OREGON STATE UNIVERSITY

Mechanism discovered for intestinal malfunction among patients with immune system disorders

11/30/2011

CORVALLIS, Ore. - Patients with HIV and other immune system disorders often suffer from poor food absorption, leading to weight loss and malnutrition. Researchers at Oregon State University have discovered the mechanism for this intestinal malfunction – a three-way interaction among the immune system, the intestinal lining and the microorganisms that live in the gut.

The discovery of this genetic and cellular “trialogue” opens up new avenues for therapy by upending some basic assumptions in immunology, according to Andrey Morgun, a new assistant professor in OSU’s College of Pharmacy and author on the study.

“In textbook immunology, the immune system exists mainly to fight harmful microbes, tumors and so forth,” said Morgun. “Any connection between the immune system and metabolism is outside the standard paradigm in the field. The idea that the immune system is directly involved in the maintenance and regulation of metabolism is a new concept.”

Results of the research have been published in the journal Nature Medicine.

Doctors long have puzzled over the link between deficient immunity and defective digestion. Scientists could find no pathogen that would explain the wasting disease afflicting patients. New light on this enigma was shed in recent years when immunologists found that the intestinal lining, called the epithelium, does more than merely metabolize food.

But the link between immune function and food metabolism remained unknown – until now.

Morgun and his colleagues discovered that the two functions are not only linked, but actually interact with and regulate each other.  When the epithelium detects a loss of B cells – white blood cells that fight infection – it steps up to help the body compensate for the loss of immune function.

“It launches its own protective mechanism,” wrote Morgun and OSU assistant research professor Natalia Shulzhenko in Nature Medicine. Once the intestinal lining takes on this new role, it drops back on its usual job, absorbing fats and other nutrients in foods. “If the immune system is dysfunctional,” they wrote, “the epithelium takes on some of the missing immune functions at the expense of metabolic activity.” Without proper fat absorption, wasting occurs.

Searching for clues to the triggering mechanism, the researchers found a network of more than 225 interconnected genes regulating metabolism and immunity in the guts of mice and humans.  These genes engage in “cross talk,” each conversant influencing the others. The authors characterize this three-way conversation between the epithelium, the B cells and the microorganisms that populate the gut as a balancing act. When one falters, the balance tips.

The findings have implications for treatment, which has focused on anti-inflammatory medications. Instead, the researchers suggest refocusing treatment on altering epithelial cell activity in specific ways. Another promising area for investigation is the possible link between epithelial cell activity and autoimmune disease.

Other authors on the study, which was conducted at the National Institute of Allergy and Infectious Diseases (NIAID), include Polly Matzinger of the T-Cell Tolerance and Memory Section of the Laboratory of Cellular and Molecular Immunology (nicknamed the “Ghost Lab”) at NIAID.