Crosstalk Between Microbiota, Microbial Metabolites, and Interferons in the Inflammatory Bowel Disease Gut.

With the prevalence of inflammatory bowel diseases (IBD) continuing to rise in Canada and globally, developing improved therapeutics that successfully treat greater percentages of patients with reduced complications is paramount. A better understanding of pertinent immune pathways in IBD will improve our ability to both successfully dampen inflammation and promote gut healing, beyond just inhibiting specific immune proteins; success of combination therapies supports this approach. Interferons (IFNs) are key cytokines that protect mucosal barrier surfaces, and their roles in regulating gut homeostasis and inflammation differ between the three IFN families (type I, II, and III). Interestingly, the gut microbiota and microbial metabolites impact IFN-signaling, yet how this system is impacted in IBD remains unclear. In this review, we discuss the current knowledge of how gut microbiota directly or indirectly impact IFN levels/responses, and what is known about IFNs differentially regulating gut homeostasis and inflammation in animal models or patients with IBD.

"They Were Talking to an Idea They Had About Me": A Qualitative Analysis of Transgender Individuals' Experiences Using Dating Apps.

Dating app use is common and has become particularly relevant for transgender and non-binary people seeking platonic, romantic, and sexual connections with others. In this qualitative study, 15 transgender and non-binary individuals (M = 22.67 years, SD = 3.09 years) were interviewed to explore their experiences using dating apps. Thematic analysis was used to generate themes and subthemes. Six themes were identified: 1) connection to queer community; 2) expression of gender identity on dating apps; 3) fetishization on dating apps; 4) impacts of dating apps on sexual experiences; 5) safety on dating apps; and 6) recommendations for dating app developers. Results show that dating apps are an important tool used by trans/non-binary individuals to connect with others in the queer community and find platonic, romantic, and sexual partners. However, there are concerns about their use such as fears for safety and experiences of fetishization. More research, education, and implementations of app development, including the involvement of trans and non-binary people, are needed to address these concerns.

Exploring the association between sexual motivation and quality of life in China and the United Kingdom.

Previous research suggests that different sexual motivations may be associated with different sexual behaviours and levels of sexual satisfaction, and these may vary with cultural differences. As such, sexual motivations and cultural factors might also be associated with quality of life (QoL); however, this has not yet been explored. Using a biopsychosocial approach, this study aimed to explore associations between sexual motivation and quality of life between participants in the United Kingdom and China. 276 participants (143 British, 133 Chinese, mean age = 21.5 years) completed an anonymous online survey including validated measures for sexual motivation (YSEX?-SF) and QoL (WHOQOL-BREF). In multivariable linear regressions, pleasure motivations for sex were associated with increased physical health QoL (aOR = 0.20, 95%CI:.15-.65), while love and commitment motivations were associated with increased psychological health QoL (aOR = 0.13, 95%CI:.01-.43). Both love and commitment motivations (aOR = 0.21, 95%CI:.09-.35) and pleasure motivations (aOR = 0.20, 95%CI:.08-.36) were associated with increased social support QoL. A significant interaction was found between emotional motivations and culture (p = 0.037) such that among individuals from China, emotional motivations (i.e., love and commitment and expression) were positively associated with psychological QoL. This suggests culture may differentially affect how sexual motivations are associated with QoL and warrants further consideration in future research.

Diversity of the microbiota communities found in the various regions of the intestinal tract in healthy individuals and inflammatory bowel diseases.

The severe and chronic inflammatory bowel diseases (IBD), Crohn disease and ulcerative colitis, are characterized by persistent inflammation and gut damage. There is an increasing recognition that the gut microbiota plays a pivotal role in IBD development and progression. However, studies of the complete microbiota composition (bacteria, fungi, viruses) from precise locations within the gut remain limited. In particular, studies have focused primarily on the bacteriome, with available methods limiting evaluation of the mycobiome (fungi) and virome (virus). Furthermore, while the different segments of the small and large intestine display different functions (e.g., digestion, absorption, fermentation) and varying microenvironment features (e.g., pH, metabolites), little is known about the biogeography of the microbiota in different segments of the intestinal tract or how this differs in IBD. Here, we highlight evidence of the differing microbiota communities of the intestinal sub-organs in healthy and IBD, along with method summaries to improve future studies.

Hormone therapy for sexual function in perimenopausal and postmenopausal women: a systematic review and meta-analysis update.

IMPORTANCE: Distressing sexual problems are a common complaint of menopausal women. In 2013, a Cochrane review assessed the effect of hormone therapy on sexual function in menopausal women; however, new evidence has since been published, which should be considered. OBJECTIVE: This systematic review and meta-analysis aims to update the evidence synthesis on the effect of hormone therapy, compared with control, on sexual function in perimenopausal and postmenopausal women. EVIDENCE REVIEW: Thirteen databases and clinical trial registries (Cochrane Central Register of Controlled Trials, EMBASE, Medical Literature Analysis and Retrieval System Online, PsycINFO, Web of Science, Cumulative Index to Nursing and Allied Health Literature, Literatura Latino-Americana e do Caribe em Ciéncias da Saúde, Database of Abstracts of Reviews of Effects, ClinicalTrials.gov , International Clinical Trials Registry Platform, Iranian Registry of Clinical Trials, Chinese Clinical Trial Registry, ISRCTN) were searched from December 2012 to March 30, 2022. Backward reference searching on all retrieved full texts was also performed. Study quality was assessed using the Cochrane ROB.2 tool. Data were pooled in random-effect model meta-analyses, which included all studies identified in the present search and all studies previously included in the 2013 Cochrane review. FINDINGS: Forty-seven randomized controlled trials (35,912 participants) were included in the systematic review, and 34 randomized controlled trials (15,079 participants) were included in the meta-analysis. The meta-analysis revealed that, in comparison to control, estrogen therapy (standardized mean difference [SMD], 0.16; 95% confidence interval [CI], 0.02 to 0.29; I2 = 59%; 2,925 participants, 16 studies), estrogen plus progestogen therapy (SMD, 0.11; 95% CI, -0.07 to 0.29; I2 = 65%; 2,432 participants, 7 studies), tibolone (SMD, 0.15; 95% CI, 0.02 to 0.28; I2 = 0%; 916 participants, 2 studies), and selective estrogen receptor modulators (SMD, 0.18; 95% CI, 0.06 to 0.30; I2 = 0%; 1,058 participants, 4 studies) may result in no effect to small benefit on sexual function composite score. CONCLUSION AND RELEVANCE: Hormone therapy may slightly improve sexual functioning. This potential small benefit should be considered when discussing treatment options for other menopausal symptoms.

Mouse mammary tumor virus is implicated in severity of colitis and dysbiosis in the IL-10-/- mouse model of inflammatory bowel disease.

BACKGROUND: Following viral infection, genetically manipulated mice lacking immunoregulatory function may develop colitis and dysbiosis in a strain-specific fashion that serves as a model for inflammatory bowel disease (IBD). We found that one such model of spontaneous colitis, the interleukin (IL)-10 knockout (IL-10-/-) model derived from the SvEv mouse, had evidence of increased Mouse mammary tumor virus (MMTV) viral RNA expression compared to the SvEv wild type. MMTV is endemic in several mouse strains as an endogenously encoded Betaretrovirus that is passaged as an exogenous agent in breast milk. As MMTV requires a viral superantigen to replicate in the gut-associated lymphoid tissue prior to the development of systemic infection, we evaluated whether MMTV may contribute to the development of colitis in the IL-10-/- model. RESULTS: Viral preparations extracted from IL-10-/- weanling stomachs revealed augmented MMTV load compared to the SvEv wild type. Illumina sequencing of the viral genome revealed that the two largest contigs shared 96.4-97.3% identity with the mtv-1 endogenous loci and the MMTV(HeJ) exogenous virus from the C3H mouse. The MMTV sag gene cloned from IL-10-/- spleen encoded the MTV-9 superantigen that preferentially activates T-cell receptor Vß-12 subsets, which were expanded in the IL-10-/- versus the SvEv colon. Evidence of MMTV cellular immune responses to MMTV Gag peptides was observed in the IL-10-/- splenocytes with amplified interferon-γ production versus the SvEv wild type. To address the hypothesis that MMTV may contribute to colitis, we used HIV reverse transcriptase inhibitors, tenofovir and emtricitabine, and the HIV protease inhibitor, lopinavir boosted with ritonavir, for 12-week treatment versus placebo. The combination antiretroviral therapy with known activity against MMTV was associated with reduced colonic MMTV RNA and improved histological score in IL-10-/- mice, as well as diminished secretion of pro-inflammatory cytokines and modulation of the microbiome associated with colitis. CONCLUSIONS: This study suggests that immunogenetically manipulated mice with deletion of IL-10 may have reduced capacity to contain MMTV infection in a mouse-strain-specific manner, and the antiviral inflammatory responses may contribute to the complexity of IBD with the development of colitis and dysbiosis. Video Abstract.

Reasons for incomplete STI vaccination among men who have sex with men in an English sexual health service.

BACKGROUND: In England, vaccination for human papillomavirus, hepatitis A, and hepatitis B is recommended for men who have sex with men (MSM). However, uptake is sub-optimal and some men do not complete all recommended vaccine doses. This service evaluation aimed to explore reasons for lack of uptake for each of these vaccines among MSM in one English sexual health service and to inform improvements in service delivery to increase full dose completion rates. METHODS: MSM, ≥18 years, who had previously attended NHS Solent Sexual Health for at least one vaccination, and who had not completed the full dosing regimen for at least one of these vaccines, were invited to participate in an anonymous, online survey between 14/12/2020-11/04/2021. RESULTS: Among 246 MSM (M = 42.1 years), the most common reason for non-vaccination was that participants thought it was unneeded and had not been recommended by a doctor or healthcare provider. None reported vaccine hesitancy. Likewise, the most common reasons for vaccination were doctor/healthcare provider recommendation (51.7-65.6%) and self-protection (60.9-68.1%). The most common reason for not having completed the full course of vaccination was being unaware that the next dose was due (30.0-37.8%). Many participants who had not completed vaccination indicated that a doctor/healthcare provider recommendation would be a motivating factor and that reminder messages and being able to book subsequent appointments in advance would facilitate vaccination. CONCLUSIONS: Sexual health clinicians should be encouraged to discuss STI vaccination with MSM and services should explore possibilities to improve ease and access to vaccine appointments to increase uptake and completion rates.

Novel Biomarkers for Inflammatory Bowel Disease and Colorectal Cancer: An Interplay between Metabolic Dysregulation and Excessive Inflammation.

Persistent inflammation can trigger altered epigenetic, inflammatory, and bioenergetic states. Inflammatory bowel disease (IBD) is an idiopathic disease characterized by chronic inflammation of the gastrointestinal tract, with evidence of subsequent metabolic syndrome disorder. Studies have demonstrated that as many as 42% of patients with ulcerative colitis (UC) who are found to have high-grade dysplasia, either already had colorectal cancer (CRC) or develop it within a short time. The presence of low-grade dysplasia is also predictive of CRC. Many signaling pathways are shared among IBD and CRC, including cell survival, cell proliferation, angiogenesis, and inflammatory signaling pathways. Current IBD therapeutics target a small subset of molecular drivers of IBD, with many focused on the inflammatory aspect of the pathways. Thus, there is a great need to identify biomarkers of both IBD and CRC, that can be predictive of therapeutic efficacy, disease severity, and predisposition to CRC. In this study, we explored the changes in biomarkers specific for inflammatory, metabolic, and proliferative pathways, to help determine the relevance to both IBD and CRC. Our analysis demonstrated, for the first time in IBD, the loss of the tumor suppressor protein Ras associated family protein 1A (RASSF1A), via epigenetic changes, the hyperactivation of the obligate kinase of the NOD2 pathogen recognition receptor (receptor interacting protein kinase 2 [RIPK2]), the loss of activation of the metabolic kinase, AMP activated protein kinase (AMPKα1), and, lastly, the activation of the transcription factor and kinase Yes associated protein (YAP) kinase, that is involved in proliferation of cells. The expression and activation status of these four elements are mirrored in IBD, CRC, and IBD-CRC patients and, importantly, in matched blood and biopsy samples. The latter would suggest that biomarker analysis can be performed non-invasively, to understand IBD and CRC, without the need for invasive and costly endoscopic analysis. This study, for the first time, illustrates the need to understand IBD or CRC beyond an inflammatory perspective and the value of therapeutics directed to reset altered proliferative and metabolic states within the colon. The use of such therapeutics may truly drive patients into remission.

Host Microbiomes Influence the Effects of Diet on Inflammation and Cancer.

Cancer is the second leading cause of death globally, and there is a growing appreciation for the complex involvement of diet, microbiomes, and inflammatory processes culminating in tumorigenesis. Although research has significantly improved our understanding of the various factors involved in different cancers, the underlying mechanisms through which these factors influence tumor cells and their microenvironment remain to be completely understood. In particular, interactions between the different microbiomes, specific dietary factors, and host cells mediate both local and systemic immune responses, thereby influencing inflammation and tumorigenesis. Developing an improved understanding of how different microbiomes, beyond just the colonic microbiome, can interact with dietary factors to influence inflammatory processes and tumorigenesis will support our ability to better understand the potential for microbe-altering and dietary interventions for these patients in future.

Three-site screening for STIs in men who have sex with men using online self-testing in an English sexual health service.

OBJECTIVES: Among men who have sex with men (MSM) in the UK,Chlamydia trachomatis (CT) and Neisseria gonorrhoea (NG) infections commonly occur asymptomatically at extragenital sites. Therefore, MSM seeking sexual health services are offered three-site (oropharyngeal, rectal and urogenital) STI screening. To increase access to screening, some UK sexual health services enable asymptomatic service users to order free STI screening kits online for self-sampling at home. We sought to assess prevalence of overall and extragenital CT/NG infection among asymptomatic MSM who used online self-testing in Hampshire, UK. METHODS: We assessed prevalence of CT/NG infections from non-pooled samples among asymptomatic cisgender MSM using an administrative database with results from 5601 STI screening kits returned between 20 December 2016 and 31 January 2020. We compared number of diagnoses of extragenital infection with urogenital results of the same individuals to determine prevalence of infection that would have been missed with urine testing alone. RESULTS: Among 5051 valid CT and 5040 valid NG asymptomatic test results, overall prevalence was 5.9% (298/5051) and 4.5% (228/5040), respectively. Among MSM with asymptomatic CT, 71.8% (214/298) had extragenital infection only, χ2 (1, n=298)=56.71, p<0.001. Among those with asymptomatic NG, 89.9% (205/228) had extragenital infection only, χ2 (1, n=228)=145.281, p<0.001. CONCLUSIONS: Overall, most CT/NG infections among asymptomatic MSM who used online self-testing were extragenital. Given this and the likelihood of onward transmission from asymptomatic infection, it is recommended that three-site testing remain standard for MSM and free screening services be expanded in easily accessible ways.

Appendix and Ulcerative Colitis: a Key to Explaining the Pathogenesis and Directing Novel Therapies?

The vermiform appendix is generally considered a redundant organ, but recent evidence suggests that the appendix could contribute to the pathogenesis of inflammatory bowel diseases, in particular ulcerative colitis (UC), and may even have a therapeutic role; however, mechanisms of the appendix involvement remain unclear. Here, we highlight current evidence on the link between the appendix and UC and consider plausible therapeutic implications. A literature search was conducted using PubMed and PubMed Central from inception to Nov 2021 using the terms "Appendix", "UC", "Appendix & UC," "Appendectomy", and "Peri-appendicular patch," including only articles published in English. Reference lists from the selected studies were manually searched and reviewed to gather additional related reports. Inflammation around the appendix ("peri-appendicular patch") has been frequently observed in UC patients without other cecal involvement, and this inflammation can even precede the onset of UC. Epidemiologic studies propose that appendectomy reduces the risk of developing UC or even the risk of flare after UC is diagnosed, although this remains controversial. We reviewed studies showing altered host-microbe interactions in the appendix in UC, which suggest that the appendix could act as a priming site for disease via alterations in the immune response and changes in microbiota carried distally to the colon. In summary, recent literature suggests a possible role for microbes and immune cells within the appendix; however, the role of the appendix in the pathogenesis of UC remains unclear. Further research could clarify the therapeutic potential related to this organ.

Unfermented ß-fructan Fibers Fuel Inflammation in Select Inflammatory Bowel Disease Patients.

BACKGROUND & AIMS: Inflammatory bowel diseases (IBD) are affected by dietary factors, including nondigestible carbohydrates (fibers), which are fermented by colonic microbes. Fibers are overall beneficial, but not all fibers are alike, and some patients with IBD report intolerance to fiber consumption. Given reproducible evidence of reduced fiber-fermenting microbes in patients with IBD, we hypothesized that fibers remain intact in select patients with reduced fiber-fermenting microbes and can then bind host cell receptors, subsequently promoting gut inflammation. METHODS: Colonic biopsies cultured ex vivo and cell lines in vitro were incubated with oligofructose (5 g/L), or fermentation supernatants (24-hour anaerobic fermentation) and immune responses (cytokine secretion [enzyme-linked immunosorbent assay/meso scale discovery] and expression [quantitative polymerase chain reaction]) were assessed. Influence of microbiota in mediating host response was examined and taxonomic classification of microbiota was conducted with Kraken2 and metabolic profiling by HUMAnN2, using R software. RESULTS: Unfermented dietary ß-fructan fibers induced proinflammatory cytokines in a subset of IBD intestinal biopsies cultured ex vivo, and immune cells (including peripheral blood mononuclear cells). Results were validated in an adult IBD randomized controlled trial examining ß-fructan supplementation. The proinflammatory response to intact ß-fructan required activation of the NLRP3 and TLR2 pathways. Fermentation of ß-fructans by human gut whole microbiota cultures reduced the proinflammatory response, but only when microbes were collected from patients without IBD or patients with inactive IBD. Fiber-induced immune responses correlated with microbe functions, luminal metabolites, and dietary fiber avoidance. CONCLUSION: Although fibers are typically beneficial in individuals with normal microbial fermentative potential, some dietary fibers have detrimental effects in select patients with active IBD who lack fermentative microbe activities. The study is publicly accessible at the U.S. National Institutes of Health database (clinicaltrials.gov identification number NCT02865707).

The Role of Mutual Masturbation within Relationships: Associations with Sexual Satisfaction and Sexual Self-Esteem.

Objectives: We explored mutual masturbation among women and men and investigated associations with sexual satisfaction and sexual self-esteem. Methods: 117 women and 151 men (Mage = 29.7 years), mostly heterosexual, all in current relationships, completed an online survey covering experiences of solo and partnered sexual activities, feelings about mutual masturbation, sexual self-esteem, and sexual satisfaction. Results: Mutual masturbation was common among both genders. Men reported significantly higher positive feelings about mutual masturbation than women. Recent mutual masturbation was positively associated with sexual satisfaction but not with sexual self-esteem. Conclusions: These findings have implications for sex and couple therapy and research.

Virological suppression among gay, bisexual, and other men who have sex with men living with HIV in Vancouver, Canada: A longitudinal cohort study from 2012-2017.

INTRODUCTION: In 2010, British Columbia (BC) implemented HIV Treatment as Prevention (TasP) as policy. We examined trends in virologic suppression and determinants of significant viremia among a prospective biobehavioural cohort of men who have sex with men (gbMSM) in Vancouver from 2012-2017. METHODS: Respondent-driven sampling was used to recruit sexually active gbMSM (≥16 years) who completed biannual study visits with a computer-assisted self-interview and clinical CD4 and viral load (VL) testing. We linked participant data with the BC HIV Drug Treatment Program to obtain antiretroviral dispensing and VL data. We conducted a trend analysis of VL suppression using univariable generalized estimating equation (GEE) multi-level modelling and multivariable GEE to identify factors associated with episodes of VL ≥200 copies/mL. RESULTS: Of 774 participants, 223 were living with HIV at baseline and 16 were diagnosed during follow-up (n = 239). We observed a significant trend towards reduced levels of unsuppressed VL (>200 copies/mL) from 22% (07/2012-12/2012) to 12% (07/2016-12/2016) (OR:0.87; 95%CI:0.83-0.91 for each 6-month period). Among those with at least one follow-up visit, (n = 178, median follow-up = 3.2 years, median age = 46.9 years), younger age (aOR:0.97; 95%CI:0.94-0.99, per year), ecstasy use (aOR:1.69; 95%CI:1.13-2.53), crystal methamphetamine use (aOR:1.71; 95%CI:1.18-2.48), seeking sex via websites (aOR:1.46; 95%CI:1.01-2.12), and lower HIV treatment optimism (aOR:0.94; 95%CI:0.90-0.97) were associated with episodes of elevated viremia. CONCLUSIONS: During a period when TasP policy was actively promoted, we observed a significant trend towards reduced levels of unsuppressed VL. Continued efforts should promote HIV treatment optimism and engagement, especially among younger gbMSM and those who use ecstasy and crystal methamphetamine.

Factors associated with transactional sex among a cohort of gay, bisexual, and other men who have sex with men in Vancouver, Canada.

Background Gay, bisexual, and other men who have sex with men (GBM) who engage in transactional sex (sex in exchange for drugs, money, or goods) experience increased risk of sexually transmitted infections (STI), including HIV. This study explored additional psychosocial and health-related factors associated with transactional sex among GBM. Methods Respondent-driven sampling was used to recruit GBM in Vancouver, Canada, from 2012 to 2015, with follow up every 6months until July2019. We examined factors associated with transactional sex using multivariable three-level mixed-effects modelling. Results Among 698 GBM, 22.1% reported ever receiving drugs, money, or goods for sex. Transactional sex was more likely to be reported by GBM who were younger (<30years) and who had lower incomes, less education, and insecure housing. GBM reporting transactional sex were more likely to report substance use (i.e. crystal methamphetamine, poppers, GHB, and non-steroid injection drugs) and higher risk sexual behaviours (i.e. more sex partners, sex party attendance, and condomless anal sex with serodifferent or unknown HIV status partners); however, they were no more likely to be living with HIV or to report a recent bacterial STI diagnosis. GBM who reported higher loneliness, anxiety, and cognitive escape were also more likely to report transactional sex. Conclusions More than one-fifth of GBM in Vancouver reported transactional sex and those who did were more likely to also experience psychosocial stressors, increased substance use, and higher risk sexual behaviours. Programs which consider the interconnections of personal, social, and structural challenges faced by GBM engaging in transactional sex are necessary to support improved mental, physical, and sexual health for these men.

Use of HIV pre-exposure prophylaxis among urban Canadian gay, bisexual and other men who have sex with men: a cross-sectional analysis of the Engage cohort study.

BACKGROUND: In Canada, gay, bisexual and other men who have sex with men (GBM) are disproportionately affected by HIV. Our objective was to describe access to HIV pre-exposure prophylaxis (PrEP) and identify factors associated with not using PrEP among self-reported HIV-negative or HIV-unknown GBM. METHODS: This was a cross-sectional analysis of the Engage study cohort. Between 2017 and 2019, sexually active GBM aged 16 years or more in Montréal, Toronto and Vancouver were recruited via respondent-driven sampling (RDS). Participation included testing for HIV and sexually transmitted and blood-borne infections, and completion of a questionnaire. We examined PrEP access using a health care services model and fit RDS-adjusted logistic regressions to determine correlates of not using PrEP among those for whom PrEP was clinically recommended and who were aware of the intervention. RESULTS: A total of 2449 GBM were recruited, of whom 2008 were HIV-negative or HIV-unknown; 1159 (511 in Montréal, 247 in Toronto and 401 in Vancouver) met clinical recommendations for PrEP. Of the 1159, 1100 were aware of PrEP (RDS-adjusted proportion: Montréal 84.6%, Toronto 94.2%, Vancouver 92.7%), 678 had felt the need for PrEP in the previous 6 months (RDS-adjusted proportion: Montréal 39.2%, Toronto 56.1%, Vancouver 49.0%), 406 had tried to access PrEP in the previous 6 months (RDS-adjusted proportion: Montréal 20.6%, Toronto 33.2%, Vancouver 29.6%) and 319 had used PrEP in the previous 6 months (RDS-adjusted proportion: Montréal 14.5%, Toronto 21.6%, Vancouver 21.8%). Not using PrEP was associated with several factors, including not feeling at high enough risk, viewing PrEP as not completely effective, not having a primary care provider and lacking medication insurance. INTERPRETATION: Although half of GBM met clinical recommendations for PrEP, less than a quarter of them reported use. Despite high levels of awareness, a programmatic response that addresses PrEP-related perceptions and health care system barriers is needed to scale up PrEP access among GBM in Canada.