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.

Keywords: animal models; canine; gut-brain axis; neurodegenerative disease; review; translational.

Figure 1

Molecular pathways involved in gut-brain axis (GBA). Suggested signaling pathways and cross-talk between the intestinal microbiota, the intestinal barrier, immune modulators, and neural (brain, vagus, and ENS) systems. The intestinal microbiota can affect the levels of circulating local cytokines, cause “leaky gut” with increase GI permeability, and ultimately affect brain function (Moloney et al., ; Carabotti et al., 2015). Intestinal bacterial metabolites such as SCFA, GABA, and serotonin precursors are neuroactive and can affect ENS and the brain (Grider and Piland, ; Kimura et al., 2011). Abbreviations: ENS, enteric nervous system; SCFAs, short-chain fatty acids; GABA, γ-aminobutyric acid; LPS, lipopolysaccharide; GI, gastrointestinal.

Figure 2

The contrasts of clinical presentations on the GBA in health and neurodegenerative diseases. A stable intestinal microbiota is essential for healthy gut physiology and contributes to appropriate signaling along the GBA, promoting healthy physiologic status as well as central nervous system (CNS) status (left). Intestinal dysbiosis can negatively influence gut physiology and lead to abnormal GBA signaling (Friedland, 2015), resulting in accumulation of misfolded amyloid species (Galloway et al., ; de Lartigue et al., 2011). This can ultimately alter CNS functions and anatomy (Wu et al., 2017) as shown with magnetic resonance imaging (MRI) volumetric scans (upper middle). In the diseased CNS and gut state (right), cortical atrophy with the widening of the subarachnoid space (*), enlargement of the lateral ventricles (LV), hippocampus atrophy (HC), and brainstem (BS) volume reduction are seen with clinical and cognitive dysfunction (Johnson et al., ; Lee et al., 2015).

Figure 3

Schematic of organoid 3D culture development and integration into Transwell and Microfluidic systems. First, the intestinal biopsy is obtained via endoscopically or surgically, then villi and crypts are isolated with intestinal stem cells (ISCs) and Paneth-like cells. When cultured in an extracellular matrix with appropriate microenvironment factors, long-term culture of 3D canine enteroids/colonoids (ENT/COL) is accomplished. Second, a single cell suspension from such 3D culture system will be integrated with Transwell (left) and microfluidic (right) systems. On the transwell insert, 3D ENT/COL is cultured on top of the porous membrane with culture medium in the apical (blue) side and then submerged in culture medium in the basolateral (red) wells. A schematic of a Gut-on-a-chip (GOAC) microdevice allows a closed system with microtubing. Arrows indicate the direction of the flow of culture medium in the apical (blue) and basolateral (red) microchannels.

Figure 4

Comparative features of neurodegenerative changes and anatomy in different mammalian species. Similarities and differences in the development of neurodegenerative diseases, such as Alzheimer’s disease (AD), in human, dog, and mouse are listed.