The Effects of Doxycycline on Inflammation and the Microbiome: 'Flipping the Script' on STI PEP

HIV and bacterial sexually transmitted infections (STI), including gonorrhea, chlamydia, and syphilis, are disproportionately concentrated among men who have sex with men (MSM) and transgender women (TGW). Doxycycline post-exposure prophylaxis (doxy-PEP) taken as a single 200mg dose <72 hours after sex is a new intervention that can significantly reduce the risk of bacterial STI including a >70-80% reduction in chlamydia and syphilis and >50% reduction in gonorrhea among MSM and TGW with and without HIV. However, significant concerns remain about the potential for substantial harms associated with increased use of doxy- PEP including antimicrobial resistance and effects on the microbiome that could influence long-term acquisition of comorbidities, such as obesity. However, absent from the conversation on the risks/benefits of doxy-PEP to date are the known direct anti-inflammatory and immunomodulatory effects of doxycycline, independent of its antimicrobial effects. Among people with HIV (PWH), chronic inflammation, in part mediated by damage to the gut mucosa and microbial translocation, is thought to contribute to increased morbidity through accelerated acquisition of comorbidities. Our group has previously characterized the altered gut immune environment among MSM with HIV and the contribution of bacterial STI to rectal mucosal inflammation and perturbations in the microbiome among MSM with HIV. In addition, our group has extensively characterized a pro-inflammatory rectal mucosal immune environment among MSM without HIV engaging in receptive anal intercourse that may be associated with HIV acquisition. Given the critical role that inflammation likely plays for MSM both with and without HIV, the potential for anti-inflammatory effects of doxy-PEP, and our preliminary data suggesting minimal effect of doxy-PEP on the gut microbiome, this begs the provocative hypothesis: Could doxy-PEP play a beneficial role in reducing systemic and gut inflammation with minimal harmful effects on the gut microbiome and resistome among MSM and TGW with and without HIV? To address our hypothesis, we will enroll a mechanistic clinical trial of MSM and TGW (n=75 with HIV on antiretroviral therapy; n= 75 without HIV on pre- exposure prophylaxis) and randomize 2:1 to take 200mg of doxycycline at least 3 times/week for 12 weeks vs. observation with biologic sampling. We will sample blood and rectal mucosal secretions and tissues before and after doxy-PEP use that will allow us to fully characterize the effects on systemic (specific aim 1) and rectal mucosal (specific aim 2) inflammation and the microbiome and resistome (specific aim 3) at high resolution and determine whether we can ‘flip the script’ on the potential harms of doxy-PEP for this high need population. Completion of the proposed aims will allow for a comprehensive assessment of the anti-inflammatory and microbiome/resistome effects of doxy-PEP and could ameliorate concerns for widespread implementation of this new intervention. Project Number: 1R01AI192319-01 | Fiscal Year: 2025 | NIH Institute/Center: National Institute of Allergy and Infectious Diseases (NIAID) | Principal Investigator: Colleen Kelley | Institution: EMORY UNIVERSITY, ATLANTA, GA | Award Amount: $797,734 | Activity Code: R01 | Study Section: Special Emphasis Panel[ZRG1 IIDB-X (02)] View on NIH RePORTER: https://reporter.nih.gov/project-details/1R01AI19231901