Cotrimoxazole reduces systemic inflammation in HIV infection by altering the gut microbiome and immune activation

Study information

Reviewed Marked as Reviewed by Atrayees on 2023-6-27

study design

randomized controlled trial

Citation

PMID PubMed identifier for scientific articles.

30944164

DOI Digital object identifier for electronic documents.

10.1126/scitranslmed.aav0537

URI

Authors

Bourke CD, Gough EK, Pimundu G, Shonhai A, Berejena C, Terry L, Baumard L, Choudhry N, Karmali Y, Bwakura-Dangarembizi M, Musiime V, Lutaakome J, Kekitiinwa A, Mutasa K, Szubert AJ, Spyer MJ, Deayton JR, Glass M, Geum HM, Pardieu C, Gibb DM, Klein N, Edens TJ, Walker AS, Manges AR, Prendergast AJ

Journal

Science translational medicine

Year

2019

Long-term cotrimoxazole prophylaxis reduces mortality and morbidity in HIV infection, but the mechanisms underlying these clinical benefits are unclear. Here, we investigate the impact of cotrimoxazole on systemic inflammation, an independent driver of HIV mortality. In HIV-positive Ugandan and Zimbabwean children receiving antiretroviral therapy, we show that plasma inflammatory markers were lower after randomization to continue (n = 144) versus stop (n = 149) cotrimoxazole. This was not explained by clinical illness, HIV progression, or nutritional status. Because subclinical enteropathogen carriage and enteropathy can drive systemic inflammation, we explored cotrimoxazole effects on the gut microbiome and intestinal inflammatory biomarkers. Although global microbiome composition was unchanged, viridans group Streptococci and streptococcal mevalonate pathway enzymes were lower among children continuing (n = 36) versus stopping (n = 36) cotrimoxazole. These changes were associated with lower fecal myeloperoxidase. To isolate direct effects of cotrimoxazole on immune activation from antibiotic effects, we established in vitro models of systemic and intestinal inflammation. In vitro cotrimoxazole had modest but consistent inhibitory effects on proinflammatory cytokine production by blood leukocytes from HIV-positive (n = 16) and HIV-negative (n = 8) UK adults and reduced IL-8 production by gut epithelial cell lines. Collectively we demonstrate that cotrimoxazole reduces systemic and intestinal inflammation both indirectly via antibiotic effects on the microbiome and directly by blunting immune and epithelial cell activation. Synergy between these pathways may explain the clinical benefits of cotrimoxazole despite high antimicrobial resistance, providing further rationale for extending coverage among people living with HIV in sub-Saharan Africa.

Experiment 1

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Reviewed Marked as Reviewed by Atrayees on 2023-6-27

Curated date: 2021/01/10

Curator: WikiWorks

Revision editor(s): Rimsha, WikiWorks, LGeistlinger

Subjects

Location of subjects: Zimbabwe

Host species Species from which microbiome was sampled. Contact us to have more species added.: Homo sapiens

Body site Anatomical site where microbial samples were extracted from according to the Uber Anatomy Ontology: Feces Cow dung,Cow pat,Droppings,Dung,Excrement,Excreta,Faeces,Fecal material,Fecal matter,Fewmet,Frass,Guano,Matières fécales@fr,Merde@fr,Ordure,Partie de la merde@fr,Piece of shit,Porción de mierda@es,Portion of dung,Portion of excrement,Portion of faeces,Portion of fecal material,Portion of fecal matter,Portion of feces,Portion of guano,Portion of scat,Portionem cacas,Scat,Spoor,Spraint,Stool,Teil der fäkalien@de,Feces,feces

Condition The experimental condition / phenotype studied according to the Experimental Factor Ontology: HIV infection , Antimicrobial agent [X]Human immunodeficiency virus disease,[X]Human immunodeficiency virus disease (disorder),[X]Unspecified human immunodeficiency virus [HIV] disease,[X]Unspecified human immunodeficiency virus [HIV] disease (disorder),HIV - Human immunodeficiency virus infection,HIV INFECT,HIV Infection,HIV infection,HIV Infections,HIV infectious disease,HTLV III INFECT,HTLV III Infections,HTLV III LAV INFECT,HTLV III LAV Infections,HTLV WIII INFECTIONS,HTLV WIII LAV INFECTIONS,HTLV-III Infection,HTLV-III Infections,HTLV-III-LAV Infection,HTLV-III-LAV Infections,HUMAN IMMUNO VIRUS DIS,human immunodeficiency virus,Human immunodeficiency virus [HIV] disease,HUMAN IMMUNOdeficiency VIRUS [HIV] INFECTION,Human immunodeficiency virus caused disease or disorder,Human immunodeficiency virus disease,Human immunodeficiency virus disease (disorder),Human immunodeficiency virus disease or disorder,Human immunodeficiency virus infection,Human immunodeficiency virus infection (disorder),Human immunodeficiency virus infection, NOS,Human immunodeficiency virus infectious disease,human immunodeficiency virus infectious disease,Infection, HIV,Infection, HTLV-III,Infection, HTLV-III-LAV,Infections, HIV,Infections, HTLV-III,Infections, HTLV-III-LAV,LYMPHOTROPIC VIRUS TYPE III INFECTIONS HUMAN T,T LYMPHOTROPIC VIRUS TYPE III INFECT HUMAN,T Lymphotropic Virus Type III Infections, Human,T-Lymphotropic Virus Type III Infections, Human,Unspecified human immunodeficiency virus [HIV] disease (disorder),hIV infection,antibiotic,antibiotics,Antibiotika,Antibiotikum,antibiotique,antimicrobial,antimicrobial agents,microbicide,microbicides,Antimicrobial agent,antimicrobial agent

Group 0 name Corresponds to the control (unexposed) group for case-control studies: stop cotrimoxazole prophylaxis

Group 1 name Corresponds to the case (exposed) group for case-control studies: continue cotrimoxazole prophylaxis

Group 1 definition Diagnostic criteria applied to define the specific condition / phenotype represented in the case (exposed) group: HIV-positive and antiretroviral therapy (ART) treated children who were randomized to continue taking cotrimoxazole prophylaxis

Group 0 sample size Number of subjects in the control (unexposed) group: 36

Group 1 sample size Number of subjects in the case (exposed) group: 36

Lab analysis

Sequencing type: WMS

16S variable region One or more hypervariable region(s) of the bacterial 16S gene: Not specified

Sequencing platform Manufacturer and experimental platform used for quantifying microbial abundance: Illumina

Statistical Analysis

Statistical test: Zero-Inflated Beta Regression

Significance threshold p-value or FDR threshold used for differential abundance testing (if any): 0.05

MHT correction Have statistical tests be corrected for multiple hypothesis testing (MHT)?: Yes

Alpha Diversity

Pielou Quantifies how equal the community is numerically: unchanged

Shannon Estimator of species richness and species evenness: more weight on species richness: unchanged

Signature 1

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Reviewed Marked as Reviewed by Atrayees on 2023-6-27

Curated date: 2021/01/10

Curator: Michael Lutete

Revision editor(s): WikiWorks, Atrayees

Source: Text, Figure S3, Figure S2

Description: Bacterial species from stool samples that differ between HIV-positive ART-treated Zimbabwean children randomized to continue versus stop cotrimoxazole prophylaxis based on protein families

Abundance in Group 1: increased abundance in continue cotrimoxazole prophylaxis

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Bacteroides xylanisolvens
Escherichia coli
Odoribacter splanchnicus
Parabacteroides goldsteinii
Parabacteroides johnsonii
Roseburia intestinalis
Alistipes communis

Revision editor(s): WikiWorks, Atrayees

Signature 2

Edit History Delete

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Your review change was submitted

Reviewed Marked as Reviewed by Atrayees on 2023-6-27

Curated date: 2021/01/10

Curator: Michael Lutete

Revision editor(s): Claregrieve1, WikiWorks, Atrayees

Source: Text, Figure S3

Description: Bacterial species from stool samples that differ between HIV-positive ART-treated Zimbabwean children randomized to continue versus stop cotrimoxazole prophylaxis based on protein families

Abundance in Group 1: decreased abundance in continue cotrimoxazole prophylaxis

NCBI	Quality Control	Links
Haemophilus parainfluenzae
Holdemanella biformis
Streptococcus parasanguinis
Faecalibacterium prausnitzii
Streptococcus salivarius
Alistipes onderdonkii
Intestinibacter bartlettii
Eggerthella lenta
Streptococcus mutans
Streptococcus vestibularis

Revision editor(s): Claregrieve1, WikiWorks, Atrayees