Paper reading (六十三）：Gut Microbiome Function Predicts to Anti-integrin Biologic Therapy in IBD

论文题目：Gut Microbiome Function Predicts Response to Anti-integrin Biologic Therapy in Inflammatory Bowel Diseases

scholar 引用：68

页数：12

发表时间：2017.05

发表刊物：Cell Host & Microbe

作者：Ashwin N. Ananthakrishnan,...,Ramnik J. Xavier

摘要：

The gut microbiome plays a central role in inflammatory bowel diseases (IBDs) pathogenesis and propagation. To determine whether the gut microbiome may predict responses to IBD therapy, we conducted a prospective study with Crohn’s disease (CD) or ulcerative colitis (UC) patients initiating anti-integrin therapy (vedolizumab). Disease activity and stool metagenomes at baseline, and weeks 14, 30, and 54 after therapy initiation were assessed. Community α-diversity was significantly higher, and Roseburia inulinivorans and a Burkholderiales species were more abundant at baseline among CD patients achieving week 14 remission. Several significant associations were identified with microbial function; 13 pathways including branched chain amino acid synthesis were significantly enriched in baseline samples from CD patients achieving remission. A neural network algorithm, vedoNet, incorporating microbiome and clinical data, provided highest classifying power for clinical remission. We hypothesize that the trajectory of early microbiome changes may be a marker of response to IBD treatment.

正文组织架构：

1. Introduction

2. Results

2.1 Study Population

2.2 Baseline Metagenomic Composition and Remission at Week 14

2.3 Longitudinal Trajectory of the Microbiome

2.4 Persistence of Changes in the Microbiome at 1 Year

2.5 Neural Network Algorithms (vedoNet) to Predict Treatment Response

2.6 Strain-level Analysis

2.7 Validation in an Anti-TNF Cohort

3. Discussion

正文部分内容摘录：

• reatment paradigms have evolved from a step-up strategy to favor up-front biologic therapy to prevent damage. The availability of diverse therapeutic targets has brought forward the importance of personalizing treatment, which requires a priori predicting response to each mechanism of action.
• the central role of the gut microbiome in many immune-mediated diseases
• we performed this study to
• (1) define the relationship between microbial metagenomic structure and function and clinical remission with vedolizumab induction;
• (2) to identify longitudinal trajectory of changes in the microbiome with maintenance treatment;
• and (3) develop a comprehensive predictive model incorporating clinical and microbiome-related data to accurately classify treatment response.

1. Biological Problem: What biological problems have been solved in this paper?

• predicting clinical remission
• 这个问题的难点：The complexity in predicting treatment response using gut microbial structure is highlighted by poor separation between the remitters and non-remitters on simple PCoA, consistent with a few previous studies

2. Main discoveries: What is the main discoveries in this paper?

• Stool metagenomes of IBD patients starting biologic therapy were prospectively assessed
• Higher abundance of butyrate producers at baseline in therapy-responsive CD patients
• Baseline enrichment of 13 microbial pathways in therapy-responsive CD patients
• Early microbial changes at week 14 persist up to 1 year in responders
• A neural network algorithm, vedoNet, incorporating microbiome and clinical data, provided highest classifying power for clinical remission.
• We hypothesize that the trajectory of early microbiome changes may be a marker of response to IBD treatment.
• Our more adaptive and informative neural network-based approach performed significantly better with an AUC of 0.87 and suggested added and complementary value to both clinical and microbial parameters.
• Early clinical remission could be predicted by microbial functional composition at baseline with a weaker influence at the level of the species or genus. 
• develop a comprehensive predictive model incorporating clinical and microbiome-related data to accurately classify treatment response.

3. ML(Machine Learning) Methods: What are the ML methods applied in this paper?

• The study included 85 patients with IBD (43 UC, 42 CD) with a mean disease duration of 13 years at the start of therapy. 
• A neural network algorithm, vedoNet
• 
• The vedoNet and associated other model variates (vedoNet.tx, vedoNet.hybrid, etc.) are based on a neural network structure with an input layer, a few hidden layers with softmax dropout and rectified linear unit, and a binary output layer to classify if input data will support treatment outcome as remission or non-remission. The input data is a vector with two parts: the clinical metadata, and the microbiome profile which varies for different models (pathways, taxa, or a combination of both). The training deployed a 5-fold cross validation scheme, which resampled the subjects without replacement for test set and train set.
• vedoNet was implemented in Python with Keras library; the codes, models, and tutorials can be found at https://www.bitbucket.org/luo-chengwei/vedonet. 
• vedoNet: a neural network-based algorithm to predict the outcome of Vedolizumab treatment for IBD at baseline

4. ML Advantages: Why are these ML methods better than the traditional methods in these biological problems?

• vedoNet was able to accurately identify 11 out of the 13 patients achieving remission and was superior to models utilizing clinical data (10/13) or microbial taxa alone (9/13).

5. Biological Significance: What is the biological significance of these ML methods’ results?

• The area under curve (AUC) of the receiver operating characteristic (ROC) curve served as the main indicator of vedoNet’s performance.

6. Prospect: What are the potential applications of these machine learning methods in biological science?

• While we performed validation of our model in an independent cohort of 20 patients initiating anti-TNF therapy, we acknowledge that more robust examination in larger cohorts is essential prior to application to clinical practice. 
• Further experimental studies are important to determine the full mechanistic implications of the metagenomic pathways and bacteria identified and how they may be harnessed to improve response to existing therapy in IBD.

7. Mine Question(Optional)

Principle component analysis (PCoA) 为什么这样缩写啊。。。