High Fat Diet-Induced Dysregulation of Tyrosine Kinases Is a Novel Player in Gut–Brain Axis in Alzheimer’s Disease

Abstract

The gastrointestinal tract, home to the largest microbial population in the human body, plays a crucial role in overall health through various mechanisms. Recent studies have revealed the potential implications of gut–brain and vice-versa communication mediated by gut microbiota and their microbial products in Alzheimer’s disease (AD) pathology. AD is the most common type of dementia where most cases are sporadic with no clearly identified cause. However, multiple factors are implicated in the progression of sporadic AD and classified as non-modifiable (e.g., genetic) and modifiable (e.g., Type-2 diabetes (T2D), diet, etc.). A high fat diet (HFD) was reported to predispose individuals to AD upon the development of metabolic syndrome and systemic inflammation. Mechanistically, HFD induces gut dysbiosis with driven metabolites, which causes the loss of intestinal barrier integrity with concomitant colonic and systemic chronic low-grade inflammation (CLGI), associated with obesity and T2D. HFD-induced obesity and T2D parallel neuroinflammation lead to the deposition of Amyloid β (Aβ) and, ultimately, cognitive impairment. So far, on a molecular level, an HFD causes the dysregulation of Janus kinase 3 (JAK3) in both the colon and brain, a non-receptor tyrosine kinase with epithelial functions proposed to regulate microglia’s phagocytic and migratory functions. However, the HFD-dysregulated transcription factors that link JAK3 dysregulation to obesity regarding the gut and brain are still ill-defined. Furthermore, metabolomic studies are required to determine the metabolites involved in HFD-dysregulated JAK3. This review provides a new perspective on the impact of an HFD on brain–gut and microbiota–gut–brain communication in terms of transcription factors as a commonly spoken language between the gut and brain of obese diabetic patients who are at higher risk of developing cognitive impairment and AD. That commonality is in terms of the regulation of JAK3 expression both in the gut and brain, hence maintaining the intestinal barrier integrity and the phagocytic and migratory microglial functions, likely via the regulation of microglial actin remodeling, thereby alleviating systemic CLGI as well as Aβ deposition. Lastly, the characterization of those common transcription factors represents a novel potential pharmacological target to impede AD progression.