Combined Microbiota and Metabolic Signature in Ulcerative Colitis Predicts Anti-Inflammatory Therapy Success

Study Overview
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Brief Summary
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The primary goal of the study is to develop an early (within 4 weeks) combined microbiota/metabolic signature predicting clinical response upon anti-inflammatory treatment in UC patients.

Detailed Description
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The investigators perform a longitudinal prospective multi-center study for ulcerative colitis (UC) patients with a flare at/and after the time of starting a new treatment and healthy household controls. They will perform intense longitudinal bio-sampling and deep clinical characterization. With this information the aim is to develop a predictive signature regarding the success of a new ly started anti-inflammatory therapy after an UC flare.

Official Title
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An Early Combined Microbiota and Metabolic Signature in Ulcerative Colitis Patients Predict the Clinical Success of Anti-inflammatory Therapy

Conditions
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Ulcerative Colitis

Intervention / Treatment
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* Drug: Ozanimod
* Drug: TNF Inhibitor
* Drug: Steroids
* Drug: Vedolizumab
* Drug: Ustekinumab


Participation Criteria
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Eligibility Criteria
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Inclusion criteria ulcerative colitis: Signed informed consent Age 18-80 years General ability to understand and follow study procedures, fluency in German, French, or English Diagnosis of ulcerative colitis since ≥3 months Confirmed flare of ulcerative colitis with partial SCCAI score ≥5 points and at least one biomarker supporting intestinal inflammation Planned start with ozanimod, steroids (prednisone ≥20mg/d or equivalent), or a biological (vedolizumab, infliximab, adalimumab, golimumab, ustekinumab) Exclusion criteria ulcerative colitis Confirmed cytomegalovirus (CMV) reactivation within the previous 2 weeks (tested as part of standard medical practice at the discretion of the responsible physician) C. difficile related diarrhea, or other confirmed infectious diarrhea in the last 4 weeks (tested as part of standard medical practice at the discretion of the responsible physician) Diagnosis of Crohn's disease Current pouch or ileostomy/ colostomy Severe medical, surgical, or psychiatric comorbidities interfering with study procedures Inclusion criteria controls Signed informed consent Age 18-80 years General ability to understand and follow study procedures, fluency in German, French, or English No current or past diagnosis of inflammatory bowel disease (IBD) No current medical complaints typic for IBD e.g. Diarrhea, severe constipation, abdominal pain, blood in stool, weight loss Slight symptoms (without impact onto daily activities) are permitted No other current relevant gastrointestinal disease or condition plausibly interfering with microbiota assessment according to the discretion of the study physician Exclusion criteria controls Confirmed cytomegalovirus (CMV) reactivation within the previous 2 weeks C. difficile related diarrhea, or other confirmed infectious diarrhea in the last 4 weeks Diagnosis of Crohn's disease, ulcerative colitis Current pouch or ileostomy/ colostomy Severe medical, surgical, or psychiatric comorbidities interfering with study procedures

Ages Eligible for Study
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Minimum Age: 18 Years
Maximum Age: 80 Years

Sexes Eligible for Study
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All

Accepts Healthy Volunteers
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Accepts Healthy Volunteers

Study Plan
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How is the study designed?
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Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Ulcerative colitis patients<br>Patients with a flare of ulcerative colitis who meet the inclusion criteria. 120 patients will be included. | Drug: Ozanimod<br>* Start of standard therapy<br>Drug: TNF Inhibitor<br>* Start of standard therapy<br>* Other names: infliximab, adalimumab, etanercept, golimumab, and certolizumab.;Drug: Steroids<br>* Start of standard therapy<br>* Other names: Prednisolon;Drug: Vedolizumab<br>* Start of standard therapy<br>Drug: Ustekinumab<br>* Start of standard therapy<br>|
| Controls<br>For each patient, enrollment of a healthy control individual who shares the same living conditions (e.g., spouse or roommate) is attempted | |

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Development of a predictive score regarding success of anti-inflammatory therapy after start of a new treatment in ulcerative colitis | The predictive microbiota signature will be developed using machine learning, considering clinical data, microbiota descriptors, and metabolic changes from day 0 to week 4 (see analysis). Clinical response will be defined as a decrease in the simple clinical colitis activity index (SCCAI) score by ≥3 points 25or to a level of ≤2.5 points 26 at 8 weeks after the start of anti-inflammatory treatment. | 4 months | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Predicting clinical remission | Assessment of the microbiota/metabolic signature predicting clinical remission (SSCAI <2.5) | 8 weeks | 
| Predicting clinical remission | Assessment of the microbiota/metabolic signature predicting clinical remission (SSCAI <2.5) | 12 weeks | 
| Predicting clinical remission | Assessment of the microbiota/metabolic signature predicting clinical remission (SSCAI <2.5) | 6 months | 
| Predicting clinical remission | Assessment of the microbiota/metabolic signature predicting clinical remission (SSCAI <2.5) | 12 months | 
| Predicting calprotectin reduction | Assessment of the microbiota/metabolic signature predicting a reduction in fecal calprotectin levels | 2 weeks | 
| Predicting calprotectin reduction | Assessment of the microbiota/metabolic signature predicting a reduction in fecal calprotectin levels | 8 weeks | 
| Predicting calprotectin reduction | Assessment of the microbiota/metabolic signature predicting a reduction in fecal calprotectin levels | 12 weeks | 
| Predicting calprotectin reduction | Assessment of the microbiota/metabolic signature predicting a reduction in fecal calprotectin levels | 6 months | 
| Predicting calprotectin reduction | Assessment of the microbiota/metabolic signature predicting a reduction in fecal calprotectin levels | 12 months | 
| Differential microbiota response to therapy: Ozanimod | Sensitivity analysis in the subgroup treated with Ozanimod in regards to differential signatures in the prediction signature | 12 months | 
| Differential microbiota response to therapy: TNF-inhibitors | Sensitivity analysis in the subgroup treated with TNF-inhibitors in regards to differential signatures in the prediction signature | 12 months | 
| Differential microbiota response to therapy: Vedolizumab | Sensitivity analysis in the subgroup treated with Vedolizumab in regards to differential signatures in the prediction signature | 12 months | 
| Differential microbiota response to therapy: Ustekinumab | Sensitivity analysis in the subgroup treated with Ustekinumab in regards to differential signatures in the prediction signature | 12 months | 
| Differential microbiota response to therapy: Steroids | Sensitivity analysis in the subgroup treated with Steroids in regards to differential signatures in the prediction signature | 12 months | 
| Signature differences between ulcerative colitis and healthy controls | Comparison of microbiota/metabolic signatures between ulcerative colitis patients and controls using clustering and differential abundance analysis | 12 months | 
| Metagenomic substrain assessment | Identification of substrains in patient samples using metagenomic sequencing and follow up their persistence/loss over time | 12 months | 
| Fatigue assessment | Fatigue severity measured by the fatigue severity scale over time and assessed for reduction after therapy start | 12 months | 
| Adverse effects | Assessment regarding potential adverse effects in relation medical therapy by screening questionnaires | 12 months |