IBD-RESPONSE: Defining microbial predictors of responsiveness to biological therapies in Crohn's disease and ulcerative colitis

Crohn's disease and ulcerative colitis (UC) are types of a bowel condition known as inflammatory bowel disease (IBD) and the symptoms (diarrhoea, pain, fatigue) have a major impact on daily life. IBD affects around 1 in 125 people in the UK and this is expected to rise to 1 in 100 by 2028. "Biologicals" are powerful medications that are given to reduce inflammation in IBD. These treatments can be effective but up to 40% of patients don't respond, and in those that do, many don't respond well enough to stay on the drug after one year of treatment. Unfortunately, we have no way to predict which patients are most likely to benefit from treatment (known as responders), and we do not fully understand how medications work in responders. As these drugs may have serious side effects and are expensive to the UK healthcare system, this lack of understanding is a major obstacle in deciding which treatment is best to give to an individual patient, and when to give it to them in order to have the greatest benefit and the least risk.

Recent data from small studies in people with IBD and larger studies of people with cancer, show that certain bacteria in stool (faeces) may predict who will respond or fail to respond to treatments. In animal studies, changing the number and type of these bacteria can influence treatment outcomes. These studies strongly suggest the number and types of certain bacteria may predict which patients do and do not respond to IBD treatment. However, these studies used different techniques in varied groups of patients and were too small to give a definite answer, Nonetheless, they do suggest that if a large enough group of patients were studied it should be possible to identify which specific bacteria are important for understanding treatment response in IBD, and what the function of these bacteria are.

We are a group of researchers with a world-leading track record in clinical, bacterial, immune and genetic research. For the last 5 years we have successfully recruited 27,500 patients into a research study called the IBD Bioresource to study the human genes involved in the development or behaviour of IBD. We now seek funds to begin a separate study focussing on gut bacteria called IBD-RESPONSE. This study will benefit from the knowledge and facilities we already have from the IBD Bioresource. We will recruit 1,125 patients starting biological therapy in IBD as part of routine NHS care from 30 centres across the UK. We will collect stool, and where possible intestinal biopsies during routine endoscopy (camera into the gut), to study the gut bacteria before, and during, these treatments. By using state-of-the-art machinery and cutting-edge computer analysis techniques we will identify these microbes, study their function, and examine how microbes may interact with the human immune system. The outcome of our study will be to develop a tool that predicts which patients are likely or unlikely to respond to the different treatment options in IBD. We will create the largest collection (biobank) in the world of stool and intestinal tissue specimens, at multiple timepoints and with detailed clinical information, from this important group of patients that will be open to other researchers to use in the future.

By creating a predictive tool for response to treatment, IBD-RESPONSE will lead to clinical trials that can shape future treatment pathways in IBD. This may be by allowing the development of a test (biomarker) to help healthcare professionals decide which treatment is best suited to an individual patient, or to identify which bacteria in the intestine could be targeted (either to reduce or increase presence) in order to improve treatment outcomes for patients. This has the potential to improve quality of life, reduce patient risk and reduce unnecessary expenditure on ineffective treatments by the NHS for this debilitating disease.

IBD-RESPONSE will identify and validate a predictive model for response or failure to biological therapies in Crohn's disease and ulcerative colitis (UC), the major forms of inflammatory bowel disease (IBD) using microbiome (including microbial species and function data), and integrated clinical and human genome data. Recent immune oncology studies have identified that certain gut bacteria are associated with response or failure to immune modifying treatment, and that in mouse models, manipulation of these microbes can influence treatment outcomes. Limited data from small and heterogenous populations in IBD also suggest an association between treatment outcomes and gut microbes. We will assimilate the largest global cohort in this field to generate longitudinal gut microbiome metagenomic sequence data of stool from 1,125 patients commencing first-line biologicals, and in the event of treatment failure will follow subjects through second, and if required, third-line agents. For replication, we will generate gut microbial sequence data from patients experiencing a disease flare within an independent cohort (PREdiCCt) that studies environmental and dietary triggers of IBD relapse. Our bioinformatic pipelines will identify microbial species and genes/pathways that predict treatment response, identify how timing of stool collection impacts on this prediction, study functional pathways of these microbes, compare stool metagenomes to 16S rRNA gene amplicon sequencing data from intestinal tissue to compare luminal and mucosal microbial communities, as well as utilise human genomic data for our subjects (made available by a parallel sequencing programme) to explore host human genome-gut microbiome functional interactions. Our study will establish the largest biorepository of longitudinal stool and matched tissue in the world with detailed linked phenotypic data, in this important clinical group of subjects that will be open to other researchers to use in the future.

There are several beneficiaries of this research:

1.Patients: The principal beneficiary of this research will be patients. This study will provide timely and highly important information regarding the associations between the gut microbiome and responsiveness to treatment in IBD. It is likely this will also highlight potential mechanisms through which these microbes drive inflammation. This study could lead to a direct change in clinical management (i.e. within the 4 years of this grant), but more likely will lead to stratified randomised control trial potentially including a refined biomarker panel, or the development of experimental techniques to modify gut microbes, e.g. donor selection for faecal microbial transplantation, identification of single or multiple strains of microbes, or use of antimicrobials, phage or microbial metabolites that may be used to induce a more 'treatment responsive' microbiome. These latter translational avenues will likely take a further 3-5 years before implementation in the clinic. If proven effective in clinical trials, these interventions are highly likely to have a benefit on quality of life (and in turn social integration and work productivity) and lead to a reduction in the need for surgical intervention.

2.Healthcare economy, policy and societal benefits: The above impact on patient management will directly influence precision medicine within the routine healthcare setting allowing the selection of the best treatment for patients, at the earliest timepoint, thus minimising patient risk and maximising therapeutic impact on quality of life. As these medications cost between £4,000 and £15,000/year, avoidance of unnecessary spend on ineffective therapies will have a direct economic benefit to the NHS and help to shape and increase the effectiveness of UK healthcare policy (e.g. through NICE) for targeting of expensive medical therapies.

3.Biotechnology and pharmaceutical industry: Data from IBD-RESPONSE will be made available to industry researchers as it will be for those in public-sector academia. Microbial targets for therapeutic intervention may be identified by the vast dataset of microbial, clinical and matched human genomic data that is developed by this programme of research. As described in the case for support Section 11, any arising IP from IBD-RESPONSE, and subsequent biotechnology diagnostic or therapeutic development will be supported and promoted by the Newcastle University Business Development and Enterprise Team in partnership with relevant external entities.

4.Local study investigators: IBD-RESPONSE will recruit from 30 hospitals across the UK. The applicants and local PIs will benefit from this through research training and expansion of clinical academic networks. This study will support the employment and training of local research nurses with financial benefit to local sites via the NIHR Comprehensive Clinical Research Network.

5.Additional benefit to academics:IBD-RESPONSE data and methodologies will be published to benefit clinical, translational, laboratory and bio-informatic researchers. This will include the publication of analysis pipelines/code in repositories such as git hub (https://github.com/stewartlab). Clinical and microbiome datasets will contribute to the IBD Bioresource and recently funded HDR UK Digital Innovation Hub "G.I. Know" platforms which are available to the academic community for scientific discovery and as a platform for translational research. IBD-RESPONSE will create the largest global repository of stool and intestinal biopsies from patients commencing biologicals for IBD. This will be made available to members of the scientific community for downstream immunology and microbiology research as outlined in the Case for Support.

This combined resource will support downstream science, create research employment and patient benefit for many years, and continue to support UK large cohort, translational research in IBD.