Serum zonulin levels are increased in Alzheimer's disease but not in vascular dementia.

BACKGROUND: Zonulin is involved in the integrity and functioning of both intestinal-epithelial barrier and blood-brain barrier (BBB) by regulating tight junction molecular assembly. AIM: Since changes in microbiota and BBB may play a role in neurodegenerative disorders, we aimed to determine whether serum zonulin levels change in older patients affected by different types of dementia or mild cognitive impairment (MCI). METHODS: We evaluated serum zonulin levels in patients with late-onset AD (LOAD), vascular dementia (VAD), MIXED (AD + VAD) dementia, amnestic MCI, and in healthy controls. RESULTS: Compared with controls, serum zonulin increased in LOAD, MIXED dementia, and aMCI but not in VAD, independent of potential confounders (ANCOVA p = 0.01; LOAD vs controls, p = 0.01; MIXED vs. controls, p = 0.003; aMCI vs. controls, p = 0.04). Notably, aMCI converting to dementia showed significantly higher levels of zonulin compared with stable aMCI (p = 0.04). Serum zonulin inversely correlated with the standardized Mini-Mental State Examination (MMSE) score (p < 0.05), regardless of potential confounders. DISCUSSION: We found increased serum zonulin levels in patients with aMCI, LOAD and MIXED dementia, but not in VAD; moreover, zonulin levels were higher in aMCI converting to AD compared with stable ones. CONCLUSIONS: Our findings suggest that a dysregulation of intestinal-epithelial barrier and/or BBB may be an early specific event in AD-related neurodegeneration.

Drugs, Guts, Brains, but Not Rock and Roll: The Need to Consider the Role of Gut Microbiota in Contemporary Mental Health and Wellness of Emerging Adults.

Emerging adulthood (ages 18-25) is a critical period for neurobiological development and the maturation of the hypothalamic-pituitary-adrenal axis. Recent findings also suggest that a natural perturbation of the gut microbiota (GM), combined with other factors, may create a unique vulnerability during this period of life. The GM of emerging adults is thought to be simpler, less diverse, and more unstable than either younger or older people. We postulate that this plasticity in the GM suggests a role in the rising mental health issues seen in westernized societies today via the gut-brain-microbiota axis. Studies have paid particular attention to the diversity of the microbiota, the specific function and abundance of bacteria, and the production of metabolites. In this narrative review, we focus specifically on diet, physical activity/exercise, substance use, and sleep in the context of the emerging adult. We propose that this is a crucial period for establishing a stable and more resilient microbiome for optimal health into adulthood. Recommendations will be made about future research into possible behavioral adjustments that may be beneficial to endorse during this critical period to reduce the probability of a "dysbiotic" GM and the emergence and severity of mental health concerns.

Mutual Two-Way Interactions of Curcumin and Gut Microbiota.

Curcumin, an herbal naturally occurring polyphenol, has recently been proposed for the treatment of neurodegenerative, neurological and cancer diseases due to its pleiotropic effect. Recent studies indicated that dysbiosis is associated with the abovementioned and other diseases, and gut microflora may be a new potential therapeutic target. The new working hypothesis that could explain the curative role of curcumin, despite its limited availability, is that curcumin acts indirectly on the brain, affecting the "gut-brain-microflora axis", a complex two-way system in which the gut microbiome and its composition, are factors that preserve and determine brain health. It is therefore suspected that curcumin and its metabolites have a direct regulatory effect on gut microflora and vice versa, which may explain the paradox between curcumin's poor bioavailability and its commonly reported therapeutic effects. Curcumin and its metabolites can have health benefits by eliminating intestinal microflora dysbiosis. In addition, curcumin undergoes enzymatic modifications by bacteria, forming pharmacologically more active metabolites than their parent, curcumin. In this review, we summarize a number of studies that highlight the interaction between curcumin and gut microbiota and vice versa, and we consider the possibility of microbiome-targeted therapies using curcumin, particularly in disease entities currently without causal treatment.

Bidirectional gut-brain-microbiota axis as a potential link between inflammatory bowel disease and ischemic stroke.

Emerging evidence suggests that gut-brain-microbiota axis (GBMAx) may play a pivotal role linking gastrointestinal and neuronal disease. In this review, we summarize the latest advances in studies of GBMAx in inflammatory bowel disease (IBD) and ischemic stroke. A more thorough understanding of the GBMAx could advance our knowledge about the pathophysiology of IBD and ischemic stroke and help to identify novel therapeutic targets via modulation of the GBMAx.

Daily Changes in Composition and Diversity of the Intestinal Microbiota in Patients with Anorexia Nervosa: A Series of Three Cases.

Anorexia nervosa, a severe psychiatric illness, is associated with an intestinal microbial dysbiosis. Individual microbial signatures dominate in healthy samples, even over time and under controlled conditions, but whether microbial markers of the disorder overcome inter-individual variation during the acute stage of illness or renourishment is unknown. We characterized daily changes in the intestinal microbiota in three acutely ill patients with anorexia nervosa over the entire course of hospital-based renourishment and found significant, patient-specific changes in microbial composition and diversity. This preliminary case series suggests that even in a state of pathology, individual microbial signatures persist in accounting for the majority of intestinal microbial variation. Copyright © 2017 John Wiley & Sons, Ltd and Eating Disorders Association.

New Awareness of the Interplay Between the Gut Microbiota and Circadian Rhythms.

Circadian rhythms influence various aspects of the biology and physiology of the host, such as food intake and sleep/wake cycles. In recent years, an increasing amount of genetic and epidemiological data has shown that the light/dark cycle is the main cue that regulates circadian rhythms. Other factors, including sleep/wake cycles and food intake, have necessary effects on the composition and rhythms of the gut microbiota. Interestingly, the gut microbiota can affect the circadian rhythm of hosts in turn through contact-dependent and contact-independent mechanisms. Furthermore, the gut microbiota has been shown to regulate the sleep/wake cycles through gut-brain-microbiota interaction. In addition to diabetes, the gut microbiota can also intervene in the progression of neuro- degenerative diseases through the gut-brain-microbiota interaction, and also in other diseases such as hypertension and rheumatoid arthritis, where it is thought to have a spare therapeutic potential. Even though fecal microbiota transplantation has good potential for treating many diseases, the risk of spreading intestinal pathogens should not be ignored.

Emerging role of gut microbiota dysbiosis in neuroinflammation and neurodegeneration.

Alzheimer's disease (AD), is a chronic age-related progressive neurodegenerative disorder, characterized by neuroinflammation and extracellular aggregation of Aß peptide. Alzheimer's affects every 1 in 14 individuals aged 65 years and above. Recent studies suggest that the intestinal microbiota plays a crucial role in modulating neuro-inflammation which in turn influences Aß deposition. The gut and the brain interact with each other through the nervous system and chemical means via the blood-brain barrier, which is termed the Microbiota Gut Brain Axis (MGBA). It is suggested that the gut microbiota can impact the host's health, and numerous factors, such as nutrition, pharmacological interventions, lifestyle, and geographic location, can alter the gut microbiota composition. Although, the exact relationship between gut dysbiosis and AD is still elusive, several mechanisms have been proposed as drivers of gut dysbiosis and their implications in AD pathology, which include, action of bacteria that produce bacterial amyloids and lipopolysaccharides causing macrophage dysfunction leading to increased gut permeability, hyperimmune activation of inflammatory cytokines (IL-1ß, IL-6, IL-8, and NLRP3), impairment of gut- blood brain barrier causing deposition of Aß in the brain, etc. The study of micro-organisms associated with dysbiosis in AD with the aid of appropriate model organisms has recognized the phyla Bacteroidetes and Firmicutes which contain organisms of the genus Escherichia, Lactobacillus, Clostridium, etc., to contribute significantly to AD pathology. Modulating the gut microbiota by various means, such as the use of prebiotics, probiotics, antibiotics or fecal matter transplantation, is thought to be a potential therapeutic intervention for the treatment of AD. This review aims to summarize our current knowledge on possible mechanisms of gut microbiota dysbiosis, the role of gut brain microbiota axis in neuroinflammation, and the application of novel targeted therapeutic approaches that modulate the gut microbiota in treatment of AD.

Bacterial Profiles of Brain in Downer Cattle with Unknown Etiology.

Downer cow can be caused by muscular paralysis, neurological damage, metabolic disorder, and/or the complication of microbial infection. However, downer cow with unknown etiology is issued because of the non-detection of its bacterial etiological agent. In this study, differences in the bacterial community in brain tissues between downer cattle with unknown etiology and healthy slaughtered cattle are investigated. Bacterial diversity and representative genera between downer and normal cattle were significantly different (p < 0.05). There are significant differences in representative genera of downer and normal cattle, especially the significance, fold change, and area under the receiver operating characteristic curve score (p < 0.05). Furthermore, the prediction of functional genes in brain microbiota between the downer and normal cattle revealed differences in the cluster of orthologous gene categories, such as lipid transport and metabolism, secondary metabolite biosynthesis, and signal transduction (p < 0.05). This study revealed a significant difference in microbiota between the downer and normal cattle. Thus, we demonstrate that representative genera from downer cattle through 16S rRNA gene amplicon sequencing and microbiota analysis have the potential as candidates for bacterial etiological agents for downer cow.

Changes to the Gut Microbiome in Young Children Showing Early Behavioral Signs of Autism.

The human gut microbiome has increasingly been associated with autism spectrum disorder (ASD), which is a neurological developmental disorder, characterized by impairments to social interaction. The ability of the gut microbiota to signal across the gut-brain-microbiota axis with metabolites, including short-chain fatty acids, impacts brain health and has been identified to play a role in the gastrointestinal and developmental symptoms affecting autistic children. The fecal microbiome of older children with ASD has repeatedly shown particular shifts in the bacterial and fungal microbial community, which are significantly different from age-matched neurotypical controls, but it is still unclear whether these characteristic shifts are detectable before diagnosis. Early microbial colonization patterns can have long-lasting effects on human health, and pre-emptive intervention may be an important mediator to more severe autism. In this study, we characterized both the microbiome and short-chain fatty acid concentrations of fecal samples from young children between 21 and 40 months who were showing early behavioral signs of ASD. The fungal richness and acetic acid concentrations were observed to be higher with increasing autism severity, and the abundance of several bacterial taxa also changed due to the severity of ASD. Bacterial diversity and SCFA concentrations were also associated with stool form, and some bacterial families were found with differential abundance according to stool firmness. An exploratory analysis of the microbiome associated with pre-emptive treatment also showed significant differences at multiple taxonomic levels. These differences may impact the microbial signaling across the gut-brain-microbiota axis and the neurological development of the children.

Epilepsy and the gut: Perpetrator or victim?

The brain and the gut are linked together with a complex, bi-path link known as the gut-brain axis through the central and enteric nervous systems. So, the brain directly affects and controls the gut through various neurocrine and endocrine processes, and the gut impacts the brain via different mechanisms. Epilepsy is a central nervous system (CNS) disorder with abnormal brain activity, causing repeated seizures due to a transient excessive or synchronous alteration in the brain's electrical activity. Due to the strong relationship between the enteric and the CNS, gastrointestinal dysfunction may increase the risk of epilepsy. Meanwhile, about 2.5% of patients with epilepsy were misdiagnosed as having gastrointestinal disorders, especially in children below the age of one year. Gut dysbiosis also has a significant role in epileptogenesis. Epilepsy, in turn, affects the gastrointestinal tract in different forms, such as abdominal aura, epilepsy with abdominal pain, and the adverse effects of medications on the gut and the gut microbiota. Epilepsy with abdominal pain, a type of temporal lobe epilepsy, is an uncommon cause of abdominal pain. Epilepsy also can present with postictal states with gastrointestinal manifestations such as postictal hypersalivation, hyperphagia, or compulsive water drinking. At the same time, antiseizure medications have many gastrointestinal side effects. On the other hand, some antiseizure medications may improve some gastrointestinal diseases. Many gut manipulations were used successfully to manage epilepsy. Prebiotics, probiotics, synbiotics, postbiotics, a ketogenic diet, fecal microbiota transplantation, and vagus nerve stimulation were used successfully to treat some patients with epilepsy. Other manipulations, such as omental transposition, still need more studies. This narrative review will discuss the different ways the gut and epilepsy affect each other.

The intestinal microbiota and metabolites in patients with anorexia nervosa.

Brain-gut microbiota interactions are intensively studied in connection with various neurological and psychiatric diseases. While anorexia nervosa (AN) pathophysiology is not entirely clear, it is presumably linked to microbiome dysbiosis. We aimed to elucidate the gut microbiota contribution in AN disease pathophysiology. We analyzed the composition and diversity of the gut microbiome of patients with AN (bacteriome and mycobiome) from stool samples before and after renourishment, and compared them to healthy controls. Further, levels of assorted neurotransmitters and short-chain fatty acids (SCFA) were analyzed in stool samples by MS and NMR, respectively. Biochemical, anthropometric, and psychometric profiles were assessed. The bacterial alpha-diversity parameter analyses revealed only increased Chao 1 index in patients with AN before the realimentation, reflecting their interindividual variation. Subsequently, core microbiota depletion signs were observed in patients with AN. Overrepresented OTUs (operation taxonomic units) in patients with AN taxonomically belonged to Alistipes, Clostridiales, Christensenellaceae, and Ruminococcaceae. Underrepresented OTUs in patients with AN were Faecalibacterium, Agathobacter, Bacteroides, Blautia, and Lachnospira. Patients exhibited greater interindividual variation in the gut bacteriome, as well as in metagenome content compared to controls, suggesting altered bacteriome functions. Patients had decreased levels of serotonin, GABA, dopamine, butyrate, and acetate in their stool samples compared to controls. Mycobiome analysis did not reveal significant differences in alpha diversity and fungal profile composition between patients with AN and healthy controls, nor any correlation of the fungal composition with the bacterial profile. Our results show the changed profile of the gut microbiome and its metabolites in patients with severe AN. Although therapeutic partial renourishment led to increased body mass index and improved psychometric parameters, SCFA, and neurotransmitter profiles, as well as microbial community compositions, did not change substantially during the hospitalization period, which can be potentially caused by only partial weight recovery.

Psychobiotics: Mechanisms of Action, Evaluation Methods and Effectiveness in Applications with Food Products.

The gut-brain-microbiota axis consists of a bilateral communication system that enables gut microbes to interact with the brain, and the latter with the gut. Gut bacteria influence behavior, and both depression and anxiety symptoms are directly associated with alterations in the microbiota. Psychobiotics are defined as probiotics that confer mental health benefits to the host when ingested in a particular quantity through interaction with commensal gut bacteria. The action mechanisms by which bacteria exert their psychobiotic potential has not been completely elucidated. However, it has been found that these bacteria provide their benefits mostly through the hypothalamic-pituitary-adrenal (HPA) axis, the immune response and inflammation, and through the production of neurohormones and neurotransmitters. This review aims to explore the different approaches to evaluate the psychobiotic potential of several bacterial strains and fermented products. The reviewed literature suggests that the consumption of psychobiotics could be considered as a viable option to both look after and restore mental health, without undesired secondary effects, and presenting a lower risk of allergies and less dependence compared to psychotropic drugs.

Effects of the Human Gut Microbiota on Cognitive Performance, Brain Structure and Function: A Narrative Review.

Enhancing or preserving cognitive performance of personnel working in stressful, demanding and/or high tempo environments is vital for optimal performance. Emerging research suggests that the human gut microbiota may provide a potential avenue to enhance cognition. This review examines the relationship between the human gut microbiota, including modulators of the microbiota on cognition and/or brain function. For this narrative review, a total of n = 17 relevant human research items of a possible 1765 published between January 2010 and November 2018 were identified. Two overarching design methods for synthesis were observed: correlational or pre/post intervention. Limited correlational design studies linking microbiota to cognitive/brain structure endpoints existed (n = 5); however, correlations between microbiota diversity and enhanced cognitive flexibility and executive function were observed. Gut microbiota intervention studies to improve cognition or brain function (n = 12) generally resulted in improved cognition (11/12), in which improvements were observed in visuospatial memory, verbal learning and memory, and aspects of attentional vigilance. Limited studies were available to draw a detailed conclusion; however, available evidence suggests that gut microbiota is linked to cognitive performance and that manipulation of gut microbiota could be a promising avenue for enhancing cognition which warrants further research.

Gut microbiota and pro/prebiotics in Alzheimer's disease.

Alzheimer's disease is characterized by the accumulation of amyloid and dysfunctional tau protein in the brain along with the final development of dementia. Accumulation of amyloid in the brain was observed 10-20 years before the onset of clinical symptoms by diagnostic methods based on image analysis. This is a serious public health problem, incidence and prevalence being expected to reach epidemic proportions over the next few decades if the disease cannot be prevented or slowed down. Recently, in addition to the strongly developing ischemic etiology of Alzheimer's disease, it is suggested that the gut microbiota may also participate in the development of this disease. The brain and gut are thought to form a network called the "gut-brain-microbiota axis", and it is strongly supported idea that the intestinal microflora can be involved in Alzheimer's disease. Lately, many new studies have been conducted that draw attention to the relationship between Alzheimer's disease and gut microbiota. This review presents a possible relationship between Alzheimer's disease and a microbiome. It is a promising idea for prevention or therapeutic intervention. Modulation of the gut microbiota through a personalized diet or beneficial microflora intervention like pro/prebiotics, changing microbiological partners and their products, including amyloid protein, can become a new treatment for Alzheimer's disease.

A cellular automaton model to find the risk of developing autism through gut-mediated effects.

BACKGROUND: One of the risk factors for the development of Autism Spectrum Disorder (ASD) is hypothesized to be an imbalance in the gut microbiome. Alterations in the relative numbers of gut microbiota may contribute to such a disruption in normal bacterial diversity. It is assumed that this process may be adequately mirrored for the purpose of the current paper by modeling the dynamic shifts in the numbers of three bacterial species, namely Clostridium, Desulfovibrio, and Bifidobacterium. Such imbalances in the gut microbiome are thought to promote the development of increased gut permeability (the so-called "leaky gut") which in turn is a potential risk factor for the development of ASD. METHODS: We constructed a mathematical model using 2-D Cellular Automata to simulate the growth rates and interactions of three bacterial species, namely Bifidobacterium, Clostridium and Desulfovibrio, with each other and with available nutrients in the gut, and particularly following the introduction of lysozyme into the gut. RESULTS: It was observed from the modeled simulation that increasing or decreasing the population of Clostridium in the gut produces key shifts in the gut microbiome which could potentially increase or decrease the risk of ASD. CONCLUSION: Simulations using our cellular automaton model suggest that it could be useful in predicting the effects produced by alterations to key components of the gut microbiome. In particular, the model demonstrated that the introduction of lysozyme in the gut results in steep reductions in Clostridium growth rate, which in turn could potentially alter the gut microbiome population in such a way as to significantly reduce the risk of developing ASD.

Omnivores Going Astray: A Review and New Synthesis of Abnormal Behavior in Pigs and Laying Hens.

Pigs and poultry are by far the most omnivorous of the domesticated farm animals and it is in their nature to be highly explorative. In the barren production environments, this motivation to explore can be expressed as abnormal oral manipulation directed toward pen mates. Tail biting (TB) in pigs and feather pecking (FP) in laying hens are examples of unwanted behaviors that are detrimental to the welfare of the animals. The aim of this review is to draw these two seemingly similar abnormalities together in a common framework, in order to seek underlying mechanisms and principles. Both TB and FP are affected by the physical and social environment, but not all individuals in a group express these behaviors and individual genetic and neurobiological characteristics play an important role. By synthesizing what is known about environmental and individual influences, we suggest a novel possible mechanism, common for pigs and poultry, involving the brain-gut-microbiota axis.