Overview of the Gut-Brain Axis: From Gut to Brain and Back Again.

The gut-brain axis refers to a bidirectional communication pathway linking the gastrointestinal system to the central nervous system. The hardware of this multifaceted pathway takes many forms, at once structural (neurons, microglia, intestinal epithelial cell barrier), chemical (neurotransmitters, enteroendocrine hormones, bacterial metabolites), and cellular (immune signaling, inflammatory pathways). The gut-brain axis is exquisitely influenced by our environment, diet, and behaviors. Here, we will describe recent progress in understanding the gut-brain axis in neurological disease, using Parkinson's disease as a guide. We will see that each component of the gut-brain axis is heavily mediated by intestinal microbiota and learn how gut-brain communication can go awry in microbial dysbiosis.

Intestinal microbiota and neuroinflammation in Parkinson's disease: At the helm of the gut-brain axis.

Emerging data suggest that disrupted intestinal microbiota, or dysbiosis, may be responsible for multiple features of Parkinson's disease (PD), from initiation, to progression, to therapeutic response. We have progressed greatly in our understanding of microbial signatures associated with PD, and have gained important insights into how dysbiosis and intestinal permeability promote neurodegeneration through neuroinflammation and Lewy body formation. These insights underscore the potential of microbiota-directed therapies, which include dietary, pharmacologic, and lifestyle interventions.

Gut-Brain Communication in Parkinson's Disease: Enteroendocrine Regulation by GLP-1.

PURPOSE OF REVIEW: Defective gut-brain communication has recently been proposed as a promoter of neurodegeneration, but mechanisms mediating communication remain elusive. In particular, the Parkinson's disease (PD) phenotype has been associated with both dysbiosis of intestinal microbiota and neuroinflammation. Here, we review recent advances in the PD field that connect these two concepts, providing an explanation based on enteroendocrine signaling from the gut to the brain. RECENT FINDINGS: There have been several recent accounts highlighting the importance of the microbiota-gut-brain axis in PD. The objective of this review is to discuss the role of the neuroendocrine system in gut-brain communication as it relates to PD pathogenesis, as this system has not been comprehensively considered in prior reviews. The incretin hormone glucagon-like peptide 1 (GLP-1) is secreted by enteroendocrine cells of the intestinal epithelium, and there is evidence that it is neuroprotective in animal models and human subjects with PD. Agonists of GLP-1 receptors used in diabetes appear to be useful for preventing neurodegeneration. New tools and models have enabled us to study regulation of GLP-1 secretion by intestinal microbiota, to understand how this process may be defective in PD, and to develop methods for therapeutically modifying disease development or progression using the enteroendocrine system. GLP-1 secretion by enteroendocrine cells may be a key mediator of neuroprotection in PD, and new findings in this field may offer unique insights into PD pathogenesis and therapeutic strategies.

Attenuated Postprandial GLP-1 Response in Parkinson's Disease.

The incretin hormone glucagon-like peptide 1 (GLP-1) has neuroprotective effects in animal models of Parkinson's disease (PD), and GLP-1 receptor agonists are associated with clinical improvements in human PD patients. GLP-1 is produced and secreted by intestinal L-cells in response to consumption of a meal. Specifically, intestinal microbiota produce short chain fatty acids (SCFA) which, in turn, promote secretion of GLP-1 into the systemic circulation, from which it can enter the brain. Our group and others have reported that PD patients have an altered intestinal microbial community that produces less SCFA compared to age-matched controls. In this report, we demonstrate that PD patients have diminished GLP-1 secretion in response to a meal compared to their household controls. Peak postprandial GLP-1 levels did not correlate with PD disease severity, motor function, or disease duration. These data provide the scientific rationale for future studies designed to elucidate the role of GLP-1 in the pathogenesis of PD and test the potential utility of GLP-1-directed therapies.

The Optical Coherence Tomographic Profile of Leber Hereditary Optic Neuropathy.

The objective of this study was to describe the changes in the retinal ganglion cell complex (GCC) relative to the retinal nerve fibre layer (RNFL) over time in Leber hereditary optic neuropathy (LHON) patients. Average RNFL and GCC thickness was measured in seven patients in the early acute (123, 68.4 µm), late acute (113.5, 57.4 µm), and chronic (72.7, 50.8 µm) phases. Patients showed thinning of the GCC with RNFL swelling in the early acute phase. GCC thinning became severe within weeks and persisted. RNFL swelling normalised during the late acute phase with eventual thinning in the chronic phase. GCC changes appear at the commencement of visual loss and in some cases prior to vision loss. These findings define an optical coherence tomography (OCT) profile in LHON.

Myotubularin-deficient myoblasts display increased apoptosis, delayed proliferation, and poor cell engraftment.

X-linked myotubular myopathy is a severe congenital myopathy caused by deficiency of the lipid phosphatase, myotubularin. Recent studies of human tissue and animal models have discovered structural and physiological abnormalities in myotubularin-deficient muscle, but the impact of myotubularin deficiency on myogenic stem cells within muscles is unclear. In the present study, we evaluated the viability, proliferative capacity, and in vivo engraftment of myogenic cells obtained from severely symptomatic (Mtm1δ4) myotubularin-deficient mice. Mtm1δ4 muscle contains fewer myogenic cells than wild-type (WT) littermates, and the number of myogenic cells decreases with age. The behavior of Mtm1δ4 myoblasts is also abnormal, because they engraft poorly into C57BL/6/Rag1null/mdx5cv mice and display decreased proliferation and increased apoptosis compared with WT myoblasts. Evaluation of Mtm1δ4 animals at 21 and 42 days of life detected fewer satellite cells in Mtm1δ4 muscle compared with WT littermates, and the decrease in satellite cells correlated with progression of disease. In addition, analysis of WT and Mtm1δ4 regeneration after injury detected similar abnormalities of satellite cell function, with fewer satellite cells, fewer dividing cells, and increased apoptotic cells in Mtm1δ4 muscle. These studies demonstrate specific abnormalities in myogenic cell number and behavior that may relate to the progression of disease in myotubularin deficiency, and may also be used to develop in vitro assays by which novel treatment strategies can be assessed.

Dominant mutation of CCDC78 in a unique congenital myopathy with prominent internal nuclei and atypical cores.

Congenital myopathies are clinically and genetically heterogeneous diseases that typically present in childhood with hypotonia and weakness and are most commonly defined by changes observed in muscle biopsy. Approximately 40% of congenital myopathies are currently genetically unresolved. We identified a family with dominantly inherited congenital myopathy characterized by distal weakness and biopsy changes that included core-like areas and increased internalized nuclei. To identify the causative genetic abnormality in this family, we performed linkage analysis followed by whole-exome capture and next-generation sequencing. A splice-acceptor variant in previously uncharacterized CCDC78 was detected in affected individuals and absent in unaffected family members and > 10,000 controls. This variant alters RNA-transcript processing and results in a 222 bp in-frame insertion. CCDC78 is expressed in skeletal muscle, enriched in the perinuclear region and the triad, and found in intracellular aggregates in patient muscle. Modeling of the CCDC78 mutation in zebrafish resulted in changes mirroring the human disease that included altered motor function and abnormal muscle ultrastructure. Using a combination of linkage analysis, next-generation sequencing, and modeling in the zebrafish, we have identified a CCDC78 mutation associated with a unique myopathy with prominent internal nuclei and atypical cores.