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

From BugSigDB
Needs review
study design
randomized controlled trial
Citation
PMID
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


Needs review

Curated date: 2021/01/10

Curator: WikiWorks743

Revision editor(s): WikiWorks743, Rimsha, WikiWorks753

Subjects

Location of subjects Country from which study subjects were recruited
Zimbabwe
Host species Species from which microbiome was sampled (if applicable)
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
Condition The experimental condition / phenotype studied according to the Experimental Factor Ontology
HIV infection , cotrimoxazole[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),cotrimoxazole

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 Experimental technique used for quantifying microbial abundance
WMS
Sequencing platform Manufacturer and experimental platform used for quantifying microbial abundance
Illumina

Statistical Analysis

Statistical test Statistical test or computational tool used for differential abundance testing
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

Needs review

Curated date: 2020-11-07

Curator: Michael Lutete

Revision editor(s): WikiWorks743

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: increased abundance in continue cotrimoxazole prophylaxis

NCBI Links
Bacteroides xylanisolvens
Escherichia coli
Odoribacter splanchnicus

Revision editor(s): WikiWorks743

Signature 2

Needs review

Curated date: 2020-11-07

Curator: Michael Lutete

Revision editor(s): WikiWorks743

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 Links
Holdemanella biformis
k__Bacteria, p__Firmicutes, c__Clostridia, o__Clostridiales, f__Ruminococcaceae, g__Faecalibacterium, s__Faecalibacterium__prausnitziis__Faecalibacterium__prausnitzii
Haemophilus parainfluenzae
Streptococcus parasanguinis
k__Bacteria, p__Firmicutes, c__Bacilli, o__Lactobacillales, f__Streptococcaceae, g__Streptococcus, s__Streptococcus__salivariuss__Streptococcus__salivarius

Revision editor(s): WikiWorks743

Signature 3

Needs review

Curated date: 2020-11-07

Curator: Michael Lutete

Revision editor(s): WikiWorks743

Source: Text, Figure S2

Description: Fecal bacterial species that differ between HIV-positive ART-treated Zimbabwean children randomized to continue versus stop cotrimoxazole prophylaxis

Abundance in Group 1: increased abundance in continue cotrimoxazole prophylaxis

NCBI Links
k__Bacteria, p__Bacteroidetes, c__Bacteroidia, o__Bacteroidales, f__Rikenellaceae, g__Alistipes, s__Alistipes_communiss__Alistipes_communis
Odoribacter splanchnicus
Parabacteroides goldsteinii
Parabacteroides johnsonii
Roseburia intestinalis

Revision editor(s): WikiWorks743

Signature 4

Needs review

Curated date: 2020-11-07

Curator: Michael Lutete

Revision editor(s): WikiWorks743

Source: Text, Figure S2

Description: Fecal bacterial species that differ between HIV-positive ART-treated Zimbabwean children randomized to continue versus stop cotrimoxazole prophylaxis

Abundance in Group 1: decreased abundance in continue cotrimoxazole prophylaxis

NCBI Links
Alistipes onderdonkii
Intestinibacter bartlettii
Eggerthella lenta
Haemophilus parainfluenzae
Streptococcus mutans
Streptococcus parasanguinis
Streptococcus vestibularis

Revision editor(s): WikiWorks743