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

The human microbiota comprises trillions of symbiotic microorganisms and is involved in regulating gastrointestinal (GI), immune, nervous system and metabolic homeostasis. Recent observations suggest a bidirectional communication between the gut microbiota and the brain via immune, circulatory and neural pathways, termed the Gut-Brain Axis (GBA). Alterations in gut microbiota composition, such as seen with an increased number of pathobionts and a decreased number of symbionts, termed gut dysbiosis or microbial intestinal dysbiosis, plays a prominent role in the pathogenesis of central nervous system (CNS)-related disorders. Clinical reports confirm that GI symptoms often precede neurological symptoms several years before the development of neurodegenerative diseases (NDDs). Pathologically, gut dysbiosis disrupts the integrity of the intestinal barrier leading to ingress of pathobionts and toxic metabolites into the systemic circulation causing GBA dysregulation. Subsequently, chronic neuroinflammation via dysregulated immune activation triggers the accumulation of neurotoxic misfolded proteins in and around CNS cells resulting in neuronal death. Emerging evidence links gut dysbiosis to the aggravation and/or spread of proteinopathies from the peripheral nervous system to the CNS and defective autophagy-mediated proteinopathies. This review summarizes the current understanding of the role of gut microbiota in NDDs, and highlights a vicious cycle of gut dysbiosis, immune-mediated chronic neuroinflammation, impaired autophagy and proteinopathies, which contributes to the development of neurodegeneration in Alzheimer's disease, Parkinson's disease, Huntington's disease, multiple sclerosis, amyotrophic lateral sclerosis and frontotemporal lobar degeneration. We also discuss novel therapeutic strategies targeting the modulation of gut dysbiosis through prebiotics, probiotics, synbiotics or dietary interventions, and faecal microbial transplantation (FMT) in the management of NDDs.

Chidambaram SB ，Essa MM ，Rathipriya AG ，Bishir M ，Ray B ，Mahalakshmi AM ，Tousif AH ，Sakharkar MK ，Kashyap RS ，Friedland RP ，Monaghan TM ... -  《-》

Understanding the Gut-Brain Axis and Its Therapeutic Implications for Neurodegenerative Disorders.

Zheng Y ，Bonfili L ，Wei T ，Eleuteri AM ... -  《Nutrients》

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

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.

Goyal D ，Ali SA ，Singh RK 《-》

The connection between gut microbiota and its metabolites with neurodegenerative diseases in humans.

The aging of populations is a global phenomenon that follows a possible increase in the incidence of neurodegenerative diseases. Alzheimer's, Parkinson's, Multiple Sclerosis, Amyotrophic Lateral Sclerosis, and Huntington's diseases are some neurodegenerative disorders that aging could initiate or aggravate. Recent research has indicated that intestinal microbiota dysbiosis can trigger metabolism and brain functioning, contributing to the etiopathogenesis of those neurodegenerative diseases. The intestinal microbiota and its metabolites show significant functions in various aspects, such as the immune system modulation (development and maturation), the maintenance of the intestinal barrier integrity, the modulation of neuromuscular functions in the intestine, and the facilitation of essential metabolic processes for both the microbiota and humans. The primary evidence supporting the connection between intestinal microbiota and its metabolites with neurodegenerative diseases are epidemiological observations and animal models experimentation. This paper reviews up-to-date evidence on the correlation between the microbiota-gut-brain axis and neurodegenerative diseases, with a specially focus on gut metabolites. Dysbiosis can increase inflammatory cytokines and bacterial metabolites, altering intestinal and blood-brain barrier permeability and causing neuroinflammation, thus facilitating the pathogenesis of neurodegenerative diseases. Clinical data supporting this evidence still needs to be improved. Most of the works found are descriptive and associated with the presence of phyla or species of bacteria with neurodegenerative diseases. Despite the limitations of recent research, the potential for elucidating clinical questions that have thus far eluded clarification within prevailing pathophysiological frameworks of health and disease is promising through investigation of the interplay between the host and microbiota.

Fabi JP 《-》

The role of gut dysbiosis in Parkinson's disease: mechanistic insights and therapeutic options.

Parkinson's disease is a common neurodegenerative disorder in which gastrointestinal symptoms may appear prior to motor symptoms. The gut microbiota of patients with Parkinson's disease shows unique changes, which may be used as early biomarkers of disease. Alterations in the gut microbiota composition may be related to the cause or effect of motor or non-motor symptoms, but the specific pathogenic mechanisms are unclear. The gut microbiota and its metabolites have been suggested to be involved in the pathogenesis of Parkinson's disease by regulating neuroinflammation, barrier function and neurotransmitter activity. There is bidirectional communication between the enteric nervous system and the CNS, and the microbiota-gut-brain axis may provide a pathway for the transmission of α-synuclein. We highlight recent discoveries about alterations to the gut microbiota in Parkinson's disease and focus on current mechanistic insights into the microbiota-gut-brain axis in disease pathophysiology. Moreover, we discuss the interactions between the production and transmission of α-synuclein and gut inflammation and neuroinflammation. In addition, we draw attention to diet modification, the use of probiotics and prebiotics and faecal microbiota transplantation as potential therapeutic approaches that may lead to a new treatment paradigm for Parkinson's disease.

Wang Q ，Luo Y ，Ray Chaudhuri K ，Reynolds R ，Tan EK ，Pettersson S ... -  《-》