Fecal Microbiota Signatures Are Associated with Response to Ustekinumab Therapy among Crohn’s Disease Patients

ABSTRACT The fecal microbiota is a rich source of biomarkers that have previously been shown to be predictive of numerous disease states. Less well studied is the effect of immunomodulatory therapy on the microbiota and its role in response to therapy. This study explored associations between the fe...

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Autores principales:	Matthew K. Doherty, Tao Ding, Charlie Koumpouras, Shannon E. Telesco, Calixte Monast, Anuk Das, Carrie Brodmerkel, Patrick D. Schloss
Formato:	article
Lenguaje:	EN
Publicado:	American Society for Microbiology 2018
Materias:	IBD Stelara biologics biomarkers inflammatory bowel disease machine learning Microbiology QR1-502
Acceso en línea:	https://doaj.org/article/1babf2df203b4e62b518a9c7af952e71
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spelling	oai:doaj.org-article:1babf2df203b4e62b518a9c7af952e712021-11-15T15:53:27ZFecal Microbiota Signatures Are Associated with Response to Ustekinumab Therapy among Crohn’s Disease Patients10.1128/mBio.02120-172150-7511https://doaj.org/article/1babf2df203b4e62b518a9c7af952e712018-05-01T00:00:00Zhttps://journals.asm.org/doi/10.1128/mBio.02120-17https://doaj.org/toc/2150-7511ABSTRACT The fecal microbiota is a rich source of biomarkers that have previously been shown to be predictive of numerous disease states. Less well studied is the effect of immunomodulatory therapy on the microbiota and its role in response to therapy. This study explored associations between the fecal microbiota and therapeutic response of Crohn’s disease (CD) patients treated with ustekinumab (UST; Stelara) in the phase 2 CERTIFI study. Using stool samples collected over the course of 22 weeks, the composition of these subjects’ fecal bacterial communities was characterized by sequencing the 16S rRNA gene. Subjects in remission could be distinguished from those with active disease 6 weeks after treatment using random forest models trained on subjects’ baseline microbiota and clinical data (area under the curve [AUC] of 0.844, specificity of 0.831, sensitivity of 0.774). The most predictive operational taxonomic units (OTUs) that were ubiquitous among subjects were affiliated with Faecalibacterium and Escherichia or Shigella. The median baseline community diversity in subjects in remission 6 weeks after treatment was 1.7 times higher than that in treated subjects with active disease (P = 0.020). Their baseline community structures were also significantly different (P = 0.017). Two OTUs affiliated with Faecalibacterium (P = 0.003) and Bacteroides (P = 0.022) were significantly more abundant at baseline in subjects who were in remission 6 weeks after treatment than those with active CD. The microbiota diversity of UST-treated clinical responders increased over the 22 weeks of the study, in contrast to nonresponsive subjects (P = 0.012). The observed baseline differences in fecal microbiota and changes due to therapeutic response support the potential for the microbiota as a response biomarker. IMPORTANCE CD is a global health concern, with increasing incidence and prevalence, causing large economic and health care impacts. Finding prognostic biomarkers that give clinicians the ability to identify patients more likely to respond to CD treatment at diagnosis will reduce the time subjects receive drugs that are unlikely to be beneficial. OTUs associated with remission after treatment induction, especially Faecalibacterium, could be biomarkers for successful UST treatment of anti-tumor necrosis factor alpha (anti-TNF-α) refractory CD patients. More broadly, these results suggest that the fecal microbiota could be a useful noninvasive biomarker for directing or monitoring the treatment of gastrointestinal diseases.Matthew K. DohertyTao DingCharlie KoumpourasShannon E. TelescoCalixte MonastAnuk DasCarrie BrodmerkelPatrick D. SchlossAmerican Society for MicrobiologyarticleIBDStelarabiologicsbiomarkersinflammatory bowel diseasemachine learningMicrobiologyQR1-502ENmBio, Vol 9, Iss 2 (2018)
institution	DOAJ
collection	DOAJ
language	EN
topic	IBD Stelara biologics biomarkers inflammatory bowel disease machine learning Microbiology QR1-502
spellingShingle	IBD Stelara biologics biomarkers inflammatory bowel disease machine learning Microbiology QR1-502 Matthew K. Doherty Tao Ding Charlie Koumpouras Shannon E. Telesco Calixte Monast Anuk Das Carrie Brodmerkel Patrick D. Schloss Fecal Microbiota Signatures Are Associated with Response to Ustekinumab Therapy among Crohn’s Disease Patients
description	ABSTRACT The fecal microbiota is a rich source of biomarkers that have previously been shown to be predictive of numerous disease states. Less well studied is the effect of immunomodulatory therapy on the microbiota and its role in response to therapy. This study explored associations between the fecal microbiota and therapeutic response of Crohn’s disease (CD) patients treated with ustekinumab (UST; Stelara) in the phase 2 CERTIFI study. Using stool samples collected over the course of 22 weeks, the composition of these subjects’ fecal bacterial communities was characterized by sequencing the 16S rRNA gene. Subjects in remission could be distinguished from those with active disease 6 weeks after treatment using random forest models trained on subjects’ baseline microbiota and clinical data (area under the curve [AUC] of 0.844, specificity of 0.831, sensitivity of 0.774). The most predictive operational taxonomic units (OTUs) that were ubiquitous among subjects were affiliated with Faecalibacterium and Escherichia or Shigella. The median baseline community diversity in subjects in remission 6 weeks after treatment was 1.7 times higher than that in treated subjects with active disease (P = 0.020). Their baseline community structures were also significantly different (P = 0.017). Two OTUs affiliated with Faecalibacterium (P = 0.003) and Bacteroides (P = 0.022) were significantly more abundant at baseline in subjects who were in remission 6 weeks after treatment than those with active CD. The microbiota diversity of UST-treated clinical responders increased over the 22 weeks of the study, in contrast to nonresponsive subjects (P = 0.012). The observed baseline differences in fecal microbiota and changes due to therapeutic response support the potential for the microbiota as a response biomarker. IMPORTANCE CD is a global health concern, with increasing incidence and prevalence, causing large economic and health care impacts. Finding prognostic biomarkers that give clinicians the ability to identify patients more likely to respond to CD treatment at diagnosis will reduce the time subjects receive drugs that are unlikely to be beneficial. OTUs associated with remission after treatment induction, especially Faecalibacterium, could be biomarkers for successful UST treatment of anti-tumor necrosis factor alpha (anti-TNF-α) refractory CD patients. More broadly, these results suggest that the fecal microbiota could be a useful noninvasive biomarker for directing or monitoring the treatment of gastrointestinal diseases.
format	article
author	Matthew K. Doherty Tao Ding Charlie Koumpouras Shannon E. Telesco Calixte Monast Anuk Das Carrie Brodmerkel Patrick D. Schloss
author_facet	Matthew K. Doherty Tao Ding Charlie Koumpouras Shannon E. Telesco Calixte Monast Anuk Das Carrie Brodmerkel Patrick D. Schloss
author_sort	Matthew K. Doherty
title	Fecal Microbiota Signatures Are Associated with Response to Ustekinumab Therapy among Crohn’s Disease Patients
title_short	Fecal Microbiota Signatures Are Associated with Response to Ustekinumab Therapy among Crohn’s Disease Patients
title_full	Fecal Microbiota Signatures Are Associated with Response to Ustekinumab Therapy among Crohn’s Disease Patients
title_fullStr	Fecal Microbiota Signatures Are Associated with Response to Ustekinumab Therapy among Crohn’s Disease Patients
title_full_unstemmed	Fecal Microbiota Signatures Are Associated with Response to Ustekinumab Therapy among Crohn’s Disease Patients
title_sort	fecal microbiota signatures are associated with response to ustekinumab therapy among crohn’s disease patients
publisher	American Society for Microbiology
publishDate	2018
url	https://doaj.org/article/1babf2df203b4e62b518a9c7af952e71
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Fecal Microbiota Signatures Are Associated with Response to Ustekinumab Therapy among Crohn’s Disease Patients

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