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Linking nervous and immune systems in psychiatric illness: A meta-analysis of the kynurenine pathway.
Tryptophan is an essential amino acid absorbed by the gut depending on a homoeostatic microbiome. Up to 95% of unbound tryptophan is converted into tryptophan catabolites (TRYCATs) through the kynurenine system. Recent studies identified conflicting associations between altered levels of TRYCATs and genetic polymorphisms in major depressive disorder (MDD), schizophrenia (SCZ), and bipolar disorder (BD). This meta-analysis aimed to understand how tryptophan catabolic pathways are altered in MDD, SCZ, and BD. When compared to healthy controls, participants with MDD had moderately lower levels of tryptophan associated with a moderate increase of kynurenine/tryptophan ratios and no differences in kynurenine. While significant differences were found in SCZ for any of the TRYCATs, studies on kynurenic acid found opposing directions of effect sizes depending on the sample source. Unique changes in levels of TRYCATs were also observed in BD. Dynamic changes in levels of cytokines and other immune/inflammatory elements modulate the transcription and activity of kynurenine system enzymes, which lastly seems to be impacting glutamatergic neurotransmission via N-methyl-D-aspartate and α-7 nicotine receptors.
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The psychobiotic revolution: comprehending the optimistic role of gut microbiota on gut-brain axis during neurological and Gastrointestinal (GI) disorders.
The microbiota-gut-brain axis is a complex central nexus, intricately communicating with human health, affecting neurophysiological and cognitive processes. In this review article, the therapeutic potential of psychobiotics is comprehensively examined as a relatively new category of probiotics that have been shown to have beneficial effects on mental health, particularly in the context of the increasing prevalence of neurological and gastrointestinal pathologies in developing economies particularly Pakistan. This current discussion examines the pathways through which psychobiotics are postulated to influence their beneficial effect such as their role in biosynthesis of neuroactive substances, the regulation of the hypothalamic-pituitary-adrenal (HPA) axis, and inflammatory response. Some specific strains of bacteria including Lactobacillus plantarum PS128, Lactobacillus helveticus NS8, Bifidobacterium longum 1714, Lactobacillus rhamnosus (JB-1), and Bifidobacterium infantis (35624) play an important role in overcoming anxiety and mood disorders. The neuroactive chemicals (gamma-aminobutyric acid (GABA), dopamine, norepinephrine, acetylcholine, and serotonin) are extracted from gut microbes and have the ability to alter the brain activity. Other metabolites and intermediate substances, such as Brain-Derived Neurotrophic Factor (BDNF) and short-chain fatty acids (SCFAs), maintain the integrity of the intestinal barrier and control the immune system and inflammatory response. The psychobiotic food pyramid aims to protect gut and mental health while psychobiotic supplements are been known to alleviate chronic stress and anxiety. They are used to treat different types of mental conditions, such as neurodegenerative, neurodevelopmental, psychiatric, and GI disorders as well. Mental health disorders (with depression having the highest percentage) are increasing in various countries including Pakistan every day, with women being affected more than men. The review incorporates existing evidence based on both preclinical and clinical studies and clarifies the nexus of critical importance between the disorder of gut microbiota and the pathogenesis of mental health disorders that were aggravated in the course of the COVID-19 pandemic. Additional research is imperative in determining the long-term effectiveness and safety of psychobiotic interventions, particularly against a diverse population and different socioeconomic environments. This study therefore, contributes to highlighting the tremendous potential of psychobiotics as a cost-effective and innovative approach to supplementing traditional mental healthcare modalities.
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Nutraceuticals in Psychiatric Disorders: A Systematic Review.
Correct nutrition and diet are directly correlated with mental health, functions of the immune system, and gut microbiota composition. Diets with a high content of some nutrients, such as fibers, phytochemicals, and short-chain fatty acids (omega-3 fatty acids), seem to have an anti-inflammatory and protective action on the nervous system. Among nutraceuticals, supplementation of probiotics and omega-3 fatty acids plays a role in improving symptoms of several mental disorders. In this review, we collect data on the efficacy of nutraceuticals in patients with schizophrenia, autism spectrum disorders, major depression, bipolar disorder, and personality disorders. This narrative review aims to provide an overview of recent evidence obtained on this topic, pointing out the direction for future research.
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Tryptophan metabolism as a key integrator within the gut-lung-brain axis: Mechanistic insights and nutritional therapeutic strategies for inflammatory and neuropsychiatric disorders.
The gut-lung-brain (GLB) axis is a multidirectional communication network linking the gastrointestinal tract, respiratory system, and central nervous system (CNS) through neural, endocrine, and immune pathways. Emerging evidence suggests that tryptophan (Trp) metabolism serves as a key integrating node within this axis, modulating host-microbe interactions involved in systemic homeostasis. Trp catabolism follows three divergent pathways: the kynurenine (Kyn) pathway, which is involved in immune tolerance but can generate neuroactive and potentially neurotoxic metabolites; the serotonin pathway, essential for mood and gastrointestinal motility; and the microbial indole pathway, which supports epithelial barrier function through aryl hydrocarbon receptor activation. Gut dysbiosis and chronic inflammation may disrupt these pathways and contribute to the "metabolic hijacking" of Trp, shifting its metabolism away from serotonin and indole synthesis toward increased production of Kyn pathway metabolites. This shift has been implicated in the pathogenesis of respiratory diseases, such as chronic obstructive pulmonary disease, asthma, and pulmonary fibrosis, as well as neuropsychiatric conditions, including depression and Alzheimer's disease. These alterations contribute to systemic low-grade inflammation and immune dysregulation, which further propagate cross-organ pathology within the GLB axis. This review synthesizes current evidence on how Trp metabolites may function as cross-organ mediators, contributing to the "leaky gut" and "leaky brain" phenotypes. Furthermore, we evaluate the potential of precision nutrition and therapeutic interventions, including psychobiotics, dietary phytochemicals, cofactor supplementation, and fecal microbiota transplantation, to restore metabolic equilibrium. Targeting the Trp-GLB metabolic axis may therefore offer an integrative therapeutic framework for managing interconnected inflammatory and neuropsychiatric comorbidities.
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Targeting the Microbiota-Gut-Brain Axis: Emerging Nanomedicine Approaches for Neurodegenerative Diseases.
The microbiota-gut-brain axis (MGBA) is a bidirectional relationship between the gut microbiota (GM) and the brain, where the GM affects the gastrointestinal tract (GIT) and the central nervous system (CNS), and vice versa. Microbiotas are important for several vital body processes, including metabolism, immunity, and homeostasis. The MGBA has three main pathways: the vagal nerve mechanism, the immune-related mechanism, and the neuroendocrine mechanism. GM imbalance, known as dysbiosis, affects the GIT, the brain, and the CNS. Furthermore, dysbiosis is linked to several neurological disorders such as Alzheimer's (AD), Parkinson's (PD), depression, autism spectrum disorder (ASD), and multiple sclerosis (MS). Studying MGBA gives researchers new therapeutic ideas using microbiota. Using special diets rich in fiber and probiotics, in addition to fecal microbiota transplantation (FMT), is being studied as a new therapy for MGBA. From the point of view that these therapeutic interventions maintain microbiota imbalance, which in turn will affect the brain and can relieve the neurological disorders caused by dysbiosis and MGBA.
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A role for the peripheral immune system in the development of alcohol use disorders?
Preclinical studies have largely supported that alcohol-consumption induces the development of an important neuro-inflammation and this neuro-inflammation contributes to alcohol-drinking behaviors, notably through TLR4 and LPS related mechanisms. The neuro-inflammation originates from a direct interaction of ethanol with the neuronal and immune brain cells, but also from the generation of an inflammation at the periphery. Ethanol in particular interacts with the intestine to develop a gut dysbiosis and an increase in gut permeability, that allows the liberation of bacterial fragments to the systemic circulation and induces a pro-inflammatory response in the systemic circulation and peripheral organs, and in particular the liver. Peripheral cytokines or activated peripheral cells may cross the blood-brain barrier and activate neuro-inflammation. In humans, peripheral inflammation and intestinal dysbiosis are related to symptoms of alcohol use disorders (AUD), such as depression, anxiety and alcohol-craving, However, the dysbiosis, could also participate in a different manner to the symptomatology of the addiction, possibly by interacting with the stress system, by interfering with the sleep processes and altering the abilities for social interactions. The role of the gut suggests that interventions with probiotics or prebiotics might in the future be of interest for the treatment of the addiction. This article is part of the Special Issue entitled "Alcoholism".
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Chronic cereulide exposure causes intestinal inflammation and gut microbiota dysbiosis in mice.
Known as a cause of food poisoning, Bacillus cereus (B. cereus) is widespread in nature. Cereulide, the heat-stable and acid-resistant emetic toxin which is produced by some B. cereus strains, is often associated with foodborne outbreaks, and causes acute emetic toxicity at high dosage exposure. However, the toxicological effect and underlying mechanism caused by chronic low-dose cereulide exposure require to be further addressed. In the study, based on mouse model, cereulide exposure (50 μg/kg body weight) for 28 days induced intestinal inflammation, gut microbiota dysbiosis and food intake reduction. According to the cell models, low dose cereulide exposure disrupted the intestinal barrier function and caused intestinal inflammation, which were resulted from endoplasmic reticulum (ER) stress IRE1/XBP1/CHOP pathway activation to induce cell apoptosis and inflammatory cytokines production. For gut microbiota, cereulide decreased the abundances of Lactobacillus and Oscillospira. Furthermore, cereulide disordered the metabolisms of gut microbiota, which exhibited the inhibitions of butyrate and tryptophan. Interestingly, cereulide exposure also inhibited the tryptophan hydroxylase to produce the serotonin in the gut and brain, which might lead to depression-like food intake reduction. Butyrate supplementation (100 mg/kg body weight) significantly reduced intestinal inflammation and serotonin biosynthesis suppression caused by cereulide in mice. In conclusion, chronic cereulide exposure induced ER stress to cause intestinal inflammation, gut microbiota dysbiosis and serotonin biosynthesis suppression. IRE1 could be the therapeutic target and butyrate supplementation is the potential prevention strategy.
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The role of the gut microbiota in development, function and disorders of the central nervous system and the enteric nervous system.
The gut microbiota has emerged as an environmental factor that modulates the development of the central nervous system (CNS) and the enteric nervous system (ENS). Before obtaining its own microbiota, eutherian foetuses are exposed to products and metabolites from the maternal microbiota. At birth, the infants are colonised by microorganisms. The microbial composition in early life is strongly influenced by the mode of delivery, the feeding method, the use of antibiotics and the maternal microbial composition. Microbial products and microbially produced metabolites act as signalling molecules that have direct or indirect effects on the CNS and the ENS. An increasing number of studies show that the gut microbiota can modulate important processes during development, including neurogenesis, myelination, glial cell function, synaptic pruning and blood-brain barrier permeability. Furthermore, numerous studies indicate that there is a developmental window early in life during which the gut microbial composition is crucial and perturbation of the gut microbiota during this period causes long-lasting effects on the development of the CNS and the ENS. However, other functions are readily modulated in adult animals, including microglia activation and neuroinflammation. Several neurobehavioural, neurodegenerative, mental and metabolic disorders, including Parkinson disease, autism spectrum disorder, schizophrenia, Alzheimer's disease, depression and obesity, have been linked to the gut microbiota. This review focuses on the role of the microorganisms in the development and function of the CNS and the ENS, as well as their potential role in pathogenesis.
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Inflammation-targeted delivery of probiotics for alleviation of colitis and associated cognitive disorders through improved vitality and colonization.
Oral probiotic biotherapies hold significant promise for addressing intestinal inflammatory disorders. Nonetheless, due to the challenging pathological microenvironment of the gastrointestinal tract, it is difficult to achieve deliver probiotics in an inflammation-targeted manner while improving their intestinal colonization and minimizing the impact of gastrointestinal environment on their vitality. To address this, an innovative probiotics oral delivery system (EcN-Apt@HG) against ulcerative colitis (UC) was developed by conjugating IL-6 aptamer to the surface of EcN and subsequently encapsulating the probiotics in a hydrogel consisting of aldehyde-functionalized chondroitin sulfate (CS) and Poly(amidoamine) (PAMAM). As expected, the encapsulated EcN demonstrated resistance to gastrointestinal conditions, and the colonization duration of probiotics in the colon was enhanced via the preferential adhesion effect of IL-6 aptamer on the inflammatory site. The EcN-Apt@HG system restored the damaged mucosal layer, suppressed hyperactive immune responses, and reshaped the dysbiosis of intestinal microflora, thereby synergistically alleviating dextran sulfate sodium (DSS)-induced colitis. Notably, EcN-Apt@HG significantly alleviated depression-like behaviors and cognitive impairment in colitis mice through gut-brain axis interaction. This approach provides a simple and promising strategy for inflammation-targeted delivery of probiotics to the intestine and shows great potential for UC therapy and associated cognitive disorders.
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Dietary-induced modulation of the hindgut microbiota is related to behavioral responses during stressful events in horses.
The bidirectional communication between the central and the enteric nervous system named the gut-brain axis has been widely recognized. The gut microbiota has been implicated in a variety of stress-related conditions including anxiety, depression and irritable bowel syndrome based on rodent studies or correlative analysis in human patients. The aim of the present study was to investigate to what extent changes in behavior during stressful events and in the microbial composition of the colonic ecosystem were associated in horses. The microbiota alterations were induced by a change from a high-fiber diet (100% hay, H diet) to a progressive low-fiber and high-starch diet (56% hay and 44% barley, HB diet) on six fistulated horses. Colonic total anaerobic, cellulolytic, amylolytic and lactate-utilizing bacteria were enumerated once on H diet and once on HB diet. Bacterial richness, diversity and structure at family and genus level were also determined. The behavior of horses was assessed through two standardized stressful tests: a novelty test and an umbrella test. The different alterations measured in the colonic microbiota demonstrated a lower fibrolytic capacity and a higher amylolytic capacity of the ecosystem when horses received HB compared to H diet. During the novelty test, the frequency of blowing was significantly higher in HB than in H diet and was positively correlated with the concentration of amylolytic bacteria and the Succinivibrionaceae relative abundance. During the umbrella test, behavioral variables were not significantly different between the diets but the colonic content pH was negatively correlated with the frequency of startle response. Behavioral responses of anxiety were related to hindgut microbiota indicators of a high-starch diet. Dietary-induced modulation of the gut microbiota composition may have changed the horses' behavioral reactions in stressful situations.