Hernandez, M. M. | Search bioRxiv

bioRxiv2026

Chronic stress remodels gut bacterial ecology and polysaccharide metabolism with neuroendocrine consequences despite unchanged behavior

The gut-microbiome-brain axis (GMBA) links the gut and brain through metabolic, immunological, and neuroendocrine pathways, and can become dysregulated during psychological stress (PS). While previous studies primarily infer microbial function and use physical stressors that incompletely model human PS, here, functional multi-omics was applied to a chronic social-isolation mouse model. Although isolation caused no measurable behavioral changes, brain proteomics revealed stress-associated molecular responses. Taxonomic and short-chain fatty acid analyses suggested limited microbiome changes; however, metaproteomics uncovered sex-specific restructuring of bacterial ecology and carbohydrate-active enzymes. In females, isolation increased Petralouisia muris proteins involved in bacterial microcompartment metabolism and {beta}-glucuronidases across Lachnospiraceae taxa. Enriched {beta}-glucuronidase abundance coincided with reduced circulating glucuronides and altered brain estrogen-receptor activity, suggesting a microbial deconjugation-host estrogen-signaling interaction. These findings demonstrate that functional GMBA alterations may precede or occur independently of overt behavioral phenotypes and highlight the value of direct functional profiling in PS.

microbiology↗

bioRxiv2019

Impact of suboptimal APOBEC3G neutralization on the emergence of HIV drug resistance in humanized mice

HIV diversification facilitates immune escape and complicates antiretroviral therapy. In this study, we take advantage of a humanized mouse model to probe the contribution of APOBEC3 mutagenesis to viral evolution. Humanized mice were infected with isogenic HIV molecular clones (HIV-WT, HIV-45G, HIV-{Delta}SLQ) that differ only in their ability to counteract APOBEC3G (A3G). Infected mice remained naive or were treated with the RT inhibitor lamivudine (3TC). Viremia, emergence of drug resistant variants and quasispecies diversification in the plasma compartment were determined throughout infection. While both HIV-WT and HIV-45G achieved robust infection, over time HIV-45G replication was significantly reduced compared to HIV-WT in the absence of 3TC treatment. In contrast, treatment response differed significantly between HIV-45G and HIV-WT infected mice. Antiretroviral treatment failed in 91% of HIV-45G infected mice while only 36% of HIV-WT infected mice displayed a similar negative outcome. Emergence of 3TC resistant variants and nucleotide diversity were determined by analyzing 155,462 single HIV reverse transcriptase (RT) and 6,985 vif sequences from 33 mice. Prior to treatment, variants with genotypic 3TC resistance (RT-M184I/V) were detected at low levels in over a third of all animals. Upon treatment, the composition of the plasma quasispecies rapidly changed leading to a majority of circulating viral variants encoding RT-184I. Interestingly, increased viral diversity prior to treatment initiation correlated with higher plasma viremia in HIV-45G but not in HIV-WT infected animals. Taken together, HIV variants with suboptimal anti-A3G activity were attenuated in the absence of selection but display a fitness advantage in the presence of antiretroviral treatment.\n\nIMPORTANCEBoth viral (e.g., reverse transcriptase, RT) and host factors (e.g., APOBEC3G (A3G)) can contribute to HIV sequence diversity. This study shows that suboptimal anti-A3G activity shapes viral fitness and drives viral evolution in the plasma compartment of humanized mice.

microbiology↗