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Uncovering the Link between the Gut and Autoimmunity in Patients with PTEN Hamartoma Tumor Syndrome

A pilot study led by Dr. Eng suggests that the gut microbiome may contribute to the development of autoimmune diseases and immune dysregulation in patients with PTEN hamartoma tumor syndrome.


A research team led by Charis Eng, MD, PhD, has uncovered a potential link between autoimmunity in patients with PTEN hamartoma tumor syndrome (PHTS) and the community of microbial organisms in the gastrointestinal tract (known as the gut microbiome). Published in JCO Precision Oncology, the pilot clinical study suggests that the gut microbiome, regulated in part by its interaction with key immune system molecules, may contribute to the development of autoimmune diseases and immune dysregulation in PHTS patients.

PHTS refers to a spectrum of rare genetic disorders defined by germline (heritable) mutations in the tumor suppressor gene PTEN. PHTS is associated with a wide range of clinical outcomes, including certain cancers, autism spectrum disorder, autoimmune diseases (e.g., Hashimoto thyroiditis and eosinophilic esophagitis) and other signs of immune dysregulation, including recurrent upper respiratory infections and lymphopenia. However, development of these outcomes is highly variable, and there are no clinical methods that precisely predict how disease will manifest in each patient.

“Knowledge of factors that determine ‘who will get what’ will enable us to take proactive actions to prevent disease from occurring rather than waiting to treat disease as it arises,” said Dr. Eng. “As such, it is imperative to understand pathogenesis and modifiers of disease in PHTS patients, including those that may play a role in susceptibility to autoimmunity and immune dysregulation.”

The interplay between the immune system and gut

Previous studies indicate a cooperative interplay between the immune system and gut microbiome. Gut microbes affect immune system development and function, while immune system components have been suggested to modulate the gut microbiome.

Notably, class II human leukocyte antigen (HLA) molecules, which belong to a family of gene variants that govern the body's immune response to foreign invaders, appear to influence the gut microbial community.

“These demonstrated associations, along with increasing evidence that PTEN is a regulator of the central immune system, prompted us to explore gut microbes and class II HLA molecules as potential contributors to autoimmunity in PHTS patients,” explained Dr. Eng.

Finding a connection

Analyzing samples from 67 PHTS patients (41 cases, 26 controls), the researchers found that PHTS patients who have autoimmune diseases and/or immune phenotypes (cases) had statistically distinct gut microbial communities from those who do not (controls).

They also determined that specific HLA molecules correlated with certain types of fungi and bacteria, which were found in different abundances between cases and controls.

“Our findings indicate a relationship between the gut microbiome and autoimmune diseases and immune dysregulation in PHTS patients. They also suggest that class II HLA molecules may play a role in modulating the gut microbiota, which could influence autoimmunity,” said Dr. Eng. “While limited by the small sample size, our study lays the foundation for future research that can ultimately derive clinical measures utilizing the gut microbiome and HLA molecule biomarkers to predict, and perhaps prevent, autoimmunity in PHTS patients.”

Dr. Eng is the inaugural chair of the Genomic Medicine Institute and inaugural director of the Center for Personalized Genetic Healthcare, which includes the PTEN Multidisciplinary Clinic (designated as a PHTS Clinical Center of Excellence by the PTEN Hamartoma Tumor Syndrome Foundation) for children and adults with a confirmed or possible diagnosis within the PHTS spectrum. She was the first to link PTEN to Cowden syndrome, which is a PHTS disorder.

Margaret Jia, a former research technician in Dr. Eng’s lab, is first author on the study, which was supported by the National Institutes of Health; American Cancer Society; Cleveland Clinic VeloSano; the Zacconi Program of PTEN Research Excellence; and the Doris Duke Distinguished Clinical Scientist Award.

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