by Hannah Buckelew

Girish Melkani, M.S., Ph.D., an associate professor in the UAB Department of Pathology’s Division of Molecular and Cellular Pathology, received funding to support his project, “Promoting circadian rhythms to optimize gut-to-brain signaling for Alzheimer’s disease.” The five-year $3.2 million R01 is funded by the National Institutes on Aging. 

Alzheimer’s disease (AD) is the leading cause of neurodegeneration worldwide and one of the leading causes of death in the United States. Alterations in gut microbiota are associated with neurodegenerative diseases, however the link between AD and gut microbiome is poorly studied. Melkani’s study will investigate the effects of microbiome disruption on AD progression.

Melkani’s team will study these interactions in a fruit fly model by testing the impact of genetic or environmental circadian rhythm disruptions (CRD) on the microbiome population and the onset and severity of cognitive decline in AD. Researchers will attempt to restore AD-induced disruption and CRD dysregulation by imposing time-restricted feeding (TRF). TRF is a behavioral intervention in which food will be provided to the fly only during active hours. Probiotics will be introduced to the model’s diet to determine whether the gut microbiome is improved.

“We’re proposing therapeutic strategies for imposing TRF to promote circadian rhythm and therapeutic probiotic treatments to promote beneficial populations of bacteria for patients with AD,” says Melkani.

The specific aims of the project are to determine whether the depletion of gut microbiota results in AD-induced neurodegeneration, examine whether TRF retains healthy microbiomes in fruit fly models, determine how disrupted gut-to-brain signaling occurs in fruit fly models of AD, and conduct a time-series comparison of the microbiomes in models implementing both a 24-hour eating cycle and TRF.

“This project will provide a deeper molecular understanding of the microbiome association in promoting circadian rhythm using TRF-optimized gut-to-brain signaling,” says Melkani.  

Melkani’s collaborators on this grant include Andrew Pickering, Ph.D., associate professor, University of Texas Health Science Center at San Antonio, and Jonathan Roth, Ph.D., assistant professor, UAB Department of Neurobiology. Dr. Roth was previously a postdoctoral trainee in Melkani's lab. Melkani wants to acknowledge the contributions of his lab members, particularly postdoctoral fellow Ruan Carlos Macedo de Moraes, Ph.D., postdoctoral fellow, and Christopher Livelo, graduate student.

“This research will assess the efficacy of a behavioral intervention that could have major potential for adoption in humans,” says Melkani.