The Gut-Brain Axis in Neurodegenerative Diseases and Relevance of the Canine Model: A Review

Abstract

Identifying appropriate animal models is critical in developing translatable in vitro and in vivo systems for therapeutic drug development and investigating disease pathophysiology. These animal models should have direct biological and translational relevance to the underlying disease they are supposed to mimic. Aging dogs not only naturally develop a cognitive decline in many aspects including learning and memory deficits, but they also exhibit human-like individual variability in the aging process. Neurodegenerative processes that can be observed in both human and canine brains include the progressive accumulation of β-amyloid (Aβ) found as diffuse plaques in the prefrontal cortex (PFC), including the gyrus proreus (i.e., medial orbital PFC) , as well as the hippocampus and the cerebral vasculature. Tau pathology, a marker of neurodegeneration and dementia progression, was also found in canine hippocampal synapses. Various epidemiological data show that human patients with neurodegenerative diseases have concurrent intestinal lesions, and histopathological changes in the gastrointestinal (GI) tract occurs decades before neurodegenerative changes. Gut microbiome alterations have also been reported in many neurodegenerative diseases including Alzheimer’s (AD) and Parkinson’s diseases, as well as inflammatory central nervous system (CNS) diseases. Interestingly, the dog gut microbiome more closely resembles human gut microbiome in composition and functional overlap compared to rodent models. This article reviews the physiology of the gut-brain axis (GBA) and its involvement with neurodegenerative diseases in humans. Additionally, we outline the advantages and weaknesses of current in vitro and in vivo models and discuss future research directions investigating major human neurodegenerative diseases such as AD and Parkinson’s diseases using dogs.

Recapitulation of the accessible interface of biopsy-derived canine intestinal organoids to study epithelial-luminal interactions

“…This concern is most likely due to the large translational gap between highly inbred or genetically-modified laboratory animals and humans who exhibit genetic variability influenced by environmental factors [1]. Therefore, an interdisciplinary collaboration between basic scientists, engineers, and clinician-scientists using companion animals with naturally occurring diseases is critical to bridge this gap and accelerate drug development [48]. Dogs are receiving more attention as a relevant translational in vivo model compared to rodents because they share similar genetic and environmental variations seen in humans [1].…”

Gut Microbiome Composition is Associated with Age and Memory Performance in Pet Dogs

“…Several studies performed in rodents suggest that neurodevelopment is affected by gut microbiota [1][2][3]. In humans, intestinal microbiome composition has been linked to psychiatric conditions, such as depression, anxiety, and autism, as well as neurodegenerative disorders, including Parkinson's and Alzheimer's disease [4]. The primary path through which the gut microbiome is thought to affect behavior are metabolites produced by gut-inhabiting bacteria.…”

Overview of Brain-to-Gut Axis Exposed to Chronic CNS Bacterial Infection(s) and a Predictive Urinary Metabolic Profile of a Brain Infected by Mycobacterium tuberculosis

“…Considering the bottomup motif, particularly its perturbations in the gut-microbiome, can have a clear and direct effect on the host's psychological state-of-mind (depression, anxiety, bipolar disorder), behavior (autism) and also in the pathogenesis and/or progression of various neurodegenerative diseases (Alzheimer's, Parkinson's, and multiple sclerosis). These disorders associated with the bottom-up direction of communication have been succinctly and meticulously detailed in many topical research reviews (Mayer et al, 2014;Konturek et al, 2015;Powell et al, 2017;Zhu et al, 2017;Martin et al, 2018;Ambrosini et al, 2019). Perturbations of the BGA associated with non-communicable neurological diseases -to what degree, the precise mechanism involved, and their appropriate therapy -are not yet well understood.…”