Gut Microbiome and Genetic Polymorphism for Pain in Sickle Cell Disease.
thesis
posted on 2024-08-01, 00:00authored byYavnika Kashyap
Several studies have investigated the complex pathophysiology of Sickle cell disease (SCD), but mechanisms underlying the clinical manifestation of acute pain episodes, the ongoing chronic pain in SCD and the factors elemental in transition from acute to chronic pain are not well understood. Gut microbiota has been shown to play a crucial role in the pathophysiological features of sickle cell disease and although some investigations into the role of gut microbiota have been pursued, its impact on SCD pain remains unknown. Given the crucial role gut microbiota plays in various physiological processes within the body including various neurodevelopmental processes, understanding how it impacts the pain pathways would be integral to understanding the intricate bidirectional gut-brain axis, would help improve upon the existing understanding of pain mechanisms in SCD and develop more targeted therapies for pain.
The main objective of my research is to enhance our understanding of the pain in SCD and how it is influenced by changes in the gut microbiome. In this study, using techniques like 16S rRNA sequencing and metabolomics, I show distinct changes in the gut microbiome composition as well as a change in the gut microbiota-derived metabolite profile of the SCD transgenic mice. I employ multipronged approach with models like antibiotic-induced microbiota depletion and fecal material transplantation to elucidate the impact of depleting or reshaping the gut microbiome on the sensory and affective pain components in a humanized transgenic mouse model of SCD. The results reveal significant insights into the role of gut microbiome and their metabolites in SCD pain modulation, offering potential mechanisms for targeted therapy. This study also elucidates how supplementation with specific metabolites further results in pain alleviation.
In addition to exploring gut microbiome, I also investigated the role of genetic polymorphisms in SCD pain. Using bioinformatics for genetic modeling of the data from SCD patients, I elucidate how ADH7 polymorphism rs971074 is associated with increased incidence of acute pain and more severe chronic pain in patients suffering from SCD.
Overall, this research provides valuable insights and highlights the role of non-traditional pathways like gut microbiome and genetic polymorphisms in SCD pain.
History
Advisor
Dr. Zaijie Jim Wang
Department
Pharmaceutical Science
Degree Grantor
University of Illinois Chicago
Degree Level
Doctoral
Degree name
Doctor of Philosophy
Committee Member
Dr. Robert E. Molokie
Dr. Jun Sun
Dr. Waddah A. Alrefai
Dr. Alan Diamond