Review Article

How the Intestinal Microbiota may Reflect Disease Activity and Influence Therapeutic Outcome in Inflammatory Bowel Disease

Clara Caenepeel; Nasim Sadat Seyed Tabib; Sara Vieira-Silva; Séverine Vermeire

Disclosures

Aliment Pharmacol Ther. 2020;52(9):1453-1468. 

In This Article

Abstract and Introduction

Abstract

Background: Intestinal bacteria produce metabolites and by-products necessary for homeostasis. Imbalance in this equilibrium is linked to multiple pathologies including inflammatory bowel disease (IBD). The role of the gut microbiota in determining treatment response is becoming apparent, and may act as biomarker for efficacy.

Aim: To describe knowledge about the intestinal microbiota on disease severity and treatment outcomes in IBD

Methods: Descriptive review using PubMed to identify literature on the intestinal microbiota in IBD

Results: Severe IBD has a less diverse microbiota with fewer commensal microbiota communities and more opportunistic pathogenic bacteria originating from the oral cavity or respiratory tract. IBD treatments can alter gut microbiota composition, but in vitro/in vivo studies are needed to prove causation. A diversification of the microbiota is observed during remission. Patients with a more diverse baseline microbiome and higher microbial diversity show better response to anti-tumour necrosis factor-α, vedolizumab and ustekinumab therapy. Higher abundance of short chain fatty acid-producing bacteria, fewer mucus-colonising bacteria and lower abundance of pro-inflammatory bacteria have also been associated with a favourable outcome. Predictive models, based on a combination of microbiota, clinical data and serological markers, have good accuracy for treatment outcome and disease severity.

Conclusion: The intestinal microbiota in IBD carries a set of promising biomarkers of disease activity and prediction of therapeutic outcome. Current insights may also help in designing microbiota modulation strategies to improve outcomes in IBD.

Introduction

The Urgent Need For Better Therapeutic Prediction in IBD

Deviations in the interaction between the innate and adaptive immune system and the intestinal microbiota are increasingly shown to contribute to the onset of inflammatory diseases, such as gingivitis, clostridium difficile infection, obesity, diabetes mellitus type 1, pulmonary disease, colorectal cancer, rheumatoid arthritis, IBD, cardiovascular disease and non-alcoholic fatty liver disease.[1–10] Several factors may modify or dysregulate the intestinal immune system including dietary regimens, antibiotic treatments and pathogen invasions, which in turn cause a widespread disruption of the microbial composition community. Authors are trying to indicate that the relationship works both ways.

The last two decades have been marked by significant therapeutic advances in the field of IBD, mainly with the approval of targeted biological agents but also in microbiota-modulating therapies such as diet, faecal microbiota transplantation, pre- and probiotics and antibiotics.[11] Three distinct therapeutic classes (anti-tumour necrosis factor alpha [anti-TNFα], anti-integrin and anti-interleukin [IL] 12/23 therapy) have received regulatory approval, and recently, tofacitinib, a small molecule belonging to the family of Janus kinase inhibitors, was added to the therapeutic arsenal. Biologic therapy has enabled the expansion of treatment goals to clinical steroid-free remission and endoscopic healing, and more recently, histological remission has shown to be a reachable target in ulcerative colitis (UC). However, these biological therapies have also significantly increased healthcare expenses. Park et al[12] demonstrated that—while fewer than 20% of IBD patients were receiving biologic therapies—this subset of the population incurred two to three times the total costs of care per year compared with patients not receiving biologic therapies. There is therefore a pressing need for cost-effective strategies and lifestyle changes could be one of them.

Variability in Drug Response

Inter-individual differences in response to a specific drug can affect either the efficacy and/or toxicity of the treatment. Response rates to mesalazine (mesalamine) or 5-aminosalicylic acid used in UC, are 60%, indicating that 40% of patients may not experience any benefit or may even suffer from adverse drug reactions.[13] Primary non-response has also been observed in 20%-30% of the patients receiving anti-TNFα, vedolizumab and/or ustekinumab therapy. Incomplete patient assessment preceding the start of a biological therapy may partially explain this high rate of non-response. Accurate prediction of responsiveness prior to therapy start would be of great value, but clinical predictors have proven insufficient and targeted assays are still lacking.

The inter-individual variability in drug response affects not only patient's well-being, it also poses an enormous financial burden.

A variety of factors, among which genetic background, physiological status (eg gender, age, concomitant diseases, starvation and circadian rhythm) and environmental contributors (eg co-administered medications, diet, smoking behaviour and environmental pollutants) may all impact drug response. These multi-factorial contributors have been particularly well studied for anti-TNFα medication in IBD, as summarized in Figure 1. Genetic markers have been extensively scrutinized in attempt to predict response to infliximab or other anti-TNFα medication, but no predictive signature has successfully been validated. The large (N = 1610) PANTS (Personalized anti-TNFα therapy in Crohn's disease) cohort of Crohn's disease (CD) patients naive to anti-TNFα therapy (UK; ClinicalTrials.gov identifier: NCT03088449) demonstrated that the human leukocyte antigen allele, HLA-DQA1*05, carried by approximately 40% of Europeans, is associated with a twofold risk of developing immunogenicity against anti-TNFα therapies, leading to loss of response.[14–18] Pre-treatment genetic testing for HLA-DQA1*05, may therefore help personalising therapy choice in IBD patients, including taking the necessary precautions to prevent immunogenicity in patients at risk.

Figure 1.

Genetic, environmental treatment (concomitant medication and treatment-related factors (eg trough levels)) and clinical factors impacting anti-TNFα therapy response in IBD.15,112–137

Less well studied is the effect of the microbiota—especially the gut microbiota—in predicting response to therapy. Pharmacomicrobiomics is an emerging field that investigates the interplay of microbiome variation and drug response and disposition (absorption, distribution, metabolism and excretion). The gut microbiota can, for example, influence cancer pathogenesis and its therapeutic outcome by metabolising anti-tumoral compounds, or by modulating the host's immune response and inflammation pathways.[19]

Patient Stratification in IBD: The Key to a Personalized Medicine Strategy

Personalized medicine is tailoring medical treatment to the individual characteristics of a patient.

It relies on the identification of signatures for accurate patient stratification.

In IBD, until recently, this meant identifying genetic, clinical and environmental information, which allowed advances in our understanding of how a patient's unique portfolio makes them vulnerable to certain diseases and disease phenotypes. The personalized medicine approach, as opposed to the classical approach ("one size fits all"), aims to increase our ability to predict which medical treatments will be safe and effective for which patients, and which ones will not, to reduce financial and time expenses, and ultimately increase quality of life. The adoption of personalized medicine in IBD would not only facilitate treatment choice (no treatment, biological treatment, immunomodulators, etc), enhance treatment efficacy, but also allow an earlier detection of possible treatment side effects.[20,21]

The gut microbiota has more recently been proposed as a potential biomarker and predictor that should be added to a patient's stratification to address some of the above problems.

To be truly valuable, biomarkers need to be reproducibly more accurate, safer and/or cheaper than the biomarkers or procedures that we currently use to make these decisions (eg serum C-reactive protein [CRP], faecal calprotectin [FCal], endoscopy, histology, genetic screening, etc). Such a high standard patient stratification tool will likely require the assessment and integration of different layers of -omics information from the patients (metagenomics, metabolomics, genomics, proteomics, etc.), supplemented with high-resolution phenotype data, to achieve a successful personalized medicine strategy.

Multiple research groups and consortia have in recent years joined forces and are generating datasets combining clinical data with genomic data, proteomic data, transcriptome data or gut microbiome data. These datasets hold the hope to unravel promising biomarker signatures for IBD treatment in the future.

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