Biology subjects

Engen, P.

Publications and source records attributed to Engen, P..

2 recordsLinked to original sources

bioRxiv2026

Senescence-associated loss of intestinal α1,2-fucose disrupts a modifiable host-microbiome homeostasis axis in people with HIV

BackgroundPeople with HIV (PWH), despite effective antiretroviral therapy (ART), experience disrupted intestinal homeostasis characterized by microbial dysbiosis and impaired intestinal barrier integrity, which contribute to chronic inflammation and aging-associated comorbidities. However, tractable mechanisms contributing to this dysfunction remain poorly defined. ObjectiveTo determine whether acquired loss of intestinal 1,2-fucose, a host-derived intrinsic prebiotic glycan that supports colonization by short-chain fatty acid (SCFA)-producing bacteria essential for intestinal barrier integrity, contributes to microbiome disruption, impaired epithelial resilience, inflammation, and biological aging in PWH. DesignIleal and colonic biopsies, isolated crypts, stool, and blood from PWH on ART and controls underwent multi-omic analyses. Findings were mechanistically interrogated using stool anaerobic fermentation assays and 3D intestinal organoid models of stress-mediated epithelial disruption. ResultsIn intestinal tissues, PWH exhibited reduced 1,2-fucosylation and increased senescence-associated expression of the fucose-degrading enzyme -L-fucosidase. Lower 1,2-fucose tracked with depletion of SCFA-producing bacteria, increased inflammation, and premature biological aging. In anaerobic fermentations, stool from PWH produced fewer SCFAs than controls, whereas supplementation with the human-milk-oligosaccharide-derived 1,2-fucose donor 2'-fucosyllactose restored SCFA production and improved intestinal organoid resilience to stress-mediated disruption. ConclusionThese findings identify acquired loss of intestinal 1,2-fucose as a modifiable host-microbiome mechanism linking epithelial senescence, microbial metabolic dysfunction, impaired barrier resilience, inflammation, and biological aging in treated HIV infection. SUMMARY BOXO_ST_ABSWhat is already known on this topicC_ST_ABSPeople with HIV on suppressive antiretroviral therapy frequently have persistent intestinal barrier dysfunction, microbial dysbiosis, chronic inflammation, and accelerated biological aging, but the host mechanisms that maintain this disrupted mucosal state remain incompletely defined. What this study addsThis study identifies acquired loss of intestinal 1,2-fucosylation as a feature of treated HIV infection and links this defect to a host fucosidase-high, senescence-enriched mucosal niche, depletion of SCFA-producing bacteria, impaired tight junction-associated barrier signatures, inflammation, and biological aging phenotypes. How this study might affect research, practice or policyThese findings support intestinal glycan ecology as a modifiable host-microbiome axis and provide a rationale for testing 1,2-fucose-replenishing strategies, such as 2'-fucosyllactose, to restore microbial metabolic output and improve epithelial resilience in people with HIV.

microbiology↗

bioRxiv2020

Sexually dimorphic responses to MPTP found in microglia, inflammation and gut microbiota in a progressive monkey model of Parkinson's disease

Inflammation has been linked to the development of nonmotor symptoms in Parkinsons disease (PD), which greatly impact patients quality of life and can often precede motor symptoms. Suitable animal models are critical for our understanding of the mechanisms underlying disease and the associated prodromal disturbances. The neurotoxin 1- methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP)-treated monkey model is commonly seen as a "gold standard" model that closely mimics the clinical motor symptoms and the nigrostriatal dopaminergic loss of PD, however MPTP toxicity extends to other nondopaminergic regions. Yet, there are limited reports monitoring the MPTP-induced progressive central and peripheral inflammation as well as other nonmotor symptoms such as gastrointestinal function and microbiota. The main objective of this study is to gain a broader understanding of central and peripheral inflammatory dysfunction triggered by exposure to a neurotoxicant known to degenerate nigral dopaminergic neurons in order to understand the potential role of inflammation in prodromal/pre-motor features of PD-like degeneration in a progressive non-human primate model of the disease. We measured inflammatory proteins in plasma and CSF and performed [18F]FEPPA PET scans to evaluate translocator proteins (TSPO) or microglial activation in a small cohort of rhesus monkeys (n=5) given weekly low doses of MPTP (0.2-0.8 mg/kg, im). Additionally, monkeys were evaluated for working memory and executive function using various behavior tasks and for gastrointestinal hyperpermeability and microbiota composition. Monkeys were also treated with novel TNF inhibitor XPro1595 (10mg/kg, n=3) or vehicle (n=2) every three days starting 11 weeks after the initiation of MPTP to determine whether nonmotor symptoms are tied to TNF signaling and whether XPro1595 would alter inflammation and microglial behavior in a progressive model of PD. Our analyses revealed sex-dependent sensitivity to MPTP that resulted in early microglial activation by PET, acute plasma IL-6 and CSF TNF, and earlier parkinsonism as measured by motor deficits in males compared to female monkeys. Sex differences were also identified in microbiota and their metabolites and targeted short chain fatty acids at both basal levels and in response to MPTP. Both sexes displayed cognitive impairment prior to a significant motor phenotype. Importantly, XPro1595 shifted peripheral and central inflammation, and significantly reduced CD68-immunoreactivity in the colon. As such, our findings revealed a sexually dimorphic inflammatory response to chronic MPTP treatment and suggest that males may have higher vulnerability than females to inflammation-induced degeneration. If these findings reflect potential differences in humans, these sex differences have significant implications for therapeutic development of inflammatory targets in the clinic.

neuroscience↗