Senescence-associated loss of intestinal α1,2-fucose disrupts a modifiable host-microbiome homeostasis axis in people with HIV
Year: 2026
Type: preprint
Study design: Observational Study
Abstract: ABSTRACT Background People 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. Objective To determine whether acquired loss of intestinal α1,2-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. Design Ileal 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. Results In intestinal tissues, PWH exhibited reduced α1,2-fucosylation and increased senescence-associated expression of the fucose-degrading enzyme α-L-fucosidase. Lower α1,2-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 α1,2-fucose donor 2′-fucosyllactose restored SCFA production and improved intestinal organoid resilience to stress-mediated disruption. Conclusion These findings identify acquired loss of intestinal α1,2-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 BOX What is already known on this topic People 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 adds This study identifies acquired loss of intestinal α1,2-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 policy These findings support intestinal glycan ecology as a modifiable host-microbiome axis and provide a rationale for testing α1,2-fucose-replenishing strategies, such as 2′-fucosyllactose, to restore microbial metabolic output and improve epithelial resilience in people with HIV.
Authors: Leila B. Giron, Maliha W. Shaikh, Thaisa M. Cantu Jungles, Lijuan Zhang, Phillip A. Engen, Nuseybe Bulut, Shalini Singh, Jenna M. Hasson, Ellen Zhang, Shivanjali Shankaran, Corey Neumann, Michelle Villanueva, Alan L. Landay, Thomas J. Hope, Frank J. Palella, Michael J. Corley, Hiroaki Tateno, Bruce Hamaker, Noam Auslander, Ramon Lorenzo Redondo, Ali Keshavarzian, Mohamed Abdel-Mohsen
Institutions: Northwestern University, Rush University Medical Center, Purdue University West Lafayette, The University of Texas Medical Branch at Galveston, University of California San Diego, Cellular and Molecular Biotechnology Research Institute, National Institute of Advanced Industrial Science and Technology, The Wistar Institute
Language: English
Topic: Gut microbiota and health
Subfield: Molecular Biology
Domain: Life Sciences
Open Access status: green
Awards: Glycomic Modulation of Gut Microbiome During HIV Infection, Center for Circadian Rhythms and Alcohol-Induced Tissue Damage, Glycomic Modulation of Inflammaging and Immune Functions during HIV Infection, Estrogen's Impact on IgG Glycomic Modulation of Immunity and Inflammation During HIV, Targeting Siglec-9/Sialoglycan Interactions to Enhance NK Functions During HIV Infection, Gut Microbiota-Mediated Inflammatory Interactions Between Alcohol Use Disorders and HIV Infection
OpenAlex ID: W7168017301