Researchers at the University of Maryland School of Medicine's (UMSOM) Maryland Psychiatric Center (MPRC) and Institute for Genome Sciences (IGS), along with researchers at the University of Maryland School of Pharmacy (UMSOP), have been awarded a collaborative five-year $1.78 million grant to study the brain-to-gut connection in schizophrenia.
The Principal Investigator for the research is Robert W. Buchanan, MD, UMSOM Professor of Psychiatry and Director of the MPRC. Top collaborators for this research are Claire Fraser, PhD, the Dean's Endowed Professor and Director of IGS, Deanna L. Kelly, PharmD, BCPP, UMSOM Professor of Psychiatry and Maureen Kane, PhD, Associate Professor of Pharmaceutical Sciences at the School of Pharmacy.
"I am incredibly excited to be able to collaborate with such a distinguished group of investigators on such an important project. The study has the potential to open up an entirely new avenue of treatment development research," said Dr. Buchanan.
There is considerable evidence to suggest that schizophrenia is characterized by abnormalities of the immune system, including elevated levels of cytokines, microglia activation, and genetic polymorphisms in the human leukocyte antigen (HLA) region of chromosomes, which lead to a pro-inflammatory state that causes, in part, the broad range of cognitive impairments observed in schizophrenia.
The gut microbiome has been hypothesized to effect brain development and behavior through its regulation of immune system function, by the production of short chain fatty acids (SCFAs) and other mechanisms. There are three major short chain fatty acids -- butyrate, propionate, and acetate. Among them, butyrate is of particular interest to researchers, because it appears to have the most pronounced effects on immune system function.
"This is path-breaking research that will lead to a better understanding of the role the gut microbiome plays in brain development and disorders," said Dr. Fraser. "Understanding how butyrate impacts the immune system will give us better insight into treating schizophrenia."
The research, titled "Prebiotic Treatment in People with Schizophrenia," is a R61/R33 Clinical Trial Phased Innovation Award is funded by the National Institutes of Health's National Center for Complementary and Integrative Health (NCCIH).
Experts will evaluate the hypothesis that prebiotic administration will lead to increased production of butyrate, a short chain fatty acid. Researchers will then determine whether the increase in serum butyrate levels, through the increased activity of butyrate-producing bacteria in the gut microbiota, will be associated with changes in cognitive function, symptoms, and metabolic measures.
"Serum butyrate will be one of the key metrics for assessing the biologic effect of the prebiotic treatment," said Dr. Kane of UMSOP. "The main role of the School of Pharmacy's Mass Spectrometry Center in this collaboration will be to perform the serum butyrate measurements via liquid chromatography-tandem mass spectrometry (LC-MS/MS), which will allow us to precisely quantify the levels of butyrate. In addition to investigating the brain-gut connection in schizophrenia, the study will also be useful in assessing the potential for serum butyrate to serve as a peripheral biomarker for cognitive function. That may aid in drug development or the development of new clinical trial endpoints to facilitate treatment development."
"We are excited about this opportunity to examine the effects of a prebiotic on outcomes connecting the brain to the gut in people with schizophrenia. Our collaborative project, in conjunction with Spring Grove Hospital Center, provides a unique and well-situated inpatient environment to carry out this innovative work," said Dr. Kelly.
Promoting Growth of Gut Microorganisms
Prebiotics, dietary fibers that promote the growth or activity of gut microorganisms, have been shown to increase the relative abundance and activity of multiple different bacteria species, including butyrate-producing bacteria. Researchers will evaluate the hypothesis that prebiotic administration will lead to increased production of butyrate, through increased activity of butyrate-producing bacteria in the gut microbiota. They will then determine if an increase in serum butyrate levels can be associated with changes in cognitive function, psychiatric symptoms, and metabolic measures.
In a double-blind, placebo-controlled, randomized clinical trials, researchers will examine whether the prebiotic, Prebiotin, (the hypothesized biological signature, i.e., increases serum butyrate levels. Researchers will then examine the extent to which changes in the biological signature are associated with changes in cognitive function among participants.
"We know the importance of the microbiome and the immune system. This research will further that understanding and lead to better treatments for those suffering from schizophrenia," said UMSOM Dean E. Albert Reese, MD, PhD, MBA, who is also the Executive Vice President for Medical Affairs, University of Maryland and the John Z. and Akiko K. Bowers Distinguished Professor.