Projects

1. The Stoma Study

The Stoma Study explores how ultra-processed diets (UPF) reshape the small intestine microbiome and influence host immunity. By leveraging a unique human stoma model, we integrate multi-layered “omics” data with immune profiling to map the mechanisms by which modern nutrition impacts gut health and systemic disease, as well as immune milieus in the serum and intestine.

Investigating the Impact of Ultra-Processed Diets on Small Intestine Microbe-Host Interactions

The rising consumption of ultra-processed foods (UPF) in recent decades has been closely linked to the increasing prevalence of non-communicable diseases (NCDs), including obesity, metabolic syndrome, and inflammatory bowel disease (IBD). While evidence suggests that the gut microbiome plays a key role in mediating these health effects, most existing research has focused on fecal samples, which do not reflect the dynamic interactions occurring at the primary site of nutrient absorption: the small intestine. This study aims to bridge this knowledge gap by investigating the mechanisms through which UPFs impact the nutritional, microbial, and immune environment of the human small intestinal mucosa.

Utilizing a novel human stoma model, this research provides an unprecedented opportunity to access and sample the small bowel mucosa, an area typically difficult to reach. The study employs a prospective, cross-over interventional design involving patients with a small intestinal stoma. Participants are subjected to two distinct 10-day dietary patterns: an ultra-processed diet and a whole-food diet. Through repeated intra-individual sampling, the project tracks short-term and medium-term changes in the host’s serum metabolomics, as well as the functional and taxonomic shifts in the small intestinal microbiome.

This project is conducted in collaboration with the Shen-Orr Lab and the Geva-Zatorsky Lab, both based at the Technion – Israel Institute of Technology, with generous support from the Leona M. and Harry B. Helmsley Charitable Trust.

2. GLP-1 RAs in Patients with IBD and Overweight/Obesity

A prospective observational pilot study investigating the metabolic and anti-inflammatory effects of GLP-1 receptor agonists on weight loss, disease activity, and the microbiome in patients with inflammatory bowel disease and obesity. This research focuses on how these treatments modulate gut health and metabolic profiles.

The Effects of GLP-1 Receptor Agonists on Metabolic and Inflammatory Outcomes in Patients with Inflammatory Bowel Disease and Overweight/Obesity – A Pilot Study

The rising co-occurrence of inflammatory bowel disease (IBD) and overweight/obesity presents significant clinical challenges, as visceral fat is linked to increased inflammatory burden and poorer disease outcomes. While glucagon-like peptide 1 (GLP-1) receptor agonists (RAs) have transformed obesity management, recent evidence suggests these agents may also possess anti-inflammatory properties and play a role in intestinal health. Using the epi-IIRN database, we found that GLP-1 RA use in IBD patients is associated with reduced risks of adverse outcomes, including hospitalization and steroid dependence; however, prospective data regarding their efficacy and mechanistic impact remain scarce.

This prospective observational pilot study aims to recruit adult patients with IBD and overweight/obesity (BMI ≥ 30) who are initiating GLP-1 RA as part of their standard clinical care. The primary objectives are to evaluate drug safety (adverse events) and percent total body weight (%TBW) loss at 28 weeks. Exploratory outcomes include changes in IBD disease activity (via clinical scores and biomarkers), improvement in metabolic comorbidities, and shifts in the microbiome, metabolome, and immune function.

This project is conducted in collaboration with researchers at Stanford University and funded by a mutual grant.

3. GLP-2 Agonists for Intestinal Failure Secondary to Non-Short Bowel Etiology

Evaluating the therapeutic potential of GLP-2 agonists in rare, non-short bowel intestinal failure conditions through patient-derived organoid modeling. We explore mucosal growth and regenerative capacity in a controlled clinical-lab setting.

Intestinal failure (IF) encompasses a heterogeneous group of rare conditions, including short bowel syndrome (SBS), congenital diarrheas and enteropathies (CODE), and severe dysmotility disorders like chronic intestinal pseudo-obstruction (CIPO). Glucagon-like peptide 2 (GLP-2) is a potent enterotrophic hormone that promotes intestinal growth and enhances nutrient absorption. While GLP-2 analogues, such as Teduglutide, are established treatments for SBS to improve intestinal absorption and reduce parenteral support, their efficacy in non-SBS etiologies remains largely unknown.

This study utilizes patient-derived organoids (PDO) as a 3D culture platform to model the pathogenesis of CODE and CIPO at the enterocyte level. By isolating crypts from intestinal biopsies and generating organoids, the research aims to characterize disease mechanisms and evaluate the physiological response to GLP-2 agonists ex-vivo. The core hypothesis is that Teduglutide may enhance nutrient and fluid absorption in these rare conditions by increasing epithelial nutrient transporters and brush-border digestive enzymes.

As a first-of-its-kind pilot study, this research compares the effects of Teduglutide on non-SBS enterocytes to those derived from SBS and healthy controls. The findings aim to provide a platform for precision medicine, potentially offering a new treatment modality for patients with complex, rare forms of intestinal failure.

4. Small Intestine Polyp Formation in Patients with Familial Adenomatous Polyposis (FAP)

Our research delves into the mechanistic pathways of Familial Adenomatous Polyposis (FAP) following colectomy. We map the microbial landscape and metabolite production within the ileal pouch to understand how gut bacteria influence polyp recurrence and mucosal health.

Understanding Polyp Recurrence in the Ileal Pouch in Patients with Genetic Susceptibility

Familial Adenomatous Polyposis (FAP) is an inherited condition characterized by hundreds to thousands of adenomatous polyps throughout the colon. Even after total proctocolectomy and ileal pouch-anal anastomosis (IPAA), patients remain at lifelong risk for polyp development within the pouch. Our laboratory investigates the luminal environment of the pouch, specifically focusing on how shifts in the microbiota and their metabolic byproducts trigger epithelial proliferation.

Through longitudinal multi-omics monitoring, we are identifying key microbial metabolites that may serve as early biomarkers for neoplastic progression. By integrating mucosal transcriptomics with metagenomic data, we aim to provide therapeutic targets for preventing polyp recurrence and improving long-term clinical outcomes for FAP patients.

This project is conducted in collaboration with Professor Elizabeth Half, Rambam Health Care Campus.

5. The Azenil Study

Evaluating short-course azithromycin (Azenil) pre-treatment to modulate the microbiome and prevent anti-drug antibody formation, ensuring durability in biologic therapies (anti-TNF) for inflammatory bowel disease (IBD).

Optimizing Anti-TNF Durability through Microbiome Modulation

One of the primary challenges in treating IBD with biologic agents, such as anti-TNF antibodies, is the development of anti-drug antibodies (ADAs), which leads to secondary loss of response. Emerging evidence suggests that the gut microbiome influences the immune system’s propensity to mount an immune response against these therapeutic proteins.

The Azenil trial investigates whether a short course of azithromycin, an antibiotic with unique immunomodulatory properties and the ability to shift microbial composition, can prevent ADA formation. By analyzing the interaction between the microbial landscape and the host immune environment, our laboratory aims to identify the specific biological signatures that predict treatment success, potentially offering a low-cost, effective strategy to extend the lifespan of biologic therapies for patients worldwide.

This project is generously supported by the Leona M. and Harry B. Helmsley Charitable Trust.

6. Gut Modelling

Our lab is developing physiologically relevant human intestinal models to better understand the mechanisms underlying gastrointestinal diseases. We are currently establishing a human intestinal bio-bank by curating organoids derived from patient biopsies across a variety of intestinal diseases, as well as matched immune cells from the peripheral circulation.

This repository allows us to capture the diverse genetic and phenotypic signatures associated with multiple gastroenterological conditions. By utilizing these patient-derived samples, we aim to develop more representative platforms to investigate how specific genetic backgrounds interact with environmental triggers and contribute to disease activity.

Observing how the intestinal barrier reacts to external triggers is a primary focus of our current work, particularly food additives associated with a myriad of diseases.

In collaboration with the Levenberg Lab, based at the Technion – Israel Institute of Technology, we aim to advance modeling of the intestine to study disease pathogenesis and the impact of nutrition and the microbiome on different compartments of the host.