From Gut to Blood: Redistribution of Zonulin in People Living with HIV

Overview

Journal Biomedicines

Specialty Biomedical Engineering

Date 2024 Oct 26

PMID 39457626

Authors

Max Augustin

Carola Horn

Meryem Seda Ercanoglu

Vincent Bondet

Ute Sandaradura de Silva

Isabelle Suarez

Seung-Hun Chon

Dirk Nierhoff

Alexander Zoufaly

Christoph Wenisch

Elena Knops

Eva Heger

Florian Klein

Darragh Duffy

Michaela Muller-Trutwin

Clara Lehmann

Affiliations

Soon will be listed here.

Abstract

Background: Gastrointestinal mucosal damage due to human immunodeficiency virus (HIV) infection leads to microbial translocation and immune activation, contributing to the development of non-infectious comorbidities (NICM) in people living with HIV (PLWH). Additionally, persistent proviral HIV-1 in the gut-associated lymphatic tissue (GALT) can trigger immunological changes in the epithelial environment, impacting the mucosal barrier. However, the role of zonulin, a modulator of epithelial tight junctions in GALT during HIV infection, remains poorly understood.

Methods: We measured zonulin in serum and intestinal tissue sections from five treatment-naive (HIV) and 10 cART-treated (HIV) HIV individuals, along with 11 controls (CTRL). We compared zonulin levels with clinical characteristics, inflammatory markers (IFN-α, CXCR3, and PD-1), and the viral reservoir in peripheral blood (PB) and terminal ileum (TI).

Results: Upon HIV infection, TI was found to harbor more HIV DNA than PB. Circulating zonulin levels were highest in HIV compared to HIV or CTRL. Surprisingly, in the gut tissue sections, zonulin levels were higher in CTRL than in HIV individuals. Elevated circulating zonulin levels were found to be correlated with CD4T-cell depletion in PB and TI, and with intestinal IFN-α.

Conclusions: The findings of this study indicate a shift in zonulin levels from the gut to the bloodstream in response to HIV infection. Furthermore, elevated systemic zonulin levels are associated with the depletion of intestinal CD4 T cells and increased gut inflammation, suggesting a potential link between systemic zonulin and intestinal damage. Gaining insight into the regulation of gut tight junctions during HIV infection could offer valuable understanding for preventing NICM in PLWH.

References

Pinto-Cardoso S, Klatt N, Reyes-Teran G . Impact of antiretroviral drugs on the microbiome: unknown answers to important questions. Curr Opin HIV AIDS. 2017; 13(1):53-60. PMC: 5718259. DOI: 10.1097/COH.0000000000000428. View

Powles T, Robinson D, Stebbing J, Shamash J, Nelson M, Gazzard B . Highly active antiretroviral therapy and the incidence of non-AIDS-defining cancers in people with HIV infection. J Clin Oncol. 2008; 27(6):884-90. DOI: 10.1200/JCO.2008.19.6626. View

Koay W, Lindsey J, Uprety P, Bwakura-Dangarembizi M, Weinberg A, Levin M . Intestinal Integrity Biomarkers in Early Antiretroviral-Treated Perinatally HIV-1-Infected Infants. J Infect Dis. 2018; 218(7):1085-1089. PMC: 6107740. DOI: 10.1093/infdis/jiy271. View

Ponte R, Mehraj V, Ghali P, Couedel-Courteille A, Cheynier R, Routy J . Reversing Gut Damage in HIV Infection: Using Non-Human Primate Models to Instruct Clinical Research. EBioMedicine. 2016; 4:40-9. PMC: 4776249. DOI: 10.1016/j.ebiom.2016.01.028. View

Fasano A . All disease begins in the (leaky) gut: role of zonulin-mediated gut permeability in the pathogenesis of some chronic inflammatory diseases. F1000Res. 2020; 9. PMC: 6996528. DOI: 10.12688/f1000research.20510.1. View

Shah A, Stelzle D, Lee K, Beck E, Alam S, Clifford S . Global Burden of Atherosclerotic Cardiovascular Disease in People Living With HIV: Systematic Review and Meta-Analysis. Circulation. 2018; 138(11):1100-1112. PMC: 6221183. DOI: 10.1161/CIRCULATIONAHA.117.033369. View

Chomont N, El-Far M, Ancuta P, Trautmann L, Procopio F, Yassine-Diab B . HIV reservoir size and persistence are driven by T cell survival and homeostatic proliferation. Nat Med. 2009; 15(8):893-900. PMC: 2859814. DOI: 10.1038/nm.1972. View

Petoumenos K, Huang R, Hoy J, Bloch M, Templeton D, Baker D . Prevalence of self-reported comorbidities in HIV positive and HIV negative men who have sex with men over 55 years-The Australian Positive & Peers Longevity Evaluation Study (APPLES). PLoS One. 2017; 12(9):e0184583. PMC: 5590989. DOI: 10.1371/journal.pone.0184583. View

Fasano A, Not T, Wang W, Uzzau S, Berti I, Tommasini A . Zonulin, a newly discovered modulator of intestinal permeability, and its expression in coeliac disease. Lancet. 2000; 355(9214):1518-9. DOI: 10.1016/S0140-6736(00)02169-3. View

10.

Pelsers M, Namiot Z, Kisielewski W, Namiot A, Januszkiewicz M, Hermens W . Intestinal-type and liver-type fatty acid-binding protein in the intestine. Tissue distribution and clinical utility. Clin Biochem. 2003; 36(7):529-35. DOI: 10.1016/s0009-9120(03)00096-1. View

11.

Pastor L, Langhorst J, Schroder D, Casellas A, Ruffer A, Carrillo J . Different pattern of stool and plasma gastrointestinal damage biomarkers during primary and chronic HIV infection. PLoS One. 2019; 14(6):e0218000. PMC: 6559643. DOI: 10.1371/journal.pone.0218000. View

12.

Pourcher V, Gourmelen J, Bureau I, Bouee S . Comorbidities in people living with HIV: An epidemiologic and economic analysis using a claims database in France. PLoS One. 2020; 15(12):e0243529. PMC: 7746269. DOI: 10.1371/journal.pone.0243529. View

13.

Cheung J, Puhr R, Petoumenos K, Cooper D, Woolley I, Gunathilake M . Chronic kidney disease in Australian Human Immunodeficiency Virus-infected patients: Analysis of the Australian HIV Observational Database. Nephrology (Carlton). 2017; 23(8):778-786. PMC: 5799037. DOI: 10.1111/nep.13100. View

14.

Mavigner M, Watkins B, Lawson B, Lee S, Chahroudi A, Kean L . Persistence of virus reservoirs in ART-treated SHIV-infected rhesus macaques after autologous hematopoietic stem cell transplant. PLoS Pathog. 2014; 10(9):e1004406. PMC: 4177994. DOI: 10.1371/journal.ppat.1004406. View

15.

Brenchley J, Douek D . Microbial translocation across the GI tract. Annu Rev Immunol. 2012; 30:149-73. PMC: 3513328. DOI: 10.1146/annurev-immunol-020711-075001. View

16.

Heron J, Norman S, Yoo J, Lembke K, OConnor C, Weston C . The prevalence and risk of non-infectious comorbidities in HIV-infected and non-HIV infected men attending general practice in Australia. PLoS One. 2019; 14(10):e0223224. PMC: 6784917. DOI: 10.1371/journal.pone.0223224. View

17.

Augustin M, Horn C, Ercanoglu M, de Silva U, Bondet V, Suarez I . CXCR3 Expression Pattern on CD4+ T Cells and IP-10 Levels with Regard to the HIV-1 Reservoir in the Gut-Associated Lymphatic Tissue. Pathogens. 2022; 11(4). PMC: 9027803. DOI: 10.3390/pathogens11040483. View

18.

Estes J, Kityo C, Ssali F, Swainson L, Makamdop K, Del Prete G . Defining total-body AIDS-virus burden with implications for curative strategies. Nat Med. 2017; 23(11):1271-1276. PMC: 5831193. DOI: 10.1038/nm.4411. View

19.

Klatt N, Funderburg N, Brenchley J . Microbial translocation, immune activation, and HIV disease. Trends Microbiol. 2012; 21(1):6-13. PMC: 3534808. DOI: 10.1016/j.tim.2012.09.001. View

20.

Fasano A . Zonulin and its regulation of intestinal barrier function: the biological door to inflammation, autoimmunity, and cancer. Physiol Rev. 2011; 91(1):151-75. DOI: 10.1152/physrev.00003.2008. View