Gut dysbiosis, defective autophagy and altered immune responses in neurodegenerative diseases: Tales of a vicious cycle

Chidambaram, Saravana Babu; Essa, Musthafa Mohamed; Rathipriya, Annan Gopinath; Bishir, Muhammed; Ray, Bipul; Mahalakshmi, Arehally M.; Tousif, A. H.; Sakharkar, Meena Kishore; Kashyap, Rajpal S.; Friedland, Robert P.; Monaghan, Tanya

doi:10.1016/j.pharmthera.2021.107988

Cited by 103 publications

(68 citation statements)

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“…2 For example, a vicious cycle of gut dysbiosis, immunemediated chronic neuroinflammation can impair autophagy and proteinopathies, leading to the development of neurodegeneration in AD. 3 The epithelial barrier hypothesis has been proposed for the chronic development condition of AD, 4 as the risk of AD is more enhanced by a "leaky gut" and microbiome dysbiosis.…”

Section: Introductionmentioning

confidence: 99%

“…Recent advances have indicated that the dysbiosis of gut microbiota is associated with Alzheimer’s disease (AD) development, with causal links identified in both epidemiological and animal experimental studies . For example, a vicious cycle of gut dysbiosis, immune-mediated chronic neuroinflammation can impair autophagy and proteinopathies, leading to the development of neurodegeneration in AD . The epithelial barrier hypothesis has been proposed for the chronic development condition of AD, as the risk of AD is more enhanced by a “leaky gut” and microbiome dysbiosis.…”

Section: Introductionmentioning

confidence: 99%

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Helicobacter pylori and Alzheimer’s Disease-Related Metabolic Dysfunction: Activation of TLR4/Myd88 Inflammation Pathway from p53 Perspective and a Case Study of Low-Dose Radiation Intervention

Zhao

Shen

Zhou

et al. 2022

ACS Chem. Neurosci.

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Gut dysbiosis is observed in Alzheimer's disease (AD) and is frequently associated with AD-induced metabolic dysfunction. However, the extent and specific underlying molecular mechanisms triggered by alterations of gut microbiota composition and function mediating ADinduced metabolic dysfunction in AD remain incompletely uncovered. Here, we indicate that Helicobacter pylori (H. pylori) is abundant in AD patients with relative metabolic dysfunction. Fecal microbiota transplantation from the AD patients promoted metabolic dysfunction in mice and increased gut permeability. H. pylori increased gut permeability through activation of the TLR4/Myd88 inflammation pathway in a p53-dependent manner, leading to metabolic dysfunction. Moreover, p53 deficiency reduced bile acid concentration, leading to an increased abundance of H. pylori colonization. Overall, these data identify H. pylori as a key promoter of ADinduced metabolic dysfunction.

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Section: Introductionmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

Helicobacter pylori and Alzheimer’s Disease-Related Metabolic Dysfunction: Activation of TLR4/Myd88 Inflammation Pathway from p53 Perspective and a Case Study of Low-Dose Radiation Intervention

Zhao

Shen

Zhou

et al. 2022

ACS Chem. Neurosci.

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“…More recent reports have indicated the important roles of gut leakiness and gut-derived bacteria with their products like LPS, which can be transported to other tissues such as the liver and brain to cause inflammatory tissue injury through the gut-liver-brain axis [63][64][65]. The manifestation of gut leakiness and endotoxemia has been implicated by not only alcohol but also other diets (i.e., fructose and Western-style high-fat diets, HFDs) [10,66,67] or in different pathological conditions e.g., neurodegenerative diseases, HIV-mediated full-blown AIDS symptoms, obesity, and nonalcoholic steatohepatitis (NASH) [65,68,69]. Despite these active mechanistic studies, the exact molecular mechanisms of gut leakiness and its impacts on promoting inflammatory injury in other tissues are still incompletely understood.…”

Section: Discussionmentioning

confidence: 99%

Aldh2 Deficiency Increases Susceptibility to Binge Alcohol-Induced Gut Leakiness, Endotoxemia, and Acute Liver Injury in Mice Through the Gut-Liver Axis

Rungratanawanich

Wang

Kawamoto

et al. 2022

Preprint

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Mitochondrial aldehyde dehydrogenase 2 (ALDH2) is the major enzyme responsible for metabolizing toxic acetaldehyde to acetate and acts as a protective or defensive protein against various disease states associated with alcohol used disorder (AUD), including alcoholic liver disease (ALD), and elevated oxidative stress. We hypothesized that Aldh2-knockout (KO) mice are susceptible to binge alcohol-mediated liver injury than wild-type (WT) mice through increased gut leakiness and endotoxemia. Therefore, this study aimed to investigate the protective role of ALDH2 in binge alcohol-induced gut permeability, endotoxemia, and acute inflammatory liver injury by exposing Aldh2-KO or WT mice to a single oral dose of binge alcohol 3.5, 4.0, or 5.0 g/kg. Our findings showed for the first time that ALDH2 deficiency in Aldh2-KO mice increases their sensitivity to alcohol-induced oxidative and nitrative stress, enterocyte apoptosis, and nitration of gut tight junction (TJ) and adherent junction (AJ) proteins, leading to their degradation. These resulted in gut leakiness and endotoxemia in Aldh2-KO mice after exposure to a single dose of ethanol even at 3.5 g/kg, while no changes were observed in the corresponding WT mice. The elevated serum endotoxin (lipopolysaccharide, LPS) and/or bacterial translocation contributed to systemic inflammation, hepatocyte apoptosis, and subsequently acute liver injury, indicating the disruption in the gut-liver axis. Furthermore, treatment with Daidzin, an ALDH2 inhibitor, exacerbated ethanol-induced cell permeability and reduced TJ/AJ proteins in T84 human colonic cells. These changes were reversed by Alda-1, an ALDH2 activator, indicating a crucial role of ALDH2 in protecting against alcohol-induced epithelial barrier dysfunction. All these findings suggest that ALDH2 deficiency or gene mutation in humans is a risk factor to alcohol-mediated gut and liver injury, and ALDH2 could be an important therapeutic target against alcohol-associated tissue/organ damage.HighlightsBinge alcohol increases oxidative and nitrative stress in the intestine and liver.Binge alcohol causes gut leakiness, endotoxemia, and acute liver injury.Leaky gut is caused by elevated degradation of nitrated intestinal TJ/AJ proteins.Aldh2-KO mice are susceptible to binge-alcohol-induced leaky gut and liver injury.ALDH2 inhibition increases alcohol-induced T84 colonic epithelial cell permeability.

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“…The pathological alterations in the composition (or diversity) and abundance of gut microbes, leading to altered gut-immune and neuroimmune status, is termed gut dysbiosis or gut microbial dysbiosis [ 44 ]. Gut dysbiosis, frequently associated with elevated intestinal-barrier dysfunction and local inflammation [ 45 , 46 , 47 ], usually contributes to disrupted GBA signaling, which results in pathophysiological consequences [ 48 ]. Increased translocation of bacteria and their toxic products into systemic circulation predisposes to a vast array of GI, metabolic, endotoxemia, cardiovascular, and neurological disorders [ 46 , 48 , 49 ].…”

Section: Gut Microbiotamentioning

confidence: 99%

The Influence of Gut Dysbiosis in the Pathogenesis and Management of Ischemic Stroke

Babu

Rathipriya

Mahalakshmi

et al. 2022

Cells

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Recent research on the gut microbiome has revealed the influence of gut microbiota (GM) on ischemic stroke pathogenesis and treatment outcomes. Alterations in the diversity, abundance, and functions of the gut microbiome, termed gut dysbiosis, results in dysregulated gut–brain signaling, which induces intestinal barrier changes, endotoxemia, systemic inflammation, and infection, affecting post-stroke outcomes. Gut–brain interactions are bidirectional, and the signals from the gut to the brain are mediated by microbially derived metabolites, such as trimethylamine N-oxide (TMAO) and short-chain fatty acids (SCFAs); bacterial components, such as lipopolysaccharide (LPS); immune cells, such as T helper cells; and bacterial translocation via hormonal, immune, and neural pathways. Ischemic stroke affects gut microbial composition via neural and hypothalamic–pituitary–adrenal (HPA) pathways, which can contribute to post-stroke outcomes. Experimental and clinical studies have demonstrated that the restoration of the gut microbiome usually improves stroke treatment outcomes by regulating metabolic, immune, and inflammatory responses via the gut–brain axis (GBA). Therefore, restoring healthy microbial ecology in the gut may be a key therapeutic target for the effective management and treatment of ischemic stroke.

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Gut dysbiosis, defective autophagy and altered immune responses in neurodegenerative diseases: Tales of a vicious cycle

Cited by 103 publications

References 471 publications

Helicobacter pylori and Alzheimer’s Disease-Related Metabolic Dysfunction: Activation of TLR4/Myd88 Inflammation Pathway from p53 Perspective and a Case Study of Low-Dose Radiation Intervention

Helicobacter pylori and Alzheimer’s Disease-Related Metabolic Dysfunction: Activation of TLR4/Myd88 Inflammation Pathway from p53 Perspective and a Case Study of Low-Dose Radiation Intervention

Aldh2 Deficiency Increases Susceptibility to Binge Alcohol-Induced Gut Leakiness, Endotoxemia, and Acute Liver Injury in Mice Through the Gut-Liver Axis

The Influence of Gut Dysbiosis in the Pathogenesis and Management of Ischemic Stroke

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