Kelly, D. L. | bioRxiv Science

bioRxiv2026

The effect of minocycline on the gut microbiome in individuals with alcohol use disorder and healthy controls

Alcohol Use Disorder (AUD) is associated with altered gut microbial composition. Yet, many microbiome studies have included AUD populations with co-occurring conditions (e.g., alcohol associated liver disease; ALD), limiting insight into unique contributions of AUD to gut dysbiosis. Further, preclinical studies show that gut microbiome composition can mediate the behavioral effects of minocycline, including alcohol-related and affective behaviors, but no studies have tested these effects in humans with AUD. This study aimed to 1) compare gut microbiome features between healthy controls (HCs) and individuals with AUD, without ALD, and 2) determine the effects of minocycline on the human gut microbiome. We conducted a four-week randomized, double-blind, placebo-controlled trial of minocycline (100-200 mg/day) in adults with AUD (n=31) and HCs (n=26). We collected fecal samples (n=244) at baseline and each weekly visit for 16S rRNA gene sequencing. Alpha diversity (richness and evenness of taxa within a sample) did not differ by diagnostic group, treatment, or time. In contrast, beta diversity (microbiome composition differences between samples) differed between AUD and controls and was shifted by minocycline over time. AUD, vs. controls, was associated with differences in several taxa prevalences, including reduced Dialister and Subdoligranulum and increased Collinsella, Streptococcus, and Phascolarctobacterium. Minocycline, vs. placebo, rapidly and robustly restructured the microbiome, altering numerous taxa, including Lachnospira, Ruminococcaceae, Clostridium sensu stricto, and Christensenellaceae, and metabolic pathways (e.g., ubiquinol biosynthesis and methylphosphonate degradation). AUD is associated with a distinct gut microbial composition, whereas minocycline produces rapid, sustained, diagnosis-independent gut microbiome restructuring, without altering alpha diversity.

genomics↗

bioRxiv2026

A Multi-Kinase Inhibitor Screen Identifies mTOR Signaling as a Vulnerability in Advanced Prostate Cancer.

The receptor tyrosine kinase AXL has context-dependent roles in prostate cancer (PCa). Although AXL signaling has been implicated in PCa progression, it can also promote disseminated tumor cell dormancy. Paradoxically, AXL expression has been reported to be lost in metastatic PCa. This raises two critical questions: Is AXL loss associated with aggressive disease, and does it create therapeutically exploitable vulnerabilities? In this study, we comprehensively analyzed AXL expression across pan-cancer and PCa cohorts and found that AXL downregulation was significantly associated with treatment resistance, aggressive PCa phenotypes, and shorter overall survival. To investigate the functional consequences of AXL loss, we used CRISPR-Cas9 based gene editing to generate isogenic AXLKO cells and characterized their proliferative and migratory properties. To identify therapeutically exploitable vulnerabilities associated with AXL loss, we screened these cells against a library of 1,814 kinase inhibitors using the isogenic cell lines. We identified Torin-2 as a candidate therapeutic agent and validated its activity using dose-response assays, which demonstrated an ~ 18-fold lower IC50 in AXLKO cells than in AXLWT cells. In parallel, PRISM/DepMap analysis provided orthogonal evidence of drug dependencies associated with low AXL expression and revealed a selective vulnerability of AXLKO cells to PI3K/AKT/mTOR pathway inhibition. Collectively, our findings link AXL downregulation to aggressive PCa phenotypes and identify mTOR inhibition as a potential therapeutic strategy for AXL-deficient PCa.

cancer biology↗