The Latest Articles on Brain-Gut Axis and Neurodegenerative Diseases

Our staff editors continue to share exciting, interesting, and thought-provoking reading material in the recommended articles series.

This week, we would like to share several latest articles on Brain-Gut Axis and Neurodegenerative Diseases.

Title: Gut microbiome composition may be an indicator of preclinical Alzheimer’s disease
Authors: AURA L. FERREIRO, JOOHEE CHOI, JIAN RYOU, ERIN P. NEWCOMER, REGINA THOMPSON, REBECCA M. BOLLINGER, CARLA HALL-MOORE, I. MALICK NDAO, LAURIE SAX, TAMMIE L. S. BENZINGER, SUSAN L. STARK, DAVID M. HOLTZMAN, ANNE M. FAGAN, SUZANNE E. SCHINDLER, CARLOS CRUCHAGA, OMAR H. BUTT, JOHN C. MORRIS, PHILLIP I. TARR, BEAU M. ANCES, GAUTAM DANTAS
Type: Research Article
Abstract:
Alzheimer’s disease (AD) pathology is thought to progress from normal cognition through preclinical disease and ultimately to symptomatic AD with cognitive impairment. Recent work suggests that the gut microbiome of symptomatic patients with AD has an altered taxonomic composition compared with that of healthy, cognitively normal control individuals. However, knowledge about changes in the gut microbiome before the onset of symptomatic AD is limited. In this cross-sectional study that accounted for clinical covariates and dietary intake, we compared the taxonomic composition and gut microbial function in a cohort of 164 cognitively normal individuals, 49 of whom showed biomarker evidence of early preclinical AD. Gut microbial taxonomic profiles of individuals with preclinical AD were distinct from those of individuals without evidence of preclinical AD. The change in gut microbiome composition correlated with β-amyloid (Aβ) and tau pathological biomarkers but not with biomarkers of neurodegeneration, suggesting that the gut microbiome may change early in the disease process. We identified specific gut bacterial taxa associated with preclinical AD. Inclusion of these microbiome features improved the accuracy, sensitivity, and specificity of machine learning classifiers for predicting preclinical AD status when tested on a subset of the cohort (65 of the 164 participants). Gut microbiome correlates of preclinical AD neuropathology may improve our understanding of AD etiology and may help to identify gut-derived markers of AD risk.
Access this article: https://www.science.org/doi/10.1126/scitranslmed.abo2984

Title: Metabolic disturbances in the gut-brain axis of a mouse model of MPTP-induced Parkinsonism evaluated by Nuclear Magnetic Resonance
Authors: Dionísio Pedro Amorim Neto, João Vitor Pereira de Godoy, Katiane Tostes, Beatriz Pelegrini Bosque, Paulla Vieira Rodrigues, Silvana Aparecida Rocco, Mauricio Luis Sforça, Matheus de Castro Fonseca
Type: Research Article
Abstract:
Parkinson's Disease is a synucleinopathy that primarily affects the dopaminergic cells of the central nervous system, leading to motor and gastrointestinal disturbances. However, intestinal peripheral neurons undergo a similar neurodegeneration process, marked by α-synuclein (αSyn) accumulation and loss of mitochondrial homeostasis. We investigated the metabolic alterations in different biometrics that compose the gut-brain axis (blood, brain, large intestine, and feces) in an MPTP-induced mouse model of sporadic Parkinson's Disease. Animals received escalating administration of MPTP. Tissues and fecal pellets were collected, and the metabolites were identified through the untargeted Nuclear Magnetic Resonance spectroscopic (1H NMR) technique. We found differences in many metabolites from all the tissues evaluated. The differential expression of metabolites in these samples mainly reflects inflammatory aspects, cytotoxicity, and mitochondrial impairment (oxidative stress and energy metabolism) in the animal model used. The direct evaluation of fecal metabolites revealed changes in several classes of metabolites. This data reinforces previous studies showing that Parkinson’s disease is associated with metabolic perturbation not only in brain-related tissues, but also in periphery structures such as the gut. In addition, the evaluation of the microbiome and metabolites from gut and feces emerge as promising sources of information for understanding the evolution and progression of sporadic Parkinson's Disease.
Access this article: https://doi.org/10.1016/j.neuroscience.2023.06.010

Title: Gut microbes influence the development of central nervous system disorders through epigenetic inheritance
Authors: Tianyou Liu, Dongru Du, Rui Zhao, Qinglian Xie, Zaiquan Dong
Type: Review
Abstract:
Central nervous system (CNS) disorders, such as depression, anxiety, and Alzheimer's disease (AD), affect quality of life of patients and pose significant economic and social burdens worldwide. Due to their obscure and complex pathogeneses, current therapies for these diseases have limited efficacy. Over the past decade, the gut microbiome has been shown to exhibit direct and indirect influences on the structure and function of the CNS, affecting multiple pathological pathways. In addition to the direct interactions between the gut microbiota and CNS, the gut microbiota and their metabolites can regulate epigenetic processes, including DNA methylation, histone modification, and regulation of non-coding RNAs. In this review, we discuss the tripartite relationship among gut microbiota, epigenetic inheritance, and CNS disorders. We suggest that gut microbes and their metabolites influence the pathogenesis of CNS disorders at the epigenetic level, which may inform the development of effective therapeutic strategies for CNS disorders.
Access this article: https://doi.org/10.1016/j.micres.2023.127440

Title: Ambient Particulate Matter (PM2.5) exposure contributes to neurodegeneration through the microbiome-gut-brain axis: therapeutic role of melatonin
Authors: Samir Ranjan Panda, Vishal Balu Chaudhari, Sahabuddin Ahmed, Mohit Kwatra, Aishwarya Jala, Srikant Ponneganti, Sharad D Pawar, Roshan M. Borkar, Pawan Sharma f, V.G.M Naidu
Type: Review
Abstract:
Exposure to ambient particulate matter (PM2.5) has been shown to disturb the gut microbiome homeostasis and cause initiation of neuroinflammation and neurodegeneration via gut-brain bi-directional axis. Polyaromatic hydrocarbons (PAHs), which are carcinogenic and mutagenic, are important organic constituents of PM2.5 that could be involved in the microbiome-gut-brain axis-mediated neurodegeneration. Melatonin (ML) has been shown to modulate the microbiome and curb inflammation in the gut and brain. However, no studies have been reported for its effect on PM2.5-induced neuroinflammation. In the current study, it was observed that treatment with ML at 100 µM significantly inhibits microglial activation (HMC-3 cells) and colonic inflammation (CCD-841 cells) by the conditioned media from PM2.5 exposed BEAS2B cells. Further, melatonin treatment at a dose of 50 mg/kg to C57BL/6 mice exposed to PM2.5 (at a dose of 60 µg/animal) for 90 days significantly alleviated the neuroinflammation and neurodegeneration caused by PAHs in PM2.5 by modulating olfactory-brain and microbiome-gut-brain axis.
Access this article: https://doi.org/10.1016/j.etap.2023.104183

Title: Protective effects of dioscin against Parkinson's disease via regulating bile acid metabolism through remodeling gut microbiome/GLP-1 signaling
Authors: Zhang Mao, Haochen Hui, Xuerong Zhao, Lina Xu, Yan Qi, Lianhong Yin, Liping Qu, Lan Han, Jinyong Peng
Type: Original article
Abstract:
It is necessary to explore potent therapeutic agents via regulating gut microbiota and metabolism to combat Parkinson's disease (PD). Dioscin, a bioactive steroidal saponin, shows various activities. However, its effects and mechanisms against PD are limited. In this study, dioscin dramatically alleviated neuroinflammation and oxidative stress, and restored the disorders of mice induced by 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP). 16S rDNA sequencing assay demonstrated that dioscin reversed MPTP-induced gut dysbiosis to decrease Firmicutes-to-Bacteroidetes ratio and the abundances of Enterococcus, Streptococcus, Bacteroides;and Lactobacillus genera, which further inhibited bile salt hydrolase (BSH) activity and blocked bile acid (BA) deconjugation. Fecal microbiome transplantation test showed that the anti-PD effect of dioscin was gut microbiota-dependent. In addition, non-targeted fecal metabolomics assays revealed many differential metabolites in adjusting steroid biosynthesis and primary bile acid biosynthesis. Moreover, targeted bile acid metabolomics assay indicated that dioscin increased the levels of ursodeoxycholic acid, tauroursodeoxycholic acid, taurodeoxycholic acid and β-muricholic acid in feces and serum. In addition, ursodeoxycholic acid administration markedly improved the protective effects of dioscin against PD in mice. Mechanistic test indicated that dioscin significantly up-regulated the levels of takeda G protein-coupled receptor 5 (TGR5), glucagon-like peptide-1 receptor (GLP-1R), GLP-1, superoxide dismutase (SOD), and down-regulated NADPH oxidases 2 (NOX2) and nuclear factor-kappaB (NF-κB) levels. Our data indicated that dioscin ameliorated PD phenotype by restoring gut dysbiosis and regulating bile acid-mediated oxidative stress and neuroinflammation via targeting GLP-1 signal in MPTP-induced PD mice, suggesting that the compound should be considered as a prebiotic agent to treat PD in the future.
Access this article: https://doi.org/10.1016/j.jpha.2023.06.007