The “Second Genome” Continued from the previous page . . . gan prolapse/urinary incontinence (POP/UI) cohorts have similar microbiomes.25 However, a recent study suggests a bacterial link to incontinence.26 Bacterial communities isolated from urine of women with urinary incontinence differ depending on the type of incontinence, and the microbiota of patients with urge incontinence are readily distinguished from those with stress incontinence, with the latter having markedly reduced bacterial diversity.26 While this is the first study to provide evidence supportive of an infectious association with a subtype of urge urinary incontinence, if confirmed, it offers the promise of therapies directed at bacteria or their antigens identified in the urinary bladder of affected women, reducing symptoms and the impact on daily activities attributable to urge incontinence. Interstitial cystitis: Interstitial cystitis (IC), more common in women, is a chronic inflammatory condition of the bladder of unknown etiology. High-throughput sequencing of the 16S variable regions V1, V2, and V6 revealed reduced bacterial-sequence richness and diversity and a significant difference in the community structure of IC urine versus normal controls.27 More than 90 percent of the IC sequence reads were identified as bacterial genus Lactobacillus, compared with 60 percent in control urine. The shift in bacterial community composition and reduced microbial diversity and richness accompanied by a higher abundance of Lactobacillus in IC urine has been proposed to contribute to the symptoms experienced in patients with IC.27 This supports other independent observations correlating symptoms abating concomitantly with diminished colonization and exacerbation with accumulation of Lactobacillus.27 This approach offers an exciting area of research to understand the biological basis and potential personalized therapies of this enigmatic disorder. Asceptic bacteriuria (ABU) and urinary tract infections (UTI): In ABU, bacteria are present in the urine, but the inflammatory response and symptoms are minimal. Differentiating ABU from UTI is important because ABU overtreatment can result in antimicrobial resistance, whereas UTI undertreatment can result in increased morbidity and mortality. In a study of twenty-six healthy controls and twenty-seven healthy subjects at risk of ABU (due to spinal cord injury and neuropathic bladder), Venter and colleagues28 reported that urine microbiomes differ by normal bladder function, gender, and type of bladder catheter used (intermittent transurethral catheterization, indwelling Foley catheter, normal voiding). Ten bacterial taxa (Lactobacillales, Enterobacteriales, Actinomycetales, Bacillales, Clostridiales, Bacteroidales, Burkholderiales, Pseudomonadales, Bifidobacteriales, and Coriobacteriales) showed the most relative abundance, and metaproteomics confirmed the 16S data. Functional human protein-pathogen interactions were noted in subjects where host defenses were initiated and, interestingly, different taxa were differentially predominant in urine from men versus women. These studies form the basis of a novel approach to determine candidate communities for targeted therapies, if needed. Metagenomics has been used to assess possible bacterial communities in leukocyte esterase-positive/culture-negative urine from symptomatic patients. Using culture and targeted PCR, the majority of UTIs were found to be caused by Escherichia coli (35.15 percent), followed by miscellaneous bacteria (23.03 percent), and 22
by Enterococcus faecalis (19.39 percent).29 However, a large fraction of fastidious and anaerobic bacteria (22.43 percent) was only detected using PCR and is commonly undetected in routine diagnostic laboratories examining urine specimens with culture only. The molecular approach using broad-range 16S rDNA PCR, sequencing, and bioinformatic analysis to uncover these “hidden” pathogens offers an opportunity to get a more complete assessment of urinary pathogens, especially in leukocyte esterase-positive and culturenegative urine specimens. Sex and age differences: Comparing urinary microbiomes from asymptomatic adult women and men reveals that women have a more heterogenous mix of bacterial genera and representative members of Actinobacteria and Bacteroides phyla, and that conventional microbiological methods were inadequate to identify about two-thirds of bacteria found in these specimens.24 Fouts et al found a preponderance of Lactobacillales in women and Corynebacterium in men.28 Also, preliminary data suggest age-related differences in the urinary microbiome, with fluctuation in abundance among age groups (twenty-six to ninety years old) and age-specific genera Jonquetella, Parvimonas, Proteiniphilum, and Saccharofermentans, although the clinical significance of this remains unclear.24
The microbiome is a new frontier in women’s health. While there are abundant data on the role of the gut microbiome in influencing host metabolism and immune homeostasis,1-3 data on hormonal effects on these processes and sex-specific differences are wanting. Many questions arise. Is there a hormonal effect on microbiomes in various habitats throughout the body or in various hormonal states through which women transition? What are the effects of antenatal steroids, prenatal vitamins, 17-hydroxyprogesterone, or tocolytics on the gut, vaginal, oral, and placental microbiomes? What is the host immune/epithelial response to communities and novel microbes? Will we be changing the way we diagnose and treat UTIs, PTB, and gastrointestinal and other disorders with enigmatic etiologies? What is the reproductive tract microbiome in endometriosis, with abnormal uterine bleeding, with uterine fibroids, or in the presence of HPV, HIV, and other viral, fungal, and bacterial infections? What are effects of race, ethnicity, SES, intercourse, numbers of sexual partners, family history, personal habits (douching, environmental exposures) on microbiomes of various habitats? Perhaps some microbiomes are protective and treatment may cause more harm than good. What an opportunity for development of novel diagnostic and therapeutic approaches to a variety of disorders more common to or specific to women, and what an exciting time to be a physician who cares for women and a researcher and teacher focusing on women’s health and the female microbiome! Linda C. Giudice, MD, PhD, is a distinguished professor and chair of the Department of Obstetrics, Gynecology & Reproductive Sciences at UCSF. Review of this article by Dr. Michael Fischbach of UCSF is gratefully acknowledged. A full list of references is available online at www.sfms.org.
SAN FRANCISCO MEDICINE SEPTEMBER 2014 WWW.SFMS.ORG
San Francisco Medicine, Vol. 87, No. 7, September 2014