TY - JOUR
T1 - Effect of seven anti-tuberculosis treatment regimens on sputum microbiome
T2 - a retrospective analysis of the HIGHRIF study 2 and PanACEA MAMS-TB clinical trials
AU - PanACEA consortium
AU - Musisi, Emmanuel
AU - Wyness, Adam
AU - Eldirdiri, Sahar
AU - Dombay, Evelin
AU - Mtafya, Bariki
AU - Ntinginya, Nyanda E.
AU - Heinrich, Norbert
AU - Kibiki, Gibson S.
AU - Hoelscher, Michael
AU - Boeree, Martin
AU - Aarnoutse, Rob
AU - Gillespie, Stephen H.
AU - Sabiiti, Wilber
AU - Ntinginya, Nyanda E.
AU - Kibiki, Gibson S.
AU - Gillespie, Stephen
AU - Sloan, Derek
AU - Hoffmann, Larissa
AU - Noreña, Ivan
AU - Lutchmun, Wandini
AU - Dreisbach, Julia
AU - Demel, Petra Gross
AU - Kelly, Andrea
AU - Brake, Lindsey te
AU - Svensson, Elin
AU - Honeyborne, Isobella
AU - Wildner, Leticia Muraro
AU - Hunt, Robert
AU - McHugh, Timothy D.
AU - Nunn, Andrew J.
AU - Phillips, Patrick P. J.
AU - Gong, Xue
AU - Dawson, Rodney
AU - Narunsky, Kim
AU - Diacon, Andreas
AU - de Jager, Veronique
AU - Friedrich, Sven
AU - Sanne, Ian
AU - Rassool, Mohammed
AU - Mangu, Chacha
AU - Manyama, Christina
AU - Sabi, Issa
AU - Minja, Lilian T.
AU - Mhimbira, Francis
AU - Mbeya, Benno
AU - Sasamalo, Mohamed
AU - Adegbite, Bayode Romeo
AU - Grobusch, Martin Peter
AU - Grobusch, Martin P.
AU - Ssengooba, Willy
N1 - Funding Information: We acknowledge provision of samples from PanACEA MAMS-TB and HIGHRIF study 2 trials funded by the European and Developing Countries Clinical Trials Partnership (EDCTP1; grant IP.2007·32011·013 and IP.2007·32011·012; project code IP.2007·32011·011) and by the German Ministry of Education and Research (01KA0901). Sample processing and sequencing were supported by EDCTP1 PanAfrican Biomarker Expansion Programme (grant IP.2007·32011·011) and EDCTP2 PanACEA-2 grant under the biomarker development core stream. Publisher Copyright: © 2023 The Author(s). Published by Elsevier Ltd. This is an Open Access article under the CC BY 4.0 license
PY - 2023/11/1
Y1 - 2023/11/1
N2 - Background: Respiratory tract microbiota has been described as the gatekeeper for respiratory health. We aimed to assess the impact of standard-of-care and experimental anti-tuberculosis treatment regimens on the respiratory microbiome and implications for treatment outcomes. Methods: In this retrospective study, we analysed the sputum microbiome of participants with tuberculosis treated with six experimental regimens versus standard-of-care who were part of the HIGHRIF study 2 (NCT00760149) and PanACEA MAMS-TB (NCT01785186) clinical trials across a 3-month treatment follow-up period. Samples were from participants in Mbeya, Kilimanjaro, Bagamoyo, and Dar es Salaam, Tanzania. Experimental regimens were composed of different combinations of rifampicin (R), isoniazid (H), pyrazinamide (Z), ethambutol (E), moxifloxacin (M), and a new drug, SQ109 (Q). Reverse transcription was used to create complementary DNA for each participant's total sputum RNA and the V3-V4 region of the 16S rRNA gene was sequenced using the Illumina metagenomic technique. Qiime was used to analyse the amplicon sequence variants and estimate alpha diversity. Descriptive statistics were applied to assess differences in alpha diversity pre-treatment and post-treatment initiation and the effect of each treatment regimen. Findings: Sequence data were obtained from 397 pre-treatment and post-treatment samples taken between Sept 26, 2008, and June 30, 2015, across seven treatment regimens. Pre-treatment microbiome (206 genera) was dominated by Firmicutes (2860 [44%] of 6500 amplicon sequence variants [ASVs]) at the phylum level and Streptococcus (2340 [36%] ASVs) at the genus level. Two regimens had a significant depressing effect on the microbiome after 2 weeks of treatment, HR20mg/kgZM (Shannon diversity index p=0·0041) and HR35mg/kgZE (p=0·027). Gram-negative bacteria were the most sensitive to bactericidal activity of treatment with the highest number of species suppressed being under the moxifloxacin regimen. By week 12 after treatment initiation, microbiomes had recovered to pre-treatment level except for the HR35mg/kgZE regimen and for genus Mycobacterium, which did not show recovery across all regimens. Tuberculosis culture conversion to negative by week 8 of treatment was associated with clearance of genus Neisseria, with a 98% reduction of the pre-treatment level. Interpretation: HR20mg/kgZM was effective against tuberculosis without limiting microbiome recovery, which implies a shorter efficacious anti-tuberculosis regimen with improved treatment outcomes might be achieved without harming the commensal microbiota. Funding: European and Developing Countries Clinical Trials Partnership and German Ministry of Education and Research.
AB - Background: Respiratory tract microbiota has been described as the gatekeeper for respiratory health. We aimed to assess the impact of standard-of-care and experimental anti-tuberculosis treatment regimens on the respiratory microbiome and implications for treatment outcomes. Methods: In this retrospective study, we analysed the sputum microbiome of participants with tuberculosis treated with six experimental regimens versus standard-of-care who were part of the HIGHRIF study 2 (NCT00760149) and PanACEA MAMS-TB (NCT01785186) clinical trials across a 3-month treatment follow-up period. Samples were from participants in Mbeya, Kilimanjaro, Bagamoyo, and Dar es Salaam, Tanzania. Experimental regimens were composed of different combinations of rifampicin (R), isoniazid (H), pyrazinamide (Z), ethambutol (E), moxifloxacin (M), and a new drug, SQ109 (Q). Reverse transcription was used to create complementary DNA for each participant's total sputum RNA and the V3-V4 region of the 16S rRNA gene was sequenced using the Illumina metagenomic technique. Qiime was used to analyse the amplicon sequence variants and estimate alpha diversity. Descriptive statistics were applied to assess differences in alpha diversity pre-treatment and post-treatment initiation and the effect of each treatment regimen. Findings: Sequence data were obtained from 397 pre-treatment and post-treatment samples taken between Sept 26, 2008, and June 30, 2015, across seven treatment regimens. Pre-treatment microbiome (206 genera) was dominated by Firmicutes (2860 [44%] of 6500 amplicon sequence variants [ASVs]) at the phylum level and Streptococcus (2340 [36%] ASVs) at the genus level. Two regimens had a significant depressing effect on the microbiome after 2 weeks of treatment, HR20mg/kgZM (Shannon diversity index p=0·0041) and HR35mg/kgZE (p=0·027). Gram-negative bacteria were the most sensitive to bactericidal activity of treatment with the highest number of species suppressed being under the moxifloxacin regimen. By week 12 after treatment initiation, microbiomes had recovered to pre-treatment level except for the HR35mg/kgZE regimen and for genus Mycobacterium, which did not show recovery across all regimens. Tuberculosis culture conversion to negative by week 8 of treatment was associated with clearance of genus Neisseria, with a 98% reduction of the pre-treatment level. Interpretation: HR20mg/kgZM was effective against tuberculosis without limiting microbiome recovery, which implies a shorter efficacious anti-tuberculosis regimen with improved treatment outcomes might be achieved without harming the commensal microbiota. Funding: European and Developing Countries Clinical Trials Partnership and German Ministry of Education and Research.
UR - http://www.scopus.com/inward/record.url?scp=85175295391&partnerID=8YFLogxK
U2 - https://doi.org/10.1016/S2666-5247(23)00191-X
DO - https://doi.org/10.1016/S2666-5247(23)00191-X
M3 - Article
C2 - 37832571
SN - 2666-5247
VL - 4
SP - e913-e922
JO - The Lancet. Microbe
JF - The Lancet. Microbe
IS - 11
ER -