Gut microbiota is emerging as a key regulator of many disease conditions and its dysregulation is implicated in the pathogenesis of several gastrointestinal and extraintestinal disorders. More recently, gut microbiome alterations have been linked to neurodegeneration through the increasingly defined gut microbiota brain axis, opening the possibility for new microbiota-based therapeutic options. Although several studies have been conducted to unravel the possible relationship between Alzheimer’s Disease (AD) pathogenesis and progression, the diagnostic and therapeutic potential of approaches aiming at restoring gut microbiota eubiosis remain to be fully addressed. In this narrative review, we briefly summarize the role of gut microbiota homeostasis in brain health and disease, and we present evidence for its dysregulation in AD patients. Based on these observations, we then discuss how dysbiosis might be exploited as a new diagnostic tool in early and advanced disease stages, and we examine the potential of prebiotics, probiotics, fecal microbiota transplantation, and diets as complementary therapeutic interventions on disease pathogenesis and progression, thus offering new insights into the diagnosis and treatment of this devastating and progressive disease.

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The Potential Role of Gut Microbiota in Alzheimer’s Disease: From Diagnosis to Treatment

Alzheimer's disease (AD), considered the most common type of dementia, is characterized by a progressive loss of memory, visuospatial, language and complex cognitive abilities. In addition, patients often show comorbid depression and aggressiveness. Aging is the major factor contributing to AD; however, the initial cause that triggers the disease is yet unknown. Scientific evidence demonstrates that AD, especially the late onset of AD, is not the result of a single event, but rather it appears because of a combination of risk elements with the lack of protective ones. A major risk factor underlying the disease is neuroinflammation, which can be activated by different situations, including chronic pathogenic infections, prolonged stress and metabolic syndrome. Consequently, many therapeutic strategies against AD have been designed to reduce neuro-inflammation, with very promising results improving cognitive function in preclinical models of the disease. The literature is massive; thus, in this review we will revise the translational evidence of these early strategies focusing in anti-diabetic and anti-inflammatory molecules and discuss their therapeutic application in humans. Furthermore, we review the preclinical and clinical data of nutraceutical application against AD symptoms. Finally, we introduce new players underlying neuroinflammation in AD: the activity of the endocannabinoid system and the intestinal microbiota as neuroprotectors. This review highlights the importance of a broad multimodal approach to treat successfully the neuroinflammation underlying AD.

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Can We Treat Neuroinflammation in Alzheimer's Disease?

Alzheimer’s disease (AD) is the most common cause of dementia Epidemiological studies show the association between AD and type 2 diabetes (T2DM), although the mechanisms are not fully understood Dietary habits and lifestyle, that are risk factors in both diseases, strongly modulate gut microbiota composition Also, the brain-gut axis plays a relevant role in AD, diabetes and inflammation, through products of bacterial metabolism, like short-chain fatty acids We provide a comprehensive review of current literature on the relation between dysbiosis, altered inflammatory cytokines profile and microglia in preclinical models of AD, T2DM and models that reproduce both diseases as commonly observed in the clinic Increased proinflammatory cytokines, such as IL-1β and TNF-α, are widely detected Microbiome analysis shows alterations in Actinobacteria, Bacteroidetes or Firmicutes phyla, among others Altered α- and β-diversity is observed in mice depending on genotype, gender and age; therefore, alterations in bacteria taxa highly depend on the models and approaches We also review the use of pre- and probiotic supplements, that by favoring a healthy microbiome ameliorate AD and T2DM pathologies Whereas extensive studies have been carried out, further research would be necessary to fully understand the relation between diet, microbiome and inflammation in AD and T2DM

https://www.mdpi.com/2218-273X/11/2/262/pdf

Alzheimer's Disease and Diabetes: Role of Diet, Microbiota and Inflammation in Preclinical Models.

The potential to treat neurodegenerative diseases (NDs) of the major bioactive compound of green tea, epigallocatechin-3-gallate (EGCG), is well documented. Numerous findings now suggest that EGCG targets protein misfolding and aggregation, a common cause and pathological mechanism in many NDs. Several studies have shown that EGCG interacts with misfolded proteins such as amyloid beta-peptide (Aβ), linked to Alzheimer’s disease (AD), and α-synuclein, linked to Parkinson’s disease (PD). To date, NDs constitute a serious public health problem, causing a financial burden for health care systems worldwide. Although current treatments provide symptomatic relief, they do not stop or even slow the progression of these devastating disorders. Therefore, there is an urgent need to develop effective drugs for these incurable ailments. It is expected that targeting protein misfolding can serve as a therapeutic strategy for many NDs since protein misfolding is a common cause of neurodegeneration. In this context, EGCG may offer great potential opportunities in drug discovery for NDs. Therefore, this review critically discusses the role of EGCG in NDs drug discovery and provides updated information on the scientific evidence that EGCG can potentially be used to treat many of these fatal brain disorders.

https://www.mdpi.com/2218-273X/11/5/767/pdf

Green Tea Epigallocatechin-3-gallate (EGCG) Targeting Protein Misfolding in Drug Discovery for Neurodegenerative Diseases.

Human lifestyle and dietary behaviors contribute to disease onset and progression. Neurodegenerative diseases (NDDs), considered multifactorial disorders, have been associated with changes in the gut microbiome. NDDs display pathologies that alter brain functions with a tendency to worsen over time. NDDs are a worldwide health problem; in the US alone, 12 million Americans will suffer from NDDs by 2030. While etiology may vary, the gut microbiome serves as a key element underlying NDD development and prognosis. In particular, an inflammation-associated microbiome plagues NDDs. Conversely, sequestration of this inflammatory microbiome by a correction in the dysbiotic state of the gut may render therapeutic effects on NDDs. To this end, treatment with short-chain fatty acid-producing bacteria, the main metabolites responsible for maintaining gut homeostasis, ameliorates the inflammatory microbiome. This intimate pathological link between the gut and NDDs suggests that the gut-brain axis (GBA) acts as an underexplored area for developing therapies for NDDs. Traditionally, the classification of NDDs depends on their clinical presentation, mostly manifesting as extrapyramidal and pyramidal movement disorders, with neuropathological evaluation at autopsy as the gold standard for diagnosis. In this review, we highlight the evolving notion that GBA stands as an equally sensitive pathological marker of NDDs, particularly in Alzheimer’s disease, Parkinson’s disease, amyotrophic lateral sclerosis and chronic stroke. Additionally, GBA represents a potent therapeutic target for treating NDDs.

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Gut–Brain Axis as a Pathological and Therapeutic Target for Neurodegenerative Disorders

Alzheimer's disease (AD) is a complex multifactorial disease involving chronic neuroinflammation and neurodegeneration. It has been recently recognized that gut microbiota interacts with the brain, and it is termed as microbiota-gut-brain axis. Modulation of this axis has been recently reported to affect the pathogenesis of neurodegenerative diseases, such as AD. Gut microbiota has a pivotal role in regulating multiple neuro-chemical pathways through the highly interconnected gut-brain axis. Recent emerging evidences have highlighted that the intestinal microflora takes part in bidirectional communication between the gut and the brain. Due to this, the researchers have suggested that human gut microflora may even act as the "second brain" and may be responsible for neurodegenerative disorders like Alzheimer's disease. Dysbiosis of gut microbiota can induce increased intestinal permeability and systemic inflammation. This may lead to the development of AD pathologies and cognitive impairment via the neural, immune, endocrine, and metabolic pathways. Thus, the modulation of gut microbiota through personalized diet, oral bacteriotherapy may lead to alteration of gut microbiota their products including amyloid protein. It has been demonstrated that modulation of the gut microbiota induces beneficial effects on neuronal pathways consequently leading to delay the progression of Alzheimer's disease. Thus, this approach may provide a novel therapeutic option for treatment of AD.

Emerging role of gut microbiota in modulation of neuroinflammation and neurodegeneration with emphasis on Alzheimer's disease.

Copper (Cu) is an important trace element required for several biological processes. The use of copper is increasing gradually in several applications. Previous studies suggest that excess levels of copper are attributed to induce oxidative stress and inflammation, mediating tissue damage. Inline, melatonin the hormone of darkness has been reported to exhibit various therapeutic effects including strong free radical scavenging properties and anti-inflammatory effects. However, its effects against pulmonary injury promoted by copper are not explored and remain unclear so far. Therefore, the present study was aimed to investigate the protective effect of melatonin against copper-induced lung damage. Female Sprague Dawley (SD) rats were exposed to 250 ppm of copper in drinking water for 16 weeks and treated with melatonin (i.p.) 5 and 10 mg/kg from the week (13-16th). The extent of tissue damage was assessed by tissue oxidative stress parameters, metal estimation and histological analysis. Copper-challenged rats showed altered oxidative stress variables. In addition, metal analysis revealed increased copper accumulation in the lungs and histological staining results further indicated severe tissue injury and inflammatory cell infiltration in copper-exposed rats. To this side, treatment with melatonin showed antioxidant and anti-inflammatory activities evidenced by reduced oxidative stress, tissue inflammation and collagen deposition as compared to copper-exposed animals. Moreover, spectral findings suggested melatonin treatment modulated the frequency sift, as compared to copper-challenged animals. Altogether, the present results suggest that melatonin might play a potential role in preventing copper-induced lung aberrations via inhibiting the ROS-mediated oxidative stress and inflammation. 

/pdf/melatonin-ameliorates-chronic-copper-induced-lung-injury-1w4zu78h.pdf

Syed Afroz Ali

Papers

Emerging role of gut microbiota in modulation of neuroinflammation and neurodegeneration with emphasis on Alzheimer's disease.

Melatonin ameliorates chronic copper-induced lung injury

Melatonin Attenuates Extracellular Matrix Accumulation and Cardiac Injury Manifested by Copper

Tinospora cordifolia Miers enhances the immune response in mice immunized with JEV-vaccine: A network pharmacology and experimental approach