Precision Psychobiotics for Gut-Brain Axis Health: Advancing the Discovery Pipelines to Deliver Mechanistic Pathways and Proven Health Efficacy.

Advancing microbiome-gut-brain axis science requires systematic, rational and translational approaches to bridge the critical knowledge gaps currently preventing full exploitation of the gut microbiome as a tractable therapeutic target for gastrointestinal, mental and brain health. Current research is still marked by many open questions that undermine widespread application to humans. For example, the lack of mechanistic understanding of probiotic effects means it remains unclear why even apparently closely related strains exhibit different effects in vivo.

Feeding gut microbes to nourish the brain: unravelling the diet-microbiota-gut-brain axis.

The prevalence of brain disorders, including stress-related neuropsychiatric disorders and conditions with cognitive dysfunction, is rising. Poor dietary habits contribute substantially to this accelerating trend. Conversely, healthy dietary intake supports mood and cognitive performance.

Short chain fatty acids: Microbial metabolites for gut-brain axis signalling.

The role of the intestinal microbiota as a regulator of gut-brain axis signalling has risen to prominence in recent years. Understanding the relationship between the gut microbiota, the metabolites it produces, and the brain will be critical for the subsequent development of new therapeutic approaches, including the identification of novel psychobiotics. A key focus in this regard have been the short-chain fatty acids (SCFAs) produced by bacterial fermentation of dietary fibre, which include butyrate, acetate, and propionate.

Microbiota and sleep: awakening the gut feeling.

Various lifestyle and environmental factors are known to influence sleep. Increasingly, evidence points to a role for the microbiota in regulating brain and behaviour. This article explores how the microbiota-gut-brain axis affects sleep directly and indirectly.

Of bowels, brain and behavior: A role for the gut microbiota in psychiatric comorbidities in irritable bowel syndrome.

Background: The gastrointestinal microbiota has emerged as a key regulator of gut-brain axis signalling with important implications for neurogastroenterology. There is continuous bidirectional communication between the gut and the brain facilitated by neuronal, endocrine, metabolic, and immune pathways. The microbiota influences these signalling pathways via several mechanisms.

Maternal antibiotic administration during a critical developmental window has enduring neurobehavioural effects in offspring mice.

Rates of perinatal maternal antibiotic use have increased in recent years linked to prophylactic antibiotic use following Caesarean section delivery. This antibiotic use is necessary and beneficial in the short-term; however, long-term consequences on brain and behaviour have not been studied in detail. Here, we endeavoured to determine whether maternal administration of antibiotics during a critical window of development in early life has lasting effects on brain and behaviour in offspring mice.

Microbial memories: Sex-dependent impact of the gut microbiome on hippocampal plasticity.

Germ-free rodents, raised in the absence of a measurable gut microbiome, have been a key model to study the microbiome-gut-brain axis. Germ-free mice exhibit marked behavioural and neurochemical differences to their conventionally raised counterparts. It is as yet unclear how these neurochemical differences lead to the behavioural differences.

Unusual presentation of sarcoidosis, requiring a positron emission tomography/CT (PET/CT) for diagnosis.

A 43-year-old man presented to hospital after routine laboratory tests showed an acute kidney injury and hypercalcaemia. He had no relevant medical history and normal physical examination, other than a 6-week history of lower back pain for which he had been taking naproxen. Low parathyroid hormone (PTH) levels indicated a PTH-independent hypercalcaemia.

Microbiota-gut-brain axis as a regulator of reward processes.

Our gut harbours trillions of microorganisms essential for the maintenance of homeostasis and host physiology in health and disease. In the last decade, there has been a growing interest in understanding the bidirectional pathway of communication between our microbiota and the central nervous system. With regard to reward processes there is accumulating evidence from both animal and human studies that this axis may be a key factor in gating reward valence.

A biological framework for emotional dysregulation in alcohol misuse: from gut to brain.

Alcohol use disorder (AUD) has been associated with impairments in social and emotional cognition that play a crucial role in the development and maintenance of addiction. Repeated alcohol intoxications trigger inflammatory processes and sensitise the immune system. In addition, emerging data point to perturbations in the gut microbiome as a key regulator of the inflammatory cascade in AUD.

Towards a psychobiotic therapy for depression: CCFM1025 reverses chronic stress-induced depressive symptoms and gut microbial abnormalities in mice.

Background: Accumulating evidence points to an association between gut microbial abnormalities and depression disorder. The microbiota-gut-brain axis is an emerging target for treating depression using nutritional strategies, considering the numerous limitations of current pharmacological approaches. Here we studied the effect and probable mechanisms of psychobiotic treatment on depression.

When Rhythms Meet the Blues: Circadian Interactions with the Microbiota-Gut-Brain Axis.

The microbiota-gut-brain axis encompasses a bidirectional mode of communication between the microorganisms residing in our gut, and our brain function and behavior. The composition of the gut microbiota is subject to diurnal variation and is entrained by host circadian rhythms. In turn, a diverse microbiota is essential for optimal regulation of host circadian pathways.

Dietary phospholipids: Role in cognitive processes across the lifespan.

Chronic stress and ageing are two of the most important factors that negatively affect cognitive processes such as learning and memory across the lifespan. To date, pharmacological agents have been insufficient in reducing the impact of both on brain health, and thus, novel therapeutic strategies are required. Recent research has focused on nutritional interventions to modify behaviour and reduce the deleterious consequences of both stress and ageing.

The gut microbiome in neurological disorders.

Research into the role of the gut microbiome in modulating brain function has rapidly increased over the past 10 years, albeit chiefly in animal models. Increasing clinical and preclinical evidence implicates the microbiome as a possible key susceptibility factor for neurological disorders, including Alzheimer's disease, autism spectrum disorder, multiple sclerosis, Parkinson's disease, and stroke. Cross-sectional clinical studies are bolstering the concept of altered microbial composition contributing to the pathophysiology of such diseases.

Microbiota-Gut-Brain Axis: New Therapeutic Opportunities.

The traditional fields of pharmacology and toxicology are beginning to consider the substantial impact our gut microbiota has on host physiology. The microbiota-gut-brain axis is emerging as a particular area of interest and a potential new therapeutic target for effective treatment of central nervous system disorders, in addition to being a potential cause of drug side effects. Microbiota-gut-brain axis signaling can occur via several pathways, including via the immune system, recruitment of host neurochemical signaling, direct enteric nervous system routes and the vagus nerve, and the production of bacterial metabolites.

Histone deacetylase inhibitors restore normal hippocampal synaptic plasticity and seizure threshold in a mouse model of Tuberous Sclerosis Complex.

Abnormal synaptic plasticity has been implicated in several neurological disorders including epilepsy, dementia and Autism Spectrum Disorder (ASD). Tuberous Sclerosis Complex (TSC) is an autosomal dominant genetic disorder that manifests with seizures, autism, and cognitive deficits. The abnormal intracellular signaling underlying TSC has been the focus of many studies.

Induction of Metabotropic Glutamate Receptor-Mediated Long-Term Depression in the Hippocampal Schaffer Collateral Pathway of Aging Rats.

Scientific progress in the understanding of the molecular mechanisms of aging in the brain is essential for the identification of novel targets for the treatment and prevention of age-associated cognitive disorders. Electrophysiological analysis of synaptic plasticity using extracellular field recordings in rodent hippocampal slices is a well-established method for investigating molecular mechanisms of learning and memory. These methods can be applied to the study of aging in the brain by utilizing hippocampal slices from aged animals.

Physiological activation of mGlu5 receptors supports the ion channel function of NMDA receptors in hippocampal LTD induction in vivo.

Synaptic long-term depression (LTD) is believed to underlie critical mnemonic processes in the adult hippocampus. The roles of the metabotropic and ionotropic actions of glutamate in the induction of synaptic LTD by electrical low-frequency stimulation (LFS) in the living adult animal is poorly understood. Here we examined the requirement for metabotropic glutamate (mGlu) and NMDA receptors in LTD induction in anaesthetized adult rats.

Aß Facilitates LTD at Schaffer Collateral Synapses Preferentially in the Left Hippocampus.

Promotion of long-term depression (LTD) mechanisms by synaptotoxic soluble oligomers of amyloid-β (Aß) has been proposed to underlie synaptic dysfunction in Alzheimer's disease (AD). Previously, LTD was induced by relatively non-specific electrical stimulation. Exploiting optogenetics, we studied LTD using a more physiologically diffuse spatial pattern of selective pathway activation in the rat hippocampus in vivo.

Environmental enrichment improves hippocampal function in aged rats by enhancing learning and memory, LTP, and mGluR5-Homer1c activity.

Previous studies from our laboratory have shown that environmental enrichment (EE) in young rats results in improved learning ability and enhanced metabotropic glutamate receptor-dependent long-term potentiation (mGluR-dependent LTP) resulting from sustained activation of p70S6 kinase. Here, we investigated whether 1-month EE is sufficient to improve hippocampus-dependent learning and memory and enhance hippocampal LTP in 23-24 month-old Fischer 344 male rats. Aged rats were housed in environmentally enriched, socially enriched, or standard housing conditions.

Improved proteostasis in the secretory pathway rescues Alzheimer's disease in the mouse.

The aberrant accumulation of toxic protein aggregates is a key feature of many neurodegenerative diseases, including Huntington's disease, amyotrophic lateral sclerosis and Alzheimer's disease. As such, improving normal proteostatic mechanisms is an active target for biomedical research. Although they share common pathological features, protein aggregates form in different subcellular locations.

Environmental enrichment improves learning and memory and long-term potentiation in young adult rats through a mechanism requiring mGluR5 signaling and sustained activation of p70s6k.

Previous studies from our lab have demonstrated that mild cognitive impairments identified early in life are predictive of cognitive deficits that develop with age, suggesting that enhancements in cognition at an early age can provide a buffer against age-related cognitive decline. Environmental enrichment has been shown to improve learning and memory in the rodent, but the impact of enrichment on synaptic plasticity and the molecular mechanisms behind enrichment are not completely understood. To address these unresolved issues, we have housed 2-month old rats in environmentally enriched (EE), socially enriched (SE), or standard housing (SC) and conducted tests of learning and memory formation at various time intervals.

The amyloid precursor protein (APP) intracellular domain regulates translation of p44, a short isoform of p53, through an IRES-dependent mechanism.

p44 is a short isoform of the tumor suppressor protein p53 that is regulated in an age-dependent manner. When overexpressed in the mouse, it causes a progeroid phenotype that includes premature cognitive decline, synaptic defects, and hyperphosphorylation of tau. The hyperphosphorylation of tau has recently been linked to the ability of p44 to regulate transcription of relevant tau kinases.

Potent anti-seizure effects of D-leucine.

There are no effective treatments for millions of patients with intractable epilepsy. High-fat ketogenic diets may provide significant clinical benefit but are challenging to implement. Low carbohydrate levels appear to be essential for the ketogenic diet to work, but the active ingredients in dietary interventions remain elusive, and a role for ketogenesis has been challenged.