In this study, we explored the link between gut impairment and severe COVID-19 in people with HIV (PWH). We compared PWH with COVID-19 to HIV-uninfected individuals hospitalized for the same condition. Despite more severe clinical symptoms in PWH, we did not observe significant differences in gut barrier dysfunction markers between the two groups. Our findings suggest a link between SARS-CoV-2 pneumonia and gut damage, independent of HIV status, warranting further investigation into its role in COVID-19 severity

Augello, Matteo

Bono, Valeria

Borghi, Elisa

Callegaro, Annapaola

Di Biagio, Antonio

Maggiolo, Franco

Marchetti, Giulia

Marozin, Sabrina

Mazzoccoli, Martina

Rovito, Roberta

Taramasso, Lucia

Tincati, Camilla

English

AIR Universita degli studi di Milano

Research LettersAIDS 2025, 39:921–926Comparable gut mucosal breakdown and microbialtranslocation in severe COVID-19 with andwithout HIV infectionSabrina Marozina,M, Valeria Bonoa,M,Martina Mazzoccolia, Matteo Augelloa,Roberta Rovitoa, Lucia Taramassoc,Antonio Di Biagioc,d, Annapaola Callegaroe,Franco Maggiolof, Elisa Borghib, Camilla Tincatiaand Giulia MarchettiaIn this study, we explored the link between gutimpairment and severe COVID-19 in people withHIV (PWH). We compared PWH with COVID-19to HIV-uninfected individuals hospitalized for thesame condition. Despite more severe clinicalsymptoms in PWH, we did not observe significantdifferences in gut barrier dysfunction markersbetween the two groups. Our findings suggest alink between SARS-CoV-2 pneumonia and gutdamage, independent of HIV status, warrantingfurther investigation into its role in COVID-19severity.The impact of HIV as a risk factor in the morbidity ofCOVID-19, especially early in the pandemic, has beenlong debated. Several data indicate that the severity of theclinical outcome of SARS-CoV-2 infection in peoplewith HIV (PWH) under combination antiretroviraltreatment (cART) is equivalent to people without HIV[1,2]. Yet, progression to more severe COVID-19 and itsrelated complications have been observed in PWH, inassociation with comorbidities, low CD4þ cell count anddetectable viral load [3,4]. Impaired intestinal barrierfunction as well as subsequent microbial translocation, areconsidered pathogenic hallmarks of HIV infection anddisease progression [5]. Of note, the same features havebeen linked to the development of severe SARS-CoV-2infection also in PWH [6].We, therefore, hypothesized that gut damage/microbialtranslocation represent an underlying cause of severeCOVID-19 in PWH.To this end, we enrolled 16 PWH and 18 sex-matchedand age-matched HIV-uninfected individuals, for whomfrozen plasma samples were available, who sought medicalcare for acute COVID-19 during the initial SARS-CoV-2 pandemic in 2020–2021.Individuals with COVID-19 were recruited during thefirst wave of the pandemic (March–May 2020), whereasPWH-COVID-19 participants were enrolled during thesecond wave (October 2020–April 2021). Neither studygroup had received the SARS-CoV-2 vaccine at the timeof study. All individuals were hospitalized for COVID-19-related pneumonia. SARS-CoV-2 was confirmed bypositive nasopharyngeal swab (RT-PCR) and radiologicalimaging of pneumonia. Plasma was used to determinelevels of microbial translocation [lipopolysaccharide(LPS)-binding protein (LBP), Hycult Biotech kit],microbial-driven monocyte activation [soluble clusterof differentiation 14 (CD14), Hycult Biotech kit], gutdamage [intestinal fatty-acid binding protein (I-FABP),Hycult Biotech kit] and structure [Epithelial cadherin (E-Cadherin); tight junction protein Zonulin, Elabsciencekit] by ELISA, following the manufacturer’s instructions.Descriptive and statistical analyses were performed withthe use of GraphPad Prism 9.0 (GraphPad Inc., La Jolla,California, USA). Categorical variables were reported aspercentages (Fisher’s exact test) and continuous variableswere reported as median (interquartile range, IQR).Comparisons among groups were performed by Mann–Whitney U test.The two groups were comparable for age, sex, ethnicityand major comorbidities. Regarding COVID-19 symp-tomatology, PWH more frequently reported cough(P< 0.0001), presented a later admission to the hospitalfrom the onset of the symptoms (9.5 versus 5.5 days,P¼ 0.023), had a lower PaO2/FiO2 nadir and were morefrequently treated with mechanical ventilation (31.2versus 16.7%, P¼ 0.02) as well as medical therapy duringhospitalization (P< 0.0001) compared to non-PWH(P¼ 0.0001). The median duration of symptoms beforebiological sample collection was 5.5 days in individualswith COVID-19 and 9.5 days in PWH-COVID-19. Theclinical outcome was comparable between groups (TableS1, http://links.lww.com/QAD/D492).The majority of PWH (87.5%) were on cARTand 81.2%had undetectable HIV RNA (<50 copies/ml). CD4þ T-cell nadir was 59 (IQR 12.5– 331.3 cells/ml), currentCD4þ T-cell count and CD4þ/CD8þ ratio were,respectively, 395 cells/ml (IQR 171–776 cells/ml) and0.4 (IQR 0.17–1.05).We observed a trend to higher levels of LBP in PWH-COVID-19 than individuals with COVID-19 alone[21677 ng/ml (IQR: 8447–28552) versus 16408 ng/ml(IQR: 7654–23 415); P¼ 0.09; Fig. 1a]. In contrast,sCD14 [2563 ng/ml (IQR: 1728–3587) versus 1807 ng/ml (IQR: 1757–2398); P¼ 0.4; Fig. 1b), I-FABP[128.8 pg/ml (49–502) versus 183.3 pg/ml (114–360.5); P¼ 0.4; Fig. 1c], E-Cadherin [167 ng/mlISSN 0269-9370 Copyright Q 2025 The Author(s). Published by Wolters Kluwer Health, Inc. This is an open access article distributed under theCreative Commons Attribution License 4.0 (CCBY), which permits unrestricted use, distribution, and reproduction in any medium, provided theoriginal work is properly cited. 921(128–196) versus 149.7 ng/ml (121–173); P¼ 0.3;Fig. 1d] and Zonulin [119 ng/ml (40–175) versus146.6 ng/ml (52–147); P¼ 0.8; Fig. 1e] were comparablein the two groups.The present research was conducted to assess whether gutbarrier breakdown, a known feature of both HIV andSARS-CoV-2 infection, might be a factor contributingto severe COVID-19 in PWH. We hypothesized higherlevels of microbial translocation/mucosal barrier dys-function markers in PWH hospitalized for COVID-19compared to those without HIV. Indeed, previous studiesreport that LBP, sCD14, I-FABP, E-cadherin, andZonulin levels are generally lower in healthy controlscompared to those seen in pathological conditionsinvolving systemic inflammation or intestinal barrierdysfunction [7–9]. Surprisingly, despite a tendency to amore severe clinical presentation of COVID-19 in PWH,we did not detect significant differences in LBP, sCD14,I-FABP, E-cadherin, and Zonulin levels between the twogroups. A possible explanation for our findings is thatPWH with COVID-19 pneumonia were more fre-quently treated with antiviral and steroid therapy, whichmay have contained, at least in part, SARS-CoV-2-mediated damage in the gut.Our study has several drawbacks, including the lack ofnon-COVID-19 controls, its cross-sectional design andsmall sample size; indeed, the present work wasconducted as a pilot study to investigate the trends inmarkers of gut function/damage and generate hypothesesfor future research. Furthermore, Zonulin measurement922 AIDS 2025, Vol 39 No 7COVID-19PWH-COVID-1901000020000300004000050000LBPng/mlCOVID-19PWH-COVID-1902000400060008000sCD14ng/mlCOVID-19PWH-COVID-190200400600800I-FABPpg/mLCOVID-19PWH-COVID-190100200300400E-Cadherinng/mLCOVID-19PWH-COVID-190100200300Zonulinng/ml(a) (b) (c)(d) (e)Fig. 1. (a–e) Levels of intestinal barrier permeability and microbial translocation during severe COVID-19 in non-PWH(COVID-19) and PWH (PWH-COVID-19). Serum concentrations of lipopolysaccharide (LPS)-binding protein (LBP); solublecluster of differentiation 14 (CD14); intestinal fatty-acid binding protein (I-FABP); epithelial cadherin (E-Cadherin); tight junctionprotein (Zonulin). Statistical analysis: Mann–Whitney U test. PWH, people with HIV.by ELISA might have been affected by interference fromalbumin and complement components, as reported byrecent research [10]. Despite these limitations, ourresearch highlights that gastrointestinal impairment issimilar between the two study groups, regardless of HIVstatus, and may therefore be linked to critical COVID-19condition. Future studies should focus on assessing thelong-term kinetics of gut injury and changes inmicrobiota composition in individuals with severeCOVID-19 and better understand its possible role inthe development of postacute sequelae of SARS-CoV-2infection (PASC) [11,12].AcknowledgementsThis study was supported by funding from the EuropeanUnion‘s Horizon 2020 Research and InnovationProgram under grant agreement no. 101016167 withinthe ORCHESTRA project (Connecting EuropeanCohorts to Increase Common and Effective Responseto SARS-CoV-2 Pandemic), and grant agreement no.101046016 within the EuCARE project (EuropeanCohorts of Patients and Schools to Advance Response toEpidemics).We thank Miss Maria Sgarlata and Dr Silvia Ancona fortechnical support.We are grateful to all the patients and the contributors,whose effort made this small study possible.Conflicts of interestThere are no conflicts of interest.aClinic of Infectious Diseases and Tropical Medicine,San Paolo Hospital, ASST Santi Paolo e Carlo, Depart-ment of Health Sciences, University of Milan; bLabora-tory of Microbiology and Clinical Microbiology,Department of Health Sciences, University of Milan,Milan; cInfectious Diseases Unit, SanMartino PoliclinicoHospital; dDepartment of Health Sciences, Universityof Genoa, Genoa; eBiobank Unit and Microbiology andVirology Laboratory; and fDivision of Infectious Dis-eases, ASST Papa Giovanni XXIII, Bergamo, Italy.Correspondence to Giulia Marchetti, MD, PhD, Clinic ofInfectious Diseases and Tropical Medicine, San PaoloHospital, ASST Santi Paolo e Carlo, Department ofHealth Sciences, University of Milan, Via A. Di Rudinı̀ 8,Milan, Italy.E-mail: giulia.marchetti@unimi.itS.M. and V.B. equally contributed to the manuscript.Received: 23 October 2024; revised: 31 January 2025;accepted: 5 February 2025.References1. Augello M, Bono V, Rovito R, Tincati C, Marchetti G.Immunologic interplay between HIV/AIDS and COVID-19:adding fuel to the flames?. Curr HIV/AIDS Rep 2023; 20:51–75.2. Giacomelli A, Gagliardini R, Tavelli A, De Benedittis S, Maz-zotta V, Rizzardini G, et al., COVID-19 ICONA study group.Risk of COVID-19 in-hospital mortality in people living withHIV compared to general population according to age and CD4strata: data from the ICONA network. Int J Infect Dis 2023;136:127–135.3. Spinelli MA, Jones BLH, Gandhi M. COVID-19 outcomes andrisk factors among people living with HIV. Curr HIV/AIDS Rep2022; 19:425–432.4. Augello M, Bono V, Rovito R, Tincati C, Bianchi S, Taramasso L,et al. Association between SARS-CoV-2 RNAemia, skewed Tcell responses, inflammation, and severity in hospitalizedCOVID-19 people living with HIV. iScience 2024; 27:108673.5. Marchetti G, Tincati C, Silvestri G. Microbial translocation inthe pathogenesis of HIV infection and AIDS. Clin Microbiol Rev2013; 26:2–18.6. Xue W, Honda M, Hibi T. Mechanisms of gastrointestinalbarrier dysfunction in COVID-19 patients. World J Gastroen-terol 2023; 29:2283–2293.7. Sereti I, Krebs SJ, Phanuphak N, Fletcher JL, Slike B, Pinyakorn S,et al., RV254/SEARCH 010, RV304/SEARCH 013 and SEARCH011 protocol teams. Persistent, albeit reduced, chronic inflam-mation in persons starting antiretroviral therapy in acute HIVinfection. Clin Infect Dis 2017; 64:124–131.8. Brenchley JM, Price DA, Schacker TW, Asher TE, Silvestri G,Rao S, et al. Microbial translocation is a cause of systemicimmune activation in chronic HIV infection. Nat Med 2006;12:1365–1371.9. Hunt PW, Sinclair E, Rodriguez B, Shive C, Clagett B, Funder-burg N, et al. Gut epithelial barrier dysfunction and innateimmune activation predict mortality in treated HIV infection.J Infect Dis 2014; 210:1228–1238.10. Ajamian M, Steer D, Rosella G, Gibson PR. Serum zonulin as amarker of intestinal mucosal barrier function: may not be whatit seems. PLoS One 2019; 14:e0210728.11. Mouchati C, Durieux JC, Zisis SN, Labbato D, Rodgers MA,Ailstock K, et al. Increase in gut permeability and oxidized ldlis associated with postacute sequelae of SARS-CoV-2. FrontImmunol 2023; 14:1182544.12. Ishizaka A, Koga M, Mizutani T, Yamayoshi S, Iwatsuki-Hor-imoto K, Adachi E, et al. Association of gut microbiota with thepathogenesis of SARS-CoV-2 infection in people living withHIV. BMC Microbiol 2024; 24:6.DOI:10.1097/QAD.0000000000004166Research Letters 923Research LettersAIDS 2025, 39:921–926Association of HIV status with infectionscomplicating abortion in BotswanaBogadi Loabilea, Warren B. Bilkerb,c, Khumo Khunoud,Ngwao Ngwakoe, Billy Tsimad, Merrian J. Brooksf,Thabo Moloig, Chelsea Morronih,i and Robert Grossa,b,cWomen with HIV (WWH) were found to havean increased risk of abortion-related infection rel-ative to women without HIV (WWoH) and thosewithout HIV status documented. This relationshippersisted even after accounting for factors suchas mechanical injury on pelvic examination, amarker of the least safe methods of self-induction.Whether this complication in WWH is because of

Comparable gut mucosal breakdown and microbial translocation in severe COVID-19 with and without HIV infection

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Comparable gut mucosal breakdown and microbial translocation in severe COVID-19 with and without HIV infection

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