis. These are Trachoma biovar associated with oculogenital diseases, Lymphogranuloma biovar, and rat pneumonia causative biovar. Wang and Grayston determined 15 serotypes according to antigenic structures in trachoma and LGV agents [13]. Three of these serotypes (L1–3) determined by the microimmunofluorescence method were associated with LGV, and the other 12 were associated with oculogenital diseases. The rat pneumonia-causing agent does not infect humans [8, 13, 14]. The L1, L2, and L3 serotypes of C. trachomatis are associated with Lymphogranuloma venereum (LGV) and are sexually transmitted. The A, B, Ba, and C serotypes cause endemic trachoma and are transmitted by hand-eye contact and flies. The D, E, F, G, H, I, J, and K serotypes cause inclusion conjunctivitis, nongonococcal urethritis, cervicitis, salpingitis, proctitis, epididymitis, neonatal pneumonia, and conjunctivitis and are transmitted sexually, perinatally, and by hand-eye contact. Today, C. trachomatis is one of the most important causes of sexually transmitted diseases [15]. C. trachomatis usually infects epithelial cells lining the mucous membranes. These are columnar cells in the cervix, cells of the urethra, rectum, conjunctiva, and cells of the newborn’s respiratory system [16]. C. trachomatis is the cardinal pathogen of non-gonococcal urethritis [17]. Sexually transmitted C. trachomatis infection can sometimes be asymptomatic [18]. In this case, accurate and early diagnosis is important since patients will continue to transmit the infection [19]. Undiagnosed and untreated C. trachomatis infections cause diseases such as pelvic inflammatory disease and may result in ectopic pregnancy and tubal infertility. It has also been reported that C. trachomatis infections seen during pregnancy may be associated with pregnancy complications such as postpartum endometritis, premature rupture of membranes, premature birth, stillbirth, and low birthweight. C. trachomatis is also one of the important causes of reactive arthritis [8].

Cytological examination, cell culture, antigen determination, DFA, EIA, and NAAT are used in the diagnosis of C. trachomatis. The sensitivity of the cell culture method varies from 50 to 85%. For DFA and EIA, the sensitivity is given as 45.5–85% and 52–84.4%, respectively. Various studies have shown that the sensitivity for NAAT is from 80 to 100%. The specificity of all tests varies from 90 to 100% [20].

2. Gastrointestinal chlamydial infections in humans

York and Baker reported for the first time in cattle that Chlamydia was present in the gastrointestinal (GI) tract but did not cause a pathological response [21]. Later, Storz and Thornley reported that sheep have low levels of complement-fixing antibodies despite being infected. Antibody levels were found to be high in some sheep with positive fecal isolation but were observed as returning to low levels in the follow-up [22]. Cordy, Storz, and Dungworth stated that the presence of chlamydia in the intestine does not create a resistance against parenteral and respiratory tract infections [23, 24, 25]. Perry and Hughes observed that genital chlamydial infection may be somewhat protective against respiratory tract infections, but it does not prevent infection in the GI tract [26]. The reason why chlamydial GI infection could not be eliminated is the inability of the gastrointestinal tract to produce an adequate immune response. However, there are also data showing that oral infection is a potent immunization. Oral infection with live chlamydia has been shown to elicit a strong systemic immune response and a partial protective response in the genital area in both rat and guinea pig models [27, 28]. Nichols et al. showed that oral infection may be somewhat protective against conjunctival infection in the guinea pig [29]. Although these data suggest that GI chlamydial infection may trigger immunity, this immune response is insufficient. The absence of pathological findings may also indicate the complete absence of a local host response to chlamydial GI infection. In addition to the lack of pathology seen at various times after oral infection with C. muridarum, Igietsme et al. were unable to detect expression of VCAM-1 associated with the inflammatory response after oral infection and did not observe an increase in the number and density of intraepithelial lymphocytes. Hyperplasia of Peyer’s patches was the only finding for a local immune response [30, 31]. Yeruv L et al. examined whether a local and systemic response developed as a result of C. muridarum gastrointestinal infection in rats. They showed that IgG was produced at a level similar to the serum IgG level that occurs in chlamydia genital infection and remained high during the 75-day observation period, while anti-chlamydia IgA appeared in the intestine 2–3 weeks after the infection, peaking on the 50th day and decreasing on the 75th day [32]. Since it has been determined that the natural site of infection for chlamydia in many animal hosts is the gastrointestinal tract, it comes to mind that the natural site of infection in humans is the gastrointestinal tract as well. Apart from direct infection with anal intercourse, there are indications that both men and women can be infected orally. There is evidence that chlamydia can pass through the stomach and small intestine and settle in the large intestine after oral infection of rats [32]. Dunlop et al. found that both cervical and rectal cultures were positive in 5 (13.2%) of 38 women who had intercourse with men with ocular chlamydial infection or urethritis [33, 34]. Rectal cultures were also positive in 7 of 11 women with ocular infection only, and rectum and cervix were infected simultaneously in 6 of them. LGV serotypes were not found in rectal isolated cases. For this reason, it was thought that the rectum also serves as a reservoir, same as the genital tract, for chlamydial infection in women [34]. It has been shown by Jones et al. that men and women can be orally infected. They took pharyngeal samples from 706 heterosexual men and 686 women and rectal samples from 1223 women at risk for chlamydia infection. C. trachomatis was isolated in the pharynx of 3.7% of men and 3.2% of women. C. trachomatis was also isolated in the rectal culture of 5.2% of women at risk. However, they could not find a statistical relationship between positive rectal isolation and anal intercourse [35]. A strong correlation was found between positive genital and rectal cultures. While 11% of genital culture-positive women were positive in the rectum, rectal swab was positive in only 2.7% of genital culture-negative women. Positive rectal cultures having been detected in homosexual men were not surprising. Stamm et al. found a positive rectal culture in 33 of 155 heterosexual women with STDs. A high percentage of these women were having anal intercourse. However, 16 of 29 asymptomatic women with positive rectal cultures did not report anal intercourse [36]. Another source of information on persistent gastrointestinal chlamydia infection comes from studies on neonates exposed to chlamydia infection at birth. A 5-year prospective study by Schachter et al. followed 131 infants born to mothers infected with chlamydia. Inclusion conjunctivitis was confirmed by culture in 18% of infants and chlamydial pneumonia in 16%. Serological response was present in 60% of the infants. Interestingly, asymptomatic rectal and vaginal infections were detected in 14% of infants at risk. Conjunctival infections were detected in the first 22 days of life, while rectal cultures were positive after 2–3 months, and vaginal cultures after 70–154 days. This suggested that the vaginal infection was due to possible fecal contamination. A high titer IgM increase was also detected in positive rectal cultures [37].

3. Chlamydial oropharyngitis–tonsillitis

C. trachomatis can be transmitted after oral sex. Many patients with C. trachomatis in the oropharyngeal region are asymptomatic. Rarely, it can cause oropharyngitis and tonsillitis. In this case, it can lead to symptoms such as sore throat, difficulty swallowing, and fever. Swab samples taken from this region are used for diagnosis. NAATs are one of the most sensitive tests used in the examination of samples and are recommended for use in diagnosing C. trachomatis. Its specificity and sensitivity are quite high [38]. Although the clinical significance of oropharyngeal C. trachomatis infection is unclear and oropharyngeal sampling is not routinely recommended during screening for chlamydia infection, existing evidence has shown that oropharyngeal chlamydia infection can be transmitted sexually to the genital areas [39]. Therefore, if C. trachomatis is detected in the oropharyngeal sample, the patient should be treated with azithromycin and doxycycline. There is not enough clinical information to compare the efficacy of antimicrobials in oropharyngeal C. trachomatis infection. In a double-blind randomized controlled study, no significant difference was found in terms of treatment success of urogenital C. trachomatis infection in men and women between the use of a delayed release 200 mg doxycycline tablet for 7 days and a 100 mg doxycycline tablet twice a day for 7 days, although gastrointestinal side effects were less in the group that received a single dose of 200 mg. On the other hand, the cost of a single-dose 200 mg tablet is higher [40].

4. Rectal C. trachomatis infection

C. trachomatis is the most common bacterial sexually transmitted infection in the world. There were an estimated 4 million cases of chlamydia in the United States in 2018 [41]. This has made it the most frequently reported condition nationally. Despite public health chlamydia control programs, its frequency has increased over the past 20 years [42]. Chlamydial infections are more common in young women (<25 years), especially Black, Hispanic, and Native American women, and homosexual men [43]. C. trachomatis infects epithelial cells of the oropharynx, genitourinary tract, and gastrointestinal tract. The rectum is increasingly recognized as a common anatomical site of C. trachomatis infection in humans. C. trachomatis is a common cause of symptomatic proctitis and proctocolitis, especially in homosexual men [8]. While 10–15% of homosexual men who apply to sexual health clinics have a positive rectal chlamydia test, this rate is 8–9% in cisgender women. Despite the high prevalence of rectal chlamydial infections, there is a lack of knowledge about the biological, epidemiological, and clinical aspects of these infections. Asymptomatic rectal carriage of C. trachomatis can occur in infants and adults. 85% of rectal C. trachomatis infections are asymptomatic. However, rectal infection is known to cause proctitis. Infection with the L1, L2, and L3 serotypes of C. trachomatis can cause lymphogranuloma venorum syndrome. The most common clinical manifestation of rectal LGV is proctocolitis, while urogenital LGV is inguinal and femoral painful and tender lymphadenopathies [44]. Despite the prevalence of L serotype C. trachomatis among homosexual men, 25–50% of these infections are asymptomatic [45]. Although there is a high prevalence of chlamydia among women in sexual health clinics, this has no clinical significance. It is not clear whether rectal C. trachomatis is auto-inoculated from the rectum to the genital tract, and if so, how often. Such auto-inoculation has been demonstrated in animal models [32, 46]. However, this auto-inoculation has not been proven in humans. Along with that, in several epidemiological studies, it has been emphasized that undiagnosed or inadequately treated rectal C. trachomatis infection may be the source of recurrent urogenital chlamydia infection in women [47, 48]. Rectal C. trachomatis has been described in many ways. The primary means of acquiring rectal C. trachomatis among homosexual men are through receptive anal sex. Apart from this, there are several articles showing that oral-anal sex, use of sex toys, fingering, and use of saliva as a lubricant may lead to rectal C. trachomatis acquisition [49, 50]. Considering that the prevalence of rectal chlamydia in women is similar between those who report and do not report anal sex, it is unlikely that anal sex is the primary route of acquiring of rectal C. trachomatis in women [51]. Considering the anatomical proximity of the vagina and anus, toilet hygiene practices, and the positive rectal C. trachomatis test in most (70%) women with urogenital C. trachomatis, many women can get rectal chlamydia from urogenital C. trachomatis infection. There are articles showing that up to 87% of rectal C. trachomatis infections in women are acquired from urogenital infections [52]. Several researchers have suggested that oral ingestion of C. trachomatis infection (through penile-oral sex) may lead to rectal chlamydia. In this case, in order for C. trachomatis to colonize and infect the large intestine, it must survive passing through the upper gastrointestinal tract. This has been demonstrated in animal models [30, 53, 54]. In humans, this has not been demonstrated experimentally, although is supported by some epidemiological evidence [55, 56]. We have stated that asymptomatic rectal carriage of C. trachomatis can be seen in infants and adults. However, we also emphasize that C. trachomatis is a common cause of symptomatic proctitis and proctocolitis [8]. Both LGV serotypes and D to K serotypes can cause these clinical presentations. The severity and prevalence of the infection also vary accordingly. Infection with agents other than LGV serotypes usually occurs by direct inoculation of the agent during anal intercourse. It remains as a limited superficial inflammation in the rectum. Its main symptoms include anal itching and mucus rectal discharge. LGV serotypes, on the other hand, come to the infection site by lymphatic spread and cause ulcers, granulomas, and cryptic abscesses in the rectum and colon mucosa. They cause symptoms such as rectal pain, tenesmus, rectal bleeding, and fever. Perirectal abscesses, rectovesical fistulas, strictures due to fibrous tissue formation in the intestinal wall, and lymphoid tissue accumulation similar to hemorrhoids due to obstruction of lymphatic drainage may occur in untreated individuals, and the infection may be confused with inflammatory bowel diseases [8]. Methods used in diagnosis include cytological examination, isolation in cell culture, antigen determination, serological examinations, and molecular methods in which nucleic acid of the agent is detected [8, 57, 58]. NAATs are one of the most sensitive tests used in the examination of samples [59, 60] and are recommended for use in diagnosing chlamydia infection [38]. C. trachomatis culture has been generally abandoned. Since there is no significant difference in the outcome between the samples taken by the clinician and the samples taken by the patient themself, the patient’s sampling themself can be used for rectal chlamydia infection detection [61, 62]. In chlamydia screening by NAAT, especially in cases where it is difficult to reach the clinician, the patient’s own samples can be an alternative to the samples taken by the clinician.

4.1 Treatment

Treating people infected with C. trachomatis and their partners is of great importance in preventing reproductive health-related complications, stopping the transmission of the disease to individuals, and preventing re-infection. Doxycycline and azithromycin are the most commonly used drugs for the treatment of rectal chlamydia. Before 2020, the treatment guidelines for sexually transmitted infections recommended azithromycin 1 g orally as a single dose or doxycycline 100 mg orally 2x1 for 7 days for the treatment of rectal chlamydia infection. As alternative treatments, erythromycin base 500 mg orally 4x1 for 7 days or erythromycin 800 mg orally for 4x1 7 days or levofloxacin 500 mg orally 1x1 for 7 days or ofloxacin 300 mg 2x1 for 7 days can be used. Many clinicians prefer to use azithromycin because of the ease of use of single-dose therapy and the possibility of treatment under direct supervision. In the gonorrhea treatment guideline, which was renewed in 2020, it is recommended to use doxycycline for treatment in cases where rectal chlamydial infection is not excluded. In the sexually transmitted diseases guide published in 2021, doxycycline was presented as a revised recommendation as the treatment of choice for chlamydia treatment [44, 63]. Recommendations for the treatment of rectal chlamydia have long been derived from studies of urogenital chlamydia. However, in some observational studies, it has been shown that azithromycin is less effective than doxycycline, and the difference in effectiveness in the rectum is greater than in the urogenital region [64, 65]. Two randomized controlled trials have recently been published on the treatment of rectal chlamydia among homosexual men. These studies compared azithromycin with doxycycline. While microbiological cure was achieved at a rate of 74–76% in the azithromycin group, this rate was found to be 97–100% in the doxycycline group [48, 66]. Results showing that doxycycline is superior to azithromycin in the treatment of rectal chlamydia in cisgender women have been suggested [67]. In light of this information, doxycycline treatment may be the first choice in the treatment of rectal chlamydia. In patient groups where treatment compliance may be low, direct single dose azithromycin may be preferred for treatment. If possible, it can be ensured that the patient is taking the drug under the supervision of the physician. Again, in cases where 7-day treatment with doxycycline will be given, the first dose can be given immediately and under the supervision of a physician. In order to minimize the transmission of the disease to sexual partners, it should be recommended that the patient abstain from sexual activity for the next 7 days if they received a single dose of treatment, and if they received 7 days of treatment, to abstain during the treatment and until the symptoms completely regress. To minimize the risk of re-infection, it is important for people with multiple sexual partners to avoid intercourse until all partners have completed their treatment.

4.2 Sexual partner management during treatment

All partners who have had sexual intercourse with the patient up to 60 days before the onset of symptoms of the disease should be tested for chlamydia infection. Although the frequency of intercourse and the time elapsed since the last intercourse affect the risk of transmission of the disease, the last sexual intercourse partner (even if more than 60 days have passed since the last sexual intercourse) must be treated. In cases where the partners cannot reach the doctor and medical services directly, sending the prescription or the drugs themselves to the patient’s partner can also be considered as an option. It has been shown that such practices significantly reduce the risk of persistent or recurrent infections [68, 69, 70]. In homosexual individuals, since chlamydial infection is likely to be accompanied by other sexually transmitted diseases (especially undiagnosed HIV infection), partners should be thoroughly evaluated by a physician before being treated. Suggesting that patients come with their partners during follow-up visits may also make partner treatment more effective. To prevent re-infection, patients’ partners should be advised to abstain from sexual intercourse until the disease is completely cured (within 7 days after a single dose treatment or until the end of treatment in 7 days of treatment) and until the symptoms have completely receded.

4.3 Post-treatment follow-up

Re-testing 3–4 weeks after the end of treatment is not recommended except in cases where there is doubt about the patient’s compliance with treatment, when symptoms persist, or when re-infection is suspected. Performing the NAAT test earlier than 3 weeks after the end of the treatment may lead to false positive results since non-viable microorganisms can still be found in the body. Therefore, in cases where recovery is uncertain and retesting is required, at least 3 weeks should have passed since the first treatment before the test [38, 71].

5. Conclusion

C. trachomatis is the most common bacterial sexually transmitted infection in the world. It can cause significant health problems in both men and women. C. trachomatis, a known pathogen of the genital tract, can also be routinely detected in the human GI tract. Its entry into the GI tract has risen due to increased oral-anal sex. Most remain dormant in infected people. Chlamydia proctitis is the most well-known disease caused by C. trachomatis in the GI tract. Rarely, it can cause oropharyngitis and tonsillitis. Due to these infections, the frequency of which is increasing day by day, and the possibility of patients to apply to gastroenterology outpatient clinics is also increasing. It is important to consider this situation, which is often overlooked in gastroenterology practice.