Ongoing Projects

1. Bacteria interaction networks within the small intestine

Funded by SNF to Benjamin Misselwitz (Main applicant)

Supervision: Prof. Benjamin Misselwitz, Prof. Bahtiyar Yilmaz

Additional partners: Prof. Uwe Sauer, ETH Zürich, Prof. Christian von Mering, Zurich University, Prof. Barbara Stecher, LMU Munich.

Students/ Trainees: Sebastian B. U. Jordi (MD-PhD student), Jiaqi Li (PhD student), Dr. med. Jacqueline Wyss, Isabel Bärtschi (PhD student, funded by other sources)

The small intestinal microbiota remains poorly characterized due to inaccessibility and the small intestine is considered “terra incognita” within the human body. Nevertheless, since the small intestine mediates the uptake of most nutrients including >90% of calories, the small intestinal microbiota likely plays a decisive role in human physiology. In the “NBMISI-study”, we work with patients with ileostomies and colostomies, respectively, solving the problem of inaccessibility. We are studying the dynamics of the small intestinal microbiota in a randomized cross-over trial with a chemically defined food challenge, followed by systematic biosampling of small intestinal content, mucosal biopsies, serum, and urine. After sampling, we will:

• Cultivate bacteria under aerobic conditions. So far, we created a library with >600 bacterial isolates and >160 species.
• Deeply characterize the intestinal microbiota by 16S and metagenomic shotgun sequencing to assess the bacterial species composition and metabolic potential.
• Perform bulk RNA-sequencing of small intestinal content to assess the bacterial metabolic activity.
• Assess metabolite changes in the intestine using mass spectrometry (in collaboration with Prof. Uwe Sauer, ETH Zurich).

We will use co-occurrence analyses to assess bacteria-bacteria and bacteria-metabolite interactions and identify bacterial interaction networks in the small intestine. Using the small intestinal bacterial library, we will reconstitute bacteria-metabolite and bacteria-bacteria interactions in vitro to unravel mechanistic interactions. Our well-characterized small intestinal bacterial library (>600 isolates) will be available for many additional projects in the future. 

In the complementary “MicroCarb-study”, we will recruit patients with ileostomies and colostomies. The study requires participants to sample stoma content and urine at home every day for 28 days. Individuals will record their diet daily in detail and switch to a low-carbohydrate diet after the initial 14 days. Our primary goal is to identify any long-term changes in the small intestinal microbiota caused by changes in nutrition.

2. Bacterial signatures predicting response to therapy in ulcerative colitis

Funded by BMS to Benjamin Misselwitz (Main applicant)

Supervision: Prof. Benjamin Misselwitz, Prof. Bahtiyar Yilmaz

Flares of ulcerative colitis are characterized by intestinal inflammation and accompanying microbiota changes. Timely prediction of the response to a new therapy is an unmet medical need and how much the microbiota can contribute to the prediction of therapy responses is unknown.

In the multi-center “COMMIT-study” in Switzerland, we are recruiting ulcerative colitis patients with a flare before the start of a new therapy. As part of the study, individuals will provide stool samples at 14 time points spanning up to one year after the initial flare. Analyses of the microbiota, as well as metabolites, will identify early bacterial and metabolic signatures for a response to therapy. In addition, by using metagenomic sequencing on specific strains at different time intervals, we will detect and analyze sub-strains, as well as gain insight into the dynamics of these sub-strains within the gut microbiota.

We have embarked on a bio-banking program to archive intestinal samples from inflammatory bowel disease patients and normal controls, providing resources for active and future work.

• SwissGut: longitudinal microbiota analysis of a cohort of healthy Swiss individuals including deep clinical and socio-economic characterization (serving as controls for the Swiss IBD studies and the Zimbabwean studies, see below)
• SwissBio: Biobank with intestinal biopsies from IBD patients and controls
• STUHL-Study: The longitudinal microbiota characterization of IBD patients and their household controls

3. Development of the intestinal microbiota after birth

Though starkly devoid of microbes in the womb, the infant gut is quickly colonized within the first days of life. Early nutrition, particularly breastfeeding strongly influences the development of the gut microbiota until weaning. By the age of 2-5 years, the intestinal microbiota stabilizes and reaches a mature adult-like profile. The development of the intestinal microbiota in infancy is crucial for health and disease, strongly influencing intestinal immunity and protection against invaders. It also affects susceptibility to auto-immune diseases and disorders of nutrition including obesity and malnutrition.

3.1. Malnutrition and the intestinal microbiota in Subsaharan Africa – the University of Zimbabwe birth cohort study (UZBCS).

Funded by the Botnar Foundation in a grant to Prof. R. Platt, ETH Basel (Main applicant)

Supervision: Prof. Benjamin Misselwitz, Prof. Bahtiyar Yilmaz, Prof. Kerina Duri (Zimbabwe)

Students: Privilege Munjoma, Panashe Chandiwana, Arthur Mazhandu

UZBCS has been recruiting 1200 pregnant women in high-density areas close to Harare, Zimbabwe since 2016 [9-11]. Women are followed as mother-baby pairs until the adolescence of the offspring. Extensive biosampling (breastmilk, serum, stool) and deep clinical phenotyping has been performed (e.g. 20 pages of questions at entry, covering comorbidities, nutrition, and hygiene, as well as the socio-demographic situation). The development of the children including growth, neurodevelopment, and behavior is closely documented. The cohort has initially been designed to study the development of HIV-exposed but uninfected children and by design, 50% of the mothers are HIV-infected. Besides HIV, malnutrition has been a significant problem for babies and infants, especially during the Covid-19 pandemic.

We started to collaborate with our Zimbabwean colleagues in 2018, following ethical principles of joint projects with developing countries (Nagoya protocol). Therefore, we are currently training two master’s students and one PhD student from Zimbabwe, aiming for the active participation of our Zimbabwean partners in all project-related analyses. Initial efforts focused on questions regarding the HIV epidemiology in our cohort, including HIV mother-to-child transmission, providing important data for the understanding of the local status of the HIV epidemic. We are currently studying the intestinal microbiota and markers of systemic inflammation in relation to HIV infection. A comprehensive library of biosamples has been shipped to Switzerland and will be analyzed to study predictors and markers of malnutrition in this cohort.

Benjamin Misselwitz started and advanced this collaboration and personally traveled to Zimbabwe 5 times since 2018. Further, the whole Zimbabwean team has traveled to and trained in Switzerland for several months. In addition, we organize weekly online meetings for discussion and bioinformatics training with our Zimbabwean colleagues.

3.2. The Bern Birth Cohort study (BeBiCo)

Supervision: Prof. Benjamin Misselwitz, Prof. Stephanie Ganal-Vonarburg, Prof. Daniel Surbek, PD Dr. Christiane Sokollik

In a parallel effort, we have been recruiting healthy pregnant women from the Bern area. Mirroring the Zimbabwean study, participants will be followed as mother-baby pairs until 10 years of age with dense biosampling and deep clinical phenotyping.

BeBiCo is run in collaboration with medical master’s students who performed crucial parts of the study including sampling and analyses. Altogether, 9 ongoing and 7 completed medical master’s theses have been realized within the BeBiCo project. So far, >100 mother-infant pairs have been recruited and followed for up to 2 years.

4. Environmental enteropathy and inflammatory bowel diseases in Zimbabwe

Supervision: Dr. Leolin Katsidziras, Prof. Benjamin Misselwitz

Funded by IBD-NET in a joint application of B. Misselwitz and L. Katzidziras.

Subsaharan Africa is currently experiencing the start of an epidemic of non-communicable diseases including metabolic syndrome and inflammatory bowel diseases (IBD). Studying the IBD epidemics in Zimbabwe might also offer clues for the understanding of the ongoing IBD epidemic in Western countries. We thus founded an IBD registry in Zimbabwe (funded by the Swiss IBD-NET) which will include >100 IBD patients from the gastroenterology practice of Dr. Katsidziras and his colleagues in Zimbabwe. For each patient, we are recruiting 1 family control and 1 community control individual for biosampling.

In the related environmental enteropathy project, we have been recruiting 40 individuals each from a traditional African setting (traditional hygiene and nutrition), a resource-limited setting (poor hygiene and nutrition), and a resource-abundant setting (Western hygiene and nutrition) in Zimbabwe. We noted markedly higher baseline inflammation levels in individuals with poor hygiene and mechanistic microbiota studies are ongoing. Swiss control individuals will be recruited from the SwissGut study.

5. Microsimulation of the natural history of colorectal cancer and colorectal cancer screening

Funded by the Swiss Cancer League to Benjamin Misselwitz (Main applicant)

Supervision: Prof. Benjamin Misselwitz, Prof. Jan Poleszczuk, Warsaw, and Prof. Niko Beerenwinkel, ETH Basel

PhD students: Viktor Zhaika (Bern University), Kevin Rupp (ETH Basel)

Over the past few years, we have successfully developed a microsimulation model specifically designed for colorectal cancer (CRC). In the CMOST project, we have created a comprehensive model that accurately represents the American population, encompassing individuals with varying levels of CRC risk. The model takes into account the step-by-step progression of adenomas, advanced adenomas, and cancer for individuals each individual in the virtual population. In our ongoing attempt, we intend to utilize CMOST to develop personalized screening and surveillance strategies for colorectal cancer, tailoring them to individual risk profiles. Additionally, we aim to integrate genetic information into CMOST for improved precision and accuracy. This enhanced model will utilize genetic information and epidemiological data to develop tailored prevention strategies.