Gut-brain axis in Drosophila aging.

Energy consumption and production in the human body underpin the metabolic processes essential for life. Adenosine triphosphate (ATP) is the universal energy currency for all biochemical metabolic reactions; its synthesis and turnover require a supply of energy substrates and are maintained by the body's self-regulating systems in a state of homeostasis. The concept of energy deficit is an umbrella term and is not always clinically apparent. The aim of the study was of describe the causes of and approaches to correcting the “invisible” energy deficit. Based on an analysis of the literature, we review mechanisms of ATP consumption and production in mitochondria and the causes and consequences of mitochondrial dysfunction. The roles of the immune system and the human microbiota in hidden energy deficit are described, and evidence-based approaches to correcting disturbances of energy metabolism through direct and indirect replenishment of energy substrates are presented. Metabolic energy supply in the organism is provided by anaerobic (creatine kinase, glycolytic, myokinase) and aerobic (oxidative phosphorylation) mechanisms, primarily fueled by creatine phosphate, glucose, fatty acids, and amino acids. Impaired ATP resynthesis may arise from an imbalance between supply of energy substrates and ATP demand, or from the development of mitochondrial dysfunction due to organelle damage. Mitochondrial dysfunction, in turn, leads to various pathophysiological reactions that manifest clinically as functional disorders as well as severe pathologies of different organs and systems. The most rapid way to correct an energy deficit is administration of phosphocreatine, which quickly supports ATP synthesis without additional energy expenditure. Importantly, dietary creatine and oral supplements do not suffice to compensate for a significant energy deficit, especially in cardiomyocytes; intravenous administration of phosphocreatine is required for this purpose. Oral use of L-carnitine, citrulline malate, and creatine monohydrate may serve as adjunctive energy sources to support metabolic processes. [1] There is convincing evidence that beta-hydroxy-beta-methylbutyrate (HMB), vitamin D, omega-3 polyunsaturated fatty acids, vitamin C, and collagen enhance recovery processes in functional energy deficit. Widely used pharmaceuticals and nutraceuticals from the classes of antihypoxants, adaptogens, antioxidants, and cytoprotectors protect cells from hypoxia; however, their use requires an individualized approach with monitoring of efficacy and safety. Routine modulation of the immune system to prevent and treat energy deficit also requires special consideration with respect to interference in human homeostasis. A systematic review of clinical trials demonstrated that administration of vitamin C (for prevention of acute respiratory viral infections only), vitamin D, and probiotics has a reliable level of evidence for positive effects on immune defense functions.[2] Thus, vitamin D administration is advisable not only for its immunomodulatory action; its further conversion to 1,25-dihydroxycholecalciferol positively affects the endocrine and skeletal systems, skeletal muscle, and the gastrointestinal tract, contributing to increased endurance, greater muscle mass, accelerated regeneration, enhanced mineralization, and optimization of bone matrix structure. [3] The human microbiome — the collective genomes of microbial populations residing in the host — is of particular importance for health and metabolic processes. The gut microbiome performs numerous key functions: metabolic (facilitating digestion), barrier (preventing translocation of pathogens and toxins across the intestinal mucosa), protective (participating in immune cell development), and maintenance of mucosal enzymatic activity. The microbiome also contributes to regulation of angiogenesis, biosynthesis of vitamins and amino acids, drug metabolism, and modulation of bone tissue. Bidirectional communication between the brain and the gut — the gut–microbiota–brain axis — is mediated by neural, endocrine, and immune pathways; dysregulation of these pathways leads to a range of disorders, including immune and central nervous system pathologies such as insomnia, fatigue, and depression. Pharmacological correction of microbiota disturbances is achieved by administration of probiotics (live microorganisms), prebiotics (dietary substrates), or their combination (synbiotics). Key requirements for probiotic products include a minimal effective dose of 108–109 CFU/day. The most effective probiotic formulations include strains of Lactobacillus, Bifidobacterium, Saccharomyces boulardii, and Streptococcus thermophilus. [4] In conclusion, the primary measures to prevent hidden energy deficit are adequate provision of energy substrates, maintenance of immune system homeostasis, and a balanced composition of the gut microbiota.

The human microbiota is composed of trillions of microbial cells inhabiting the oral cavity, skin, gastrointestinal (GI) tract, airways, and reproductive organs. The gut microbiota is composed of dynamic communities of microorganisms that communicate bidirectionally with the brain via cytokines, neurotransmitters, hormones, and secondary metabolites, known as the gut microbiota–brain axis. The gut microbiota–brain axis is suspected to be involved in the development of neurological diseases, including Alzheimer’s disease (AD), Parkinson’s disease, and Autism Spectrum Disorder. AD is an irreversible, neurodegenerative disease of the central nervous system (CNS), characterized by amyloid-β plaques, neurofibrillary tangles, and neuroinflammation. Microglia and astrocytes, the resident immune cells of the CNS, play an integral role in AD development, as neuroinflammation is a driving factor of disease severity. The gut microbiota–brain axis is a novel target for Alzheimer’s disease therapeutics to modulate critical neuroimmune and metabolic pathways. Potential therapeutics include probiotics, prebiotics, fecal microbiota transplantation, and dietary intervention. This review summarizes our current understanding of the role of the gut microbiota–brain axis and neuroinflammation in the onset and development of Alzheimer’s disease, limitations of current research, and potential for gut microbiota–brain axis targeted therapies.

Helicobacter pylori (H. pylori) infection is the main pathogenic factor for upper digestive tract organic diseases. In addition to direct cytotoxic and proinflammatory effects, H. pylori infection may also induce abnormalities indirectly by affecting the brain-gut axis, similar to other microorganisms present in the alimentary tract. The brain-gut axis integrates the central, peripheral, enteric and autonomic nervous systems, as well as the endocrine and immunological systems, with gastrointestinal functions and environmental stimuli, including gastric and intestinal microbiota. The bidirectional relationship between H. pylori infection and the brain-gut axis influences both the contagion process and the host's neuroendocrine-immunological reaction to it, resulting in alterations in cognitive functions, food intake and appetite, immunological response, and modification of symptom sensitivity thresholds. Furthermore, disturbances in the upper and lower digestive tract permeability, motility and secretion can occur, mainly as a form of irritable bowel syndrome. Many of these abnormalities disappear following H. pylori eradication. H. pylori may have direct neurotoxic effects that lead to alteration of the brain-gut axis through the activation of neurogenic inflammatory processes, or by microelement deficiency secondary to functional and morphological changes in the digestive tract. In digestive tissue, H. pylori can alter signaling in the brain-gut axis by mast cells, the main brain-gut axis effector, as H. pylori infection is associated with decreased mast cell infiltration in the digestive tract. Nevertheless, unequivocal data concerning the direct and immediate effect of H. pylori infection on the brain-gut axis are still lacking. Therefore, further studies evaluating the clinical importance of these host-bacteria interactions will improve our understanding of H. pylori infection pathophysiology and suggest new therapeutic approaches.

The gut microbiota plays an important role in central nervous system (CNS) disorders. Apolipoprotein E (ApoE) can affect the composition of the gut microbiota and is closely related to the CNS. However, the mechanism by which ApoE affects cognitive dysfunction through the gut microbiota–brain axis has thus far not been investigated. In this study, we used wild-type mice and ApoE knockout (ApoE–/–) mice to replicate the aging model and examined the effects of ApoE deletion on cognitive function, hippocampal ultrastructure, synaptophysin (SYP) and postsynaptic density 95 (PSD-95) in aging mice. We also explored whether ApoE deletion affects the gut microbiota and the metabolite profile of the hippocampus in aging mice and finally examined the effect of ApoE deletion on lipids and oxidative stress in aging mice. The results showed that the deletion of ApoE aggravated cognitive dysfunction, hippocampal synaptic ultrastructural damage and dysregulation of SYP and PSD-95 expression in aging mice. Furthermore, ApoE deletion reduced gut microbial makeup in aging mice. Further studies showed that ApoE deletion altered the hippocampal metabolic profile and aggravated dyslipidemia and oxidative stress in aging mice. In brief, our findings suggest that loss of ApoE alters the composition of the gut microbiota, which in turn may affect cognitive function in aging mice through the gut microbiota–brain axis.

Mental disorders and neurological diseases are becoming a rapidly increasing medical burden. Although extensive studies have been conducted, the progress in developing effective therapies for these diseases has still been slow. The current dilemma reminds us that the human being is a superorganism. Only when we take the human self and its partner microbiota into consideration at the same time, can we better understand these diseases. Over the last few centuries, the partner microbiota has experienced tremendous change, much more than human genes, because of the modern transformations in diet, lifestyle, medical care, and so on, parallel to the modern epidemiological transition. Existing research indicates that gut microbiota plays an important role in this transition. According to gut-brain psychology, the gut microbiota is a crucial part of the gut-brain network, and it communicates with the brain via the microbiota–gut–brain axis. The gut microbiota almost develops synchronously with the gut-brain, brain, and mind. The gut microbiota influences various normal mental processes and mental phenomena, and is involved in the pathophysiology of numerous mental and neurological diseases. Targeting the microbiota in therapy for these diseases is a promising approach that is supported by three theories: the gut microbiota hypothesis, the “old friend” hypothesis, and the leaky gut theory. The effects of gut microbiota on the brain and behavior are fulfilled by the microbiota–gut–brain axis, which is mainly composed of the nervous pathway, endocrine pathway, and immune pathway. Undoubtedly, gut-brain psychology will bring great enhancement to psychology, neuroscience, and psychiatry. Various microbiota-improving methods including fecal microbiota transplantation, probiotics, prebiotics, a healthy diet, and healthy lifestyle have shown the capability to promote the function of the gut-brain, microbiota–gut–brain axis, and brain. It will be possible to harness the gut microbiota to improve brain and mental health and prevent and treat related diseases in the future.

The microbiota is essential in the host's physiology, development, reproduction, immune system, nutrient metabolism, in brain chemistry and behavior. The gut microbiota plays a crucial role in the bidirectional gut–brain axis, a communication that integrates the gut and central nervous system (CNS) activities, and thus, the concept of microbiota–gut–brain axis is emerging where the microbes have considered as signaling components in the gut-brain axis. Animal studies reveals, in particular, that gut bacteria influence the brain-derived neurotrophic factor (BDNF) levels, and behavior specially after probiotic administration. How this alterations in brain chemistry are related to specific behavioral changes is unclear but it will likely be a focus of future research efforts. Among these animal studies, to our knowledge, no studies on the microbiota–gut–brain axis in zebrafish (Danio rerio) have been carried out. We hypothesized that a continuous administration of an exogenous probiotic might also influence the host's behavior and neurochemical gene expression. The purpose of this study was to determine whether probiotic strain can modulate gut commensal bacteria influencing brain neurochemistry and behavior in zebrafish. Thus, we treated adult zebrafish for 28 days with Lactobacillus rhamnosus, a probiotic strain which is one of the main components of the commensal microflora of human intestinal tract and it is widely used as a probiotic in mammals to adult male and female AB wild tipe zebrafish. We established differences between treated with probiotic strain and control group in shoaling behavior pattern, using a Video Tracker software; we quantified brain-derived neurotrophic factor (BDNF) gene expression by using RT-qPCR; we at last analyzed the microbiota profiles within two experimental groups by sing the culture-independent methods such as Denaturing Gradient Gel Electrophoresis (DGGE) and Next-Generation Sequencing (NGS). The probiotic treated group, compared to the control group, showed a statistically significant near two-fold increase in BDNF gene expression, different shoaling behavioural pattern and a shift in microbiota composition with a significant increase of Firmicutes and a reduction of Proteobacteria. The results of each approach may support the existence of a microbiota–gut–brain axis, in adult zebrafish and in line with numerous animal studies we can speculate that microbiota manipulation could influence behavior and brain expression of BDNF.

Alleviation of migraine through gut microbiota-brain axis and dietary interventions: Coupling epigenetic network information with critical literary survey

Inflammatory bowel disease (IBD) is a chronic relapsing and remitting disorder characterized by inflammation of the gastrointestinal tract and its associated with different neurological and psychiatric disorders, which are integrated among the extra‐intestinal manifestation of this disease.In fact, epidemiological studies have shown an increased incidence of depression in patients with colitis, in which strong inflammation in the gut occurs. The possible mechanisms connecting gut inflammation and neuroinflammation in the brain could be via an increase in peripheral cytokines or via damaged nerve terminals in the gut.Recent evidence demonstrated that the gut‐brain‐axis has a central function in the perpetuation of IBS, and, for this reason it can be considered as a possible therapeutic target.N‐Palmitoylethanolamine‐oxazoline (PEA‐OXA) possesses anti‐inflammatory and potent neuroprotective effects. Although, recent studies have explained the neuroprotective properties of PEA‐OXA, nothing is known about its effects on gut‐brain axis during colitis.The aim of this study is to explore the mechanism and the effect of PEA‐OXA on gut brain axis in mice subjected to experimental colitis induced by intracolonic administration of Dextran sulfate sodium. Daily orally administration of PEA‐OXA 10 mg/kg daily o.s. was able to decrease body weight loss, macroscopic score and colon length and histology alteration after DSS induction. On the other hand was able to reduce histology modification and c‐FOS expression in the hippocampus.Additionally, we demonstrate that PEA‐OXA administration significantly increase neurogenesis and promoting neurotrophic grow factor release and decrease astroglial and microglial activation DSS‐induced. Moreover, PEA‐OXA, was able to decrease inflammatory marker in both hippocampus and colon.In conclusion, in our work, we demonstrate for the fort time the action of PEAOXA on gut‐brain axis during in a model of DSS induced colitis. induced. Moreover, PEA‐OXA, was able to decrease inflammatory marker in both hippocampus and colon. In conclusion, in our work, we demonstrate for the fort time the action of PEAOXA on gut‐brain axis during in a model of DSS induced colitis.This abstract is from the Experimental Biology 2019 Meeting. There is no full text article associated with this abstract published in The FASEB Journal.

The gut and the brain communicate bidirectionally through anatomic and humoral pathways, establishing what is known as the gut-brain axis. Therefore, interventions affecting one system will impact on the other, giving the opportunity to investigate and develop future therapeutic strategies that target both systems. Alterations in the gut-brain axis may arise as a consequence of changes in microbiota composition (dysbiosis), modifications in intestinal barrier function, impairment of enteric nervous system, unbalanced local immune response and exaggerated responses to stress, to mention a few. In this review we analyze and discuss several novel pharmacological targets within the gut-brain axis, with potential applications to improve intestinal and mental health.

BackgroundThe microbiome-gut-brain axis (MGBA) is the biochemical signal of the digestive tract and central nervous system. MGBA disorders have been increasingly involved in the pathological process of neurological diseases. This study aimed to investigate the research hot spots of MGBA from 2004 to 2020.Material/MethodsUsing bibliometric analysis from the Web of Science Core Collection (WOSCC) database, 3993 documents on the MGBA were retrieved and visual analysis was conducted.ResultsThe MGBA has received attention worldwide and will continue to be a research hot spot. Emerging research organizations and scholars of the MGBA and the research of John F. Cryan and colleagues from Ireland in the MGBA have been recognized by many scholars. However, the research of Chinese scholars and organizations appeared to have less impact due to lack of research innovation and collaboration with other countries/regions. Keyword analysis showed that neuroinflammation was a hot spot and that eminent scholars had begun to work in the field of MGBA.ConclusionsThis work provided an overall view of the literature on the MGBA worldwide, and the analysis provided a comprehensive overview of MGBA research. It further revealed the interaction between the gut microbiota (eg, Akkermansia, Parabacteroides) and the specific regulatory network of the gut microbiota and metabolites, neuroinflammation, and neural networks, which can facilitate the development of effective treatment strategies using microbiota for targeting neuroinflammation and conducting large-scale clinical trials of neurological diseases.

Gastro-intestinal (GI) microbiota and the 'gut-brain axis' are proving to be increasingly relevant to early brain development and the emergence of psychiatric disorders. This review focuses on the influence of the GI tract on Brain-Derived Neurotrophic Factor (BDNF) and its relationship with receptors for N-methyl-D-aspartate (NMDAR), as these are believed to be involved in synaptic plasticity and cognitive function. NMDAR may be associated with the development of schizophrenia and a range of other psychopathologies including neurodegenerative disorders, depression and dementias. An analysis of the routes and mechanisms by which the GI microbiota contribute to the pathophysiology of BDNF-induced NMDAR dysfunction could yield new insights relevant to developing novel therapeutics for schizophrenia and related disorders. In the absence of GI microbes, central BDNF levels are reduced and this inhibits the maintenance of NMDAR production. A reduction of NMDAR input onto GABA inhibitory interneurons causes disinhibition of glutamatergic output which disrupts the central signal-to-noise ratio and leads to aberrant synaptic behaviour and cognitive deficits. Gut microbiota can modulate BDNF function in the CNS, via changes in neurotransmitter function by affecting modulatory mechanisms such as the kynurenine pathway, or by changes in the availability and actions of short chain fatty acids (SCFAs) in the brain. Interrupting these cycles by inducing changes in the gut microbiota using probiotics, prebiotics or antimicrobial drugs has been found promising as a preventative or therapeutic measure to counteract behavioural deficits and these may be useful to supplement the actions of drugs in the treatment of CNS disorders.

The gut-brain vascular axis in neuroinflammation

The concept "gut-brain axis" means a bidirectional communication between the central nervous system and the gastrointestinal (GI) tract. This axis is key in keeping the physiological homeostasis of the GI tract and its dysfunction has been implicated in a number of neuropsychiatric and gut conditions. A number of neurotransmitters are known to be involved in the performance of gut-brain axis. Our objective has been to review and critically analyze the contribution of the calcitonin gene-related peptide (CGRP) in the physiology and pathophysiology of the gut-brain axis, with emphasis in the fresh, basic, and clinical evidence supporting an outstanding role of this neuropeptide. CGRP is considered the pivotal molecule and the first biomarker of migraine, a debilitating disease combining digestive and neurological symptoms. A number of recent experimental and clinical data support a relevant protective role for CGRP, and in particular for beta-CGRP, the isoform located in the enteric nervous system, in the gut-brain axis proper functioning and in the pathophysiology of several gut diseases, including conditions such as diverticular disease, acute infectious diarrhea or inflammatory bowel disease. As examples of its adaptable behavior, circulating beta-CGRP levels are increased in patients with acute diarrhea in COVID-19 infection or reduced already in the early phases of inflammatory bowel disease. In addition, beta-CGRP antagonism could explain the constipation seen with the new CGRP antagonists used in the preventive treatment of frequent migraine. These evidences indicate a relevant role of CGRP in gut-brain axis functioning and call for analyzing a potential role of CGRP in other common diseases of the GI tract, comorbid with brain conditions, such as irritable bowel syndrome or chronic constipation.

Epilepsy is a prevalent chronic neurological disorder, affecting approximately 70 million individuals globally, with its pathogenesis primarily attributed to recurrent seizures caused by abnormal neuronal discharges in the brain. Recent research has increasingly recognized the critical role of neuroinflammation in the central nervous system in the onset and progression of epilepsy. Furthermore, the gut-brain axis, a crucial link between gut microbiota and the central nervous system, facilitates communication through intricate pathways involving neural, immune, and endocrine mechanisms, and its involvement in epilepsy pathology is gaining significant attention. This review focuses on recent advances in neuroimmune interactions within the gut-brain axis in epilepsy. It explores the roles of inflammatory factors (e.g., IL-1β, IL-6, TNF-α) and immune cells (e.g., microglia, macrophages, neutrophils) in epileptic pathophysiology, and systematically reviews relevant experimental and clinical studies. The article begins by providing an overview of the fundamental interactions between gut microbiota and the host immune system, before discussing how gut-derived immune signals influence the central nervous system via the gut-brain axis. The pathogenic mechanisms of key pro-inflammatory factors in epileptogenesis are then examined, including how IL-1β promotes neuronal hyperexcitability, how IL-6 mediates neuroinflammation, and how TNF-α disrupts the balance between neuronal excitation and inhibition. Additionally, the article highlights the significant role of inflammatory cells in the central nervous system, particularly the activation of microglia and the infiltration of peripheral immune cells in epilepsy development. In conclusion, further investigation into the mechanisms of neuroimmune interactions in the gut-brain axis may lead to the identification of novel biomarkers and therapeutic targets for epileptogenesis, offering new insights and directions for the treatment of refractory epilepsy.

BackgroundThe burden on society grows as the number of individuals with cognitive impairment rises. Numerous research have discovered a connection between cognitive impairment and the gut-brain axis, which is useful in examining the pathophysiology of cognitive impairment and potential therapeutic approaches. As a result, this article explores developments and trends in the research concerning the gut-brain axis and cognitive impairment through a bibliometric analysis of the contributions made by various countries/regions, institutions, authors, and journals.MethodsWe looked for articles on gut-brain axis and cognitive impairment from 2014 to 2023 in the Web of Science Core Collection. For the descriptive analysis, figures and tables were taken using GraphPad Prism 6 and WPS Office 2024. For the visual analysis of the countries/regions, institutions, authors, and keywords, VOSviewer was utilized.ResultsWe obtained 458 publications from 1 January 2014 to 9 September 2023. The country with the most publications (175, 38.21%) was China. The country with the greatest total number of citations (3,138, 17.22%) was the United States of America. The highest number of articles (15, 3.26%) was issued by Zhejiang University. The most published first author is Karsas M. In this field, Nutrients have published the most articles (24). The most often occurring keywords include “Alzheimer’s disease,” “cognitive impairment,” “gut microbiota,” “inflammation,” “diet,” etc. “Stroke,” “tau,” “probiotics,” “exercise,” “fecal microbiota transplantation,” etc. emerged later.ConclusionAn increasing amount of research has focused on the connection between cognitive impairment and the gut-brain axis. In this area, the United States of America and China have both made significant contributions. The author team’s collaboration has to be improved. Our study contributes to understanding the field’s current state and predicting its future trend.