Gut Microbiome Function Predicts Response to Anti-Integrin Biologic Therapy in Inflammatory Bowel Diseases

Ananthakrishnan, Ashwin N.; Luo, Chengwei; Yajnik, Vijay; Khalili, Hamed; Garber, John J.; Stevens, Betsy; Cleland, Thomas A.; Xavier, Ramnik J.

doi:10.1016/s0016-5085(17)30950-2

Cited by 48 publications

(68 citation statements)

References 37 publications

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“…Ananthakrishnan et al reported a decrease in abundance of five taxa associated with remission in response to anti-integrin biologic therapy -among them Bifidobacterium longum. 40 In contrast, we observed a large increase in abundance of two Bifidobacterium ASVs in antibiotic-associated remission samples.…”

Section: Discussioncontrasting

confidence: 58%

Treatment-Specific Composition of Gut Microbiota Is Associated with Disease Remission in a Pediatric Crohn’s Disease Cohort

Sprockett

Fischer

Boneh

et al. 2018

Preprint

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We investigated the impact of metronidazole and metronidazole plus azithromycin on the gut microbiota in pediatric Crohn's disease. Disease remission was associated with a treatment-specific microbiota configuration, and could be predicted based on pre-antibiotic microbiota profiles.3 Abstract Background: The beneficial effects of antibiotics in Crohn's disease (CD) depend in part on the gut microbiota but are inadequately understood. We investigated the impact of metronidazole (MET) and metronidazole plus azithromycin (MET+AZ) on the microbiota in pediatric CD, and the use of microbiota features as classifiers or predictors of disease remission.Methods: 16S rRNA-based microbiota profiling was performed on stool samples from 67 patients in a multinational, randomized, controlled, longitudinal, 12-week trial of MET vs.MET+AZ in children with mild to moderate CD. Profiles were analyzed together with disease activity, and then used to construct Random Forest models to classify remission or predict treatment response.Results: Both MET and MET+AZ significantly decreased diversity of the microbiota and caused large treatment-specific shifts in microbiota structure at week 4. Disease remission was associated with a treatment-specific microbiota configuration. Random Forest models constructed from microbiota profiles pre-and during antibiotic treatment with metronidazole accurately classified disease remission in this treatment group (AUC of 0.879, 95% CI 0.683, 0.9877; sensitivity 0.7778; specificity 1.000, P < 0.001). A Random Forest model trained on preantibiotic microbiota profiles predicted disease remission at week 4 with modest accuracy (AUC of 0.8, P = 0.24). Conclusions:MET and MET+AZ antibiotic regimens in pediatric CD lead to distinct gut microbiota structures at remission. It may be possible to classify and predict remission based in part on microbiota profiles, but larger cohorts will be needed to realize this goal.

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Section: Discussioncontrasting

confidence: 58%

Treatment-Specific Composition of Gut Microbiota Is Associated with Disease Remission in a Pediatric Crohn’s Disease Cohort

Sprockett

Fischer

Boneh

et al. 2018

Preprint

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“…With regard to vedolizumab, a broad number of observations has been made: While gene expression profiling identified a considerable number of genes that were significantly differentially expressed following vedolizumab therapy, none of them was able to predict treatment outcomes [28]. However, another study reported that response to vedolizumab was associated with pre-therapeutic composition of the intestinal microbiome [29]. Moreover, we had suggested that dynamic changes in the expression of α4β1 on peripheral blood CD4 + T cells in the early course of vedolizumab treatment and the baseline dynamic adhesion of CD4 + T cells to MAdCAM-1 in vitro might predict subsequent therapeutic response [17,20].…”

Section: Discussionmentioning

confidence: 99%

Baseline levels of dynamic CD4+ T cell adhesion to MAdCAM-1 correlate with clinical response to vedolizumab treatment in ulcerative colitis: a cohort study

et al. 2020

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Background: While the number of therapeutic options for treating inflammatory bowel diseases (IBD) is increasing, evidence for rational treatment decisions is scarce in many cases. In particular, appropriate biomarkers to predict the response to the anti-α4β7 integrin antibody vedolizumab are currently lacking. Methods:We performed a cohort study with 21 patients suffering from ulcerative colitis (UC), in which first-time treatment with vedolizumab was initiated. CD4 + T cells were isolated from the peripheral blood and dynamic adhesion to recombinant mucosal vascular addressin cell adhesion molecule (MAdCAM-)1 in vitro as well as the effect of vedolizumab on such adhesion in vitro was determined. The expression of α4β1 integrin on peripheral blood CD4 + T cells was quantified by flow cytometry. Electronic patient records were reviewed to determine clinical response to vedolizumab.Results: Dynamic adhesion of peripheral blood CD4 + T cells to MAdCAM-1 and the reduction of adhesion following vedolizumab treatment in vitro were higher and the change in α4β1 expression on CD4 + T cells was different in vedolizumab responders and non-responders. Responders could be identified with high specificity and positive-predictive value. Conclusions: Determining dynamic adhesion of CD4 + T cells to MAdCAM-1 and the in vitro response to vedolizumab before treatment initiation or dynamic integrin regulation in the early course of treatment seem to be promising tools to predict the clinical response to vedolizumab therapy. Larger prospective studies are warranted.

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“…92 Thus, changes in the trajectory of early microbiome after treatment may be a marker of a therapeutic response to inflammatory bowel disease (IBD). 93 Dysbiosis in patients with UC is summarized in Table 1. [66][67][68][69][70][71][72][74][75][76][77][78][79][80][81][82][83][84][85][86] Besides the effect of bacterial dysregulation, the influence of the interaction between human hosts and fungi, viruses and other microbes cannot be disregarded.…”

Section: Dysbiosis Of Intestinal Flora In Ucmentioning

confidence: 99%

Gut microbiota in ulcerative colitis: insights on pathogenesis and treatment

Guo

Liu

Hao

2020

J of Digest Diseases

190

110

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Gut microbiota constitute the largest reservoir of the human microbiome and are an abundant and stable ecosystem—based on its diversity, complexity, redundancy, and host interactions This ecosystem is indispensable for human development and health. The integrity of the intestinal mucosal barrier depends on its interactions with gut microbiota. The commensal bacterial community is implicated in the pathogenesis of inflammatory bowel disease (IBD), including ulcerative colitis (UC). The dysbiosis of microbes is characterized by reduced biodiversity, abnormal composition of gut microbiota, altered spatial distribution, as well as interactions among microbiota, between different strains of microbiota, and with the host. The defects in microecology, with the related metabolic pathways and molecular mechanisms, play a critical role in the innate immunity of the intestinal mucosa in UC. Fecal microbiota transplantation (FMT) has been used to treat many diseases related to gut microbiota, with the most promising outcome reported in antibiotic‐associated diarrhea, followed by IBD. This review evaluated the results of various reports of FMT in UC. The efficacy of FMT remains highly controversial, and needs to be regularized by integrated management, standardization of procedures, and individualization of treatment.

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Gut Microbiome Function Predicts Response to Anti-Integrin Biologic Therapy in Inflammatory Bowel Diseases

Cited by 48 publications

References 37 publications

Treatment-Specific Composition of Gut Microbiota Is Associated with Disease Remission in a Pediatric Crohn’s Disease Cohort

Treatment-Specific Composition of Gut Microbiota Is Associated with Disease Remission in a Pediatric Crohn’s Disease Cohort

Baseline levels of dynamic CD4+ T cell adhesion to MAdCAM-1 correlate with clinical response to vedolizumab treatment in ulcerative colitis: a cohort study

Gut microbiota in ulcerative colitis: insights on pathogenesis and treatment

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