Human Reproduction, Vol. 17, No. 7, 1704-1708,
July 2002
© 2002 European Society of Human Reproduction and Embryology
Endometriosis is associated with an altered profile of intestinal microflora in female rhesus monkeys
University of Wisconsin, Harlow Center for Biological Psychology, 22 N. Charter St, Madison, WI 53715, USA
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Abstract |
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BACKGROUND: The intestinal microflora provide a strong defence against intestinal pathogens, and may be altered in inflammatory conditions that impact the gut, such as endometriosis. Therefore, intestinal bacteria shed from rhesus monkeys with endometriosis were compared with age-matched healthy controls. A second study assessed the prevalence of intestinal inflammation in female monkeys to determine whether endometriosis is associated with an increased likelihood of intestinal inflammation. METHODS: Differential and selective agars were used to enumerate total and Gram-negative aerobic and facultatively anaerobic bacteria, as well as Lactobacilli, from female monkeys with or without endometriosis. In addition, the prevalence of intestinal inflammation in monkeys with or without endometriosis was determined in a retrospective analysis of necropsy reports. RESULTS: Monkeys with endometriosis had a significantly different profile of shed microflora. Endometriosis was associated with lower Lactobacilli concentrations and higher Gram-negative bacteria concentrations. Moreover, there was a higher prevalence of intestinal inflammation in monkeys with endometriosis in comparison to healthy controls. CONCLUSIONS: Endometriosis is associated with an altered profile of intestinal microflora in rhesus monkeys. Although the exact mechanisms linking endometriosis and the microflora are unknown, it is possible that the microflora were affected by endometriosis-associated intestinal inflammation.
Key words: endometriosis/intestinal microflora/Lactobacillus/rhesus monkey
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Introduction |
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The microflora of the gut include representatives of >500 co-existing species of bacteria. The types of bacteria that comprise the normal intestinal microflora, as well as their relative concentrations, are remarkably stable and provide a strong defence against infection by inhibiting colonization by pathogenic enteric organisms (Berg, 1996
). However, under certain circumstances, such as when the secretion of gastric acid or gastrointestinal motility are significantly altered, the complex make-up of the microflora can become markedly disturbed (Draser, 1986). For example, previous studies have indicated that trauma and stress disrupt gastrointestinal physiology (Lenz and Druge, 1990) and change the profile of indigenous microflora (Lyte and Bailey, 1997; Bailey and Coe, 1999). Disruption of the indigenous microflora may ultimately result in increased susceptibility to infectious diseases. For example, Candida albicans-associated diarrhoea is commonly encountered when the intestinal microflora are largely eradicated by antibiotic treatments (Gupta and Ehrinpreis, 1990). The types of environmental stimuli and range of illnesses that may alter the intestinal microflora are largely unknown; therefore, one purpose of this study was to evaluate whether an inflammatory gynaecological condition, endometriosis, is associated with an altered profile of intestinal microflora shed from rhesus monkeys.
Monkeys experience many of the same reproductive disorders as humans and, thus, have been used to investigate reproductive physiology and to model many gynaecological procedures, such as human IVF and ICSI (Sutovsky et al., 1996). Moreover, like humans, rhesus monkeys develop spontaneous endometriosis (Bertens et al., 1982) characterized by ectopic implantation of endometrial glands and stroma (Hadfield et al., 1997; Giudice et al., 1998). In many human patients with more severe forms of the disease, the endometrial implants grow along the serosal surface of the gastrointestinal tract (Prystowsky et al., 1988), where they become a source of significant pain and excretory problems. Female monkeys with this gynaecological condition show a particular predilection for having implant sites on the serosa of the lower intestine and colon (Coe et al., 1998). Because of the impact endometriosis can have on the gastrointestinal tract, we sought to compare gut microflora of monkeys with endometriosis to age-matched, healthy females with a particular focus on one genus of bacteria, Lactobacillus. This species of bacteria is known to be beneficial, and limits enteric infection by producing bacteriocin-like, antibacterial substances (Bernet-Camard et al., 1997) and by competing with pathogens for binding sites on the epithelium of the intestine (Bernet et al., 1994).
There are several factors that predispose monkeys to endometriosis, such as prolonged periods of menstruation without intervening pregnancies (D'Hooghe et al., 1996), estrogenic treatments (Dizerega et al., 1980; Hadfield et al., 1997), and exposure to certain environmental toxicants (Rier et al., 1993). Endometriosis may emerge years later, when the ectopic implants can be found aggressively invading normal tissue throughout the peritoneal cavity (Giudice et al., 1998). Both the epithelial cells of the damaged tissues, and the leukocytes responding to the implants and inflamed tissues, secrete growth factors and proinflammatory cytokines, which in turn may affect gastrointestinal secretions and motility (Taché and Saperas, 1992; Collins, 1996). Because Lactobacilli gain an ecological advantage over other bacterial species by being resistant to the low gastric pH, events that suppress acid secretion, such as intestinal inflammation, could create an internal environment less conducive to Lactobacilli proliferation. Therefore, we hypothesized that monkeys with endometriosis would have an altered profile of intestinal microflora, particularly altered Lactobacilli. In addition, a second retrospective study was conducted on the necropsy reports of >400 female rhesus monkeys to confirm that endometriosis is associated with intestinal inflammation in this species.
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Materials and methods |
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Study I
Subjects: Eighteen female rhesus monkeys (Macaca mulatta) between the ages of 10 and 31 years were evaluated. All monkeys were born and raised at either the Harlow Primate Laboratory (HPL) or the Wisconsin Regional Primate Research Center (WRPRC). At the time of the study, the monkeys were housed in single (0.7x0.8x0.8 m) or double (1.4x0.8x0.8 m) cages. Animals were fed Monkey Diet chow (PMI Nutrition International, Richmond, IN, USA) supplemented with fresh fruit 3 times weekly; water was available ad libitum. The light:dark schedule was 14:10, with lights on at 0600. The attending veterinarian previously diagnosed eight of the 18 monkeys as having endometriosis by characteristic symptoms such as cyclical constipation and abdominal pain. In all cases, the diagnoses were confirmed by diagnostic ultrasound and magnetic resonance imaging. Moreover, in five of the animals, the diagnoses were further confirmed through histological analyses of ectopic implants that were biopsied either during abdominal surgery (n = 2) or during necropsy (three of the monkeys subsequently died within 2 years of study; Table I
). Although the stage of endometriosis was not specifically rated in all of the animals, monkeys that display symptoms of endometriosis generally have severe forms of the disease affecting several peritoneal organs (McClure et al., 1971; La Regina and Vogler, 1984). The five animals that had abdominal surgeries or were necropsied had implants on several peritoneal organs, particularly the ovaries and uterus, which is consistent with a diagnosis of severe endometriosis according to the revised American Fertility Society (rAFS) classification system (American Fertility Society, 1985). Control animals were in good health and did not have any symptoms of endometriosis for 2 years subsequent to the study, suggesting that there were no undiagnosed cases of endometriosis in the control group. None of the animals was exposed to antibiotics or disruptive experimental procedures for at least 1 month prior to the day of coproculture. Moreover, the animals did not have experimental histories that would otherwise compromise gastrointestinal functioning. All procedures were approved by the Institutional Animal Care and Use Committee at the University of Wisconsin.
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Enumeration of gut microflora: Animals were briefly removed from their peers on the morning of culturing in order to obtain fresh faecal samples from clean drop pans 2.5–3 h after feeding. After weighing, the samples were suspended in sterile phosphate-buffered saline at a concentration of ~1 g/4 ml. The suspensions were mixed by vigorous vortexing and were serially diluted. An aliquot of each dilution was grown on differential and selective agars to quantify specific types of the bacterial microflora by standard pour plate and spread plate methodologies.
Three methods of estimating the integrity of the gastrointestinal microflora were utilized. Total non-fastidious aerobic and facultatively anaerobic bacteria were enumerated by pour plating with brain–heart infusion agar (Difco Laboratories, Detroit, MI, USA). This agar is rich in nutrients and allows growth of non-fastidious aerobic and facultatively anaerobic bacteria, such as members of the genera Streptococcus, Staphylococcus, Klebsiella, Proteus, and the family Enterobacteriaceae. The differential agar eosin–methylene blue (EMB; Difco Laboratories) was utilized to quantify Gram-negative aerobic and facultatively anaerobic bacteria. Although all members of the family Enterobacteriaceae will grow on EMB agar, most of the colonies are Escherichia coli or members of the genus Enterobacter (unpublished observations). Aerobic members of the genus Lactobacillus, including L. acidophilus, L. caseii and L. amylovorous, were enumerated by spread plate analysis on selective LBS agar (Becton Dickinson & Co., Cockeysville, MD, USA). After incubating the agar plates for 30 h at 37°C in a humidified atmosphere of air + 5% CO2, colonies were counted and the number of colony-forming units (CFU) per gram of faecal matter was determined.
Statistical analysis: Ageing research is typically conducted on monkeys aged >20 years, which is equivalent to >50 years in humans. Because age could impact the intestinal microflora (Hopkins et al., 2001), animals were assigned to the following groups prior to culturing based on their age and health: 10–19 years (n = 6 healthy middle-aged controls, n = 4 with endometriosis), and 20–31 years (n = 4 healthy aged controls, n = 4 with endometriosis). Although this resulted in small sample sizes, a power analysis indicated that an n = 4 was sufficient to detect differences in microflora considered to be biologically relevant. To determine whether the presence of ectopic endometrial growths influenced the intestinal microflora, a two-factor analysis of variance was performed, with the age of the animal (10–19 versus 20–31 years) and health status (control versus endometriosis) evaluated as the independent variables. A log10 transformation was performed on all bacterial concentrations prior to statistical analysis and the data are expressed as medians and the quartile range.
Study II
Subjects: To evaluate the association between endometriosis and gastrointestinal inflammation, a survey of necropsy records from a large cohort of deceased female rhesus monkeys was conducted. Necropsies have been performed for over 3 decades on all monkeys who have died from: (i) natural ageing, (ii) humane euthanasia for an incurable disease, or (iii) killed as part of a terminal research protocol. The necropsies are performed immediately after euthanasia, or within 8 h of death from natural ageing. The necropsies used for this study were performed between 1981 and 1998 and reflect the normal mortality at the WRPRC during this 18-year period. Initially, all necropsy reports were screened for the study; however, reports were excluded if monkeys were aged <10 years at the time of death, or, if it was not possible to determine the age at the time of death, resulting in 413 reports. The reports included 100 monkeys diagnosed with endometriosis by microscopic analyses of ectopic endometrial glands and stroma, as well as 313 control females without detectable endometriosis.
Descriptive statistics: Age at the time of death, presence of endometriosis, and evidence of intestinal inflammation were recorded for all females. Monkeys were categorized as having endometriosis if any ectopic endometrial growths were identified during necropsy and confirmed histologically. Endometriosis was rated as mild, moderate or severe depending on the number and distribution of implants. This schema has been used previously with monkeys (Coe et al., 1998) and is based on the rAFS classification system for characterizing endometriosis in humans (American Fertility Society, 1985). Mild disease was defined as few implants and limited fibrous adhesions; moderate endometriosis was assigned when there were more fibrous adhesions; severe endometriosis was characterized by multiple loci with extensive fibrous adhesions. In addition to endometriosis, the monkeys were recorded as having nonspecific intestinal inflammation if infiltration of leukocytes into intestinal tissue, intestinal lesions, watery intestinal contents, or evidence of chronic diarrhoea were noted in the necropsy report.
Statistical analysis: The distribution of intestinal inflammation in monkeys with and without endometriosis was examined initially by 
2 analysis. To determine if the age at the time of death was associated with the prevalence of intestinal inflammation, the distribution of intestinal inflammation in monkeys with and without endometriosis was examined in adult monkeys (10–19 years old) as well as in aged monkeys (
20 years old) by 2 analysis. Autolysis of intestinal tissue can occur rapidly after death and may result in misinterpretation of intestinal inflammation. Therefore, the prevalence of intestinal inflammation was determined in separate analyses for animals that were killed as part of a terminal research protocol or for humane purposes (with necropsy immediately following) and compared with those that died from natural causes (with necropsy occurring up to 8 h later).
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Results |
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The microflora were markedly altered in monkeys with endometriosis. These differences were evident when a single genus of bacteria (Lactobacillus) and when Gram-negative bacteria were quantified. There was a significant reduction in the number of Lactobacilli shed from monkeys with endometriosis [F(1,14) = 6.09, P < 0.05] (Figure 1
). The number of shed Lactobacilli tended to be lower in older monkeys with endometriosis, an age effect that approached but did not reach statistical significance [F(1,14) = 4.13, P = 0.06]. While shedding fewer Lactobacilli, the animals with endometriosis also shed significantly more Gram-negative aerobes and facultative anaerobes [F(1,14) = 8.69, P < 0.01] (Figure 2). This difference was seen in both middle-aged and aged females, and was manifest as a consistent elevation of Gram-negative aerobes and facultative anaerobes. Although the total number of aerobes and facultative anaerobes was also lower in aged females with endometriosis, this difference did not reach statistical significance (data not shown).
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Intestinal inflammation was documented in 38% of the necropsy reports, and was more prevalent in aged monkeys compared with adult monkeys (50% of aged versus 33% of adults) [
2 (1) = 4.80, P < 0.05]. In addition to its relationship with advanced age, intestinal inflammation was more prevalent in monkeys with endometriosis [2 (1) = 22.97, P < 0.001]. To determine whether the association between endometriosis and intestinal inflammation was similar in adult and aged monkeys, data from the two groups of monkeys were analysed separately. Adult monkeys with endometriosis were more likely to have intestinal inflammation than were the healthy controls [2 (1) = 15.38, P < 0.01] (Figure 3). This effect was evident in monkeys that were killed [2 (1) = 5.07, P < 0.025] as well as monkeys that had died from natural causes [2 (1) = 19.03, P < 0.01]. Moreover, intestinal inflammation was also more prevalent in aged monkeys with endometriosis [2 (1) = 6.05, P < 0.05] (Figure 3). Again, this pattern was evident in monkeys that were killed [2 (1) = 5.22, P < 0.025] and those that died of natural causes [2 (1) = 5.70, P < 0.025]. Overall, adult and aged monkeys with severe endometriosis were not more likely to show intestinal inflammation than were those with mild forms of the diseases [2 (2) = 0.88, not significant].
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Discussion |
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This study indicates that the inflammatory condition of endometriosis is associated with an altered profile of intestinal microflora in female monkeys. Fewer aerobic Lactobacilli were shed in the faeces in contrast to the relatively stable shedding of bacteria from healthy animals. In addition, there was a trend for Lactobacilli to be lower in aged monkeys with endometriosis compared with younger and healthy aged monkeys; however, this difference just failed to reach statistical significance with this small sample size. While Lactobacilli decreased, the number of shed Gram-negative aerobic and facultatively anaerobic bacteria increased in monkeys with endometriosis. The increased shedding of Gram-negative bacteria was found in both adult and aged monkeys with endometriosis, and concurs with a previous study demonstrating non-specific intestinal bacterial overgrowth in women with endometriosis (Mathias et al., 1998
). The Lactobacilli and Gram-negative bacteria may have been responding to changes in gut physiology, such as an inhibition of gastric acid secretion or gut motility, which can impact on the intestinal microflora. These events may lead to an internal environment less conducive to Lactobacilli replication and survival, and may lead to Gram-negative bacterial overgrowth (Justus et al., 1983; Stephen et al., 1987; Riordan et al., 1997; Neieuwenhuijs et al., 1998; Paiva et al., 1998; Bailey and Coe, 1999).
It was not possible to determine whether the magnitude of the microflora alterations was associated with the stage of endometriosis (i.e. mild to severe). However, microflora alterations are more likely to occur with severe disease, because monkeys with endometriosis typically do not show overt symptoms until several peritoneal organs are impacted (McClure et al., 1971; La Regina and Vogler, 1984). Moreover, the five animals that were confirmed as having endometriosis at abdominal surgery and post-mortem necropsy had at least three of their organs affected by endometriosis. This profile is consistent with severe endometriosis according to the rAFS classification system (American Fertility Society, 1985).
Although extrauterine endometrial cells most often invade the ovaries and exterior of the reproductive tract in women with milder forms of endometriosis (Giudice et al., 1998), with increasing severity, the gastrointestinal tract, and occasionally the urinary tract, can become inhabited by the ectopic implants (Prystowsky et al., 1988). Like uterine endometrium, the ectopic endometrial cells proliferate and mature in response to cyclic changes in steroid hormone concentrations, which becomes a significant source of abdominal pain. The cyclic proliferation can also contribute to widespread inflammation in the peritoneal cavity of women with endometriosis (Giudice et al., 1998). In our study, monkeys with endometriosis were significantly more likely to have inflamed intestines at the time of death compared with healthy animals. This finding gives support to a hypothesized mechanism through which endometriosis could affect the intestinal microflora. Endometrial cells and leukocytes, particularly macrophages and monocytes that are recruited to inflamed tissues, secrete large quantities of proinflammatory cytokines, such as interleukin (IL)-1, IL-6, and tumour necrosis factor (Rier and Yeaman, 1997). In addition to their immunomodulatory role, cytokines can have widespread effects on the gastrointestinal tract by suppressing gastric acid secretion (Taché and Saperas, 1992) as well as gut motility (Plaza et al., 1997). Although our study did not establish the causal mechanism for the change in the microflora, it is likely that pro-inflammatory mediators affected the gut, which in turn altered the profile of intestinal microflora, a hypothesis warranting further investigation in humans.
Disruption of the intestinal microflora can have adverse health consequences. In addition to aiding with proper digestion and absorption of macromolecules, the intestinal microflora act as a barrier to gut pathogens by blocking attachment to gut binding sites (Bernet et al., 1994), which is the first step of pathogenicity. For example, feeding germ-free immunodeficient rodents with Lactobacilli reduces colonization of Candida albicans after oral infection (Wagner et al., 1997). In addition, several members of the microflora, including Lactobacilli, produce antibacterial substances that can have direct inhibitory effects on pathogenic organisms (Bernet-Camard et al., 1997). Disturbance of these non-specific defences ultimately increases susceptibility to enteric infection, and could account for the increased occurrence of food allergies and opportunistic C. albicans infections in women with endometriosis (Lamb and Nichols, 1986; Nichols et al., 1987). Our study clearly demonstrates that endometriosis is associated with profoundly altered intestinal microflora, particularly Gram-negative members and members of the genus Lactobacillus. Although the specific mechanism through which endometriosis influences the intestinal microflora needs to be ascertained, it is likely that secretion of inflammatory mediators contributes to altering the make-up of the intestinal microflora. Our data thus offer a unique view of the pathology of endometriosis.
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Acknowledgements |
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The authors gratefully acknowledge Ms Rochelle Zellmer and the veterinary staff of the Wisconsin Regional Primate Research Center for their assistance with the project. The authors also thank Dr Stephen Kennedy, who independently assessed the monkeys in our study and confirmed our endometriosis diagnoses. Salary support for M.B. was provided in part by NRSA predoctoral fellowship MH12458 and the Endometriosis Association of Wisconsin. Additional support was provided by National Institutes of Health grant AI46521 to C.C. The Wisconsin Regional Primate Research Center is supported by RR00167.
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Notes |
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1 To whom correspondence should be addressed. E-mail: mtbailey{at}students.wisc.edu
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Submitted on October 26, 2001; resubmitted on January 14, 2002; accepted on March 7, 2002.
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