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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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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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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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Randomised clinical trial: faecal microbiota transplantation versus autologous placebo administered via colonoscopy in irritable bowel syndrome.
BACKGROUND: Irritable bowel syndrome (IBS) has been associated with microbial dysbiosis. AIM: To investigate the efficacy of faecal microbiota transplantation (FMT) in the treatment of IBS. METHODS: Forty-nine IBS patients were randomised to receive autologous or allogenic FMT via colonoscopy. The primary endpoint was a sustained, minimum of 50-point, reduction in the IBS Symptom Severity Score. The secondary outcomes were levels of anxiety and depression, changes in quality of life, gut microbiota and faecal water content as assessed with validated questionnaires, intestinal microbiota composition and stool dry weight. RESULTS: The primary endpoint was not achieved in either group. However, there was a transient reduction in the mean IBS Symptom Severity Score in the FMT group at 12 weeks after treatment as compared to baseline (P = 0.01). The groups did not differ in the number of patients achieving clinical response at 12 weeks. In the FMT-treated patients, microbial composition had changed to resemble that of the donor and the stool water content decreased significantly compared to baseline. The depression score decreased in patients with a reduction in IBS symptoms after FMT, but not in those placebo-treated patients who experienced a reduction in IBS symptoms. CONCLUSIONS: FMT provided only a transient relief of symptoms, although it induced a sustained alteration in the microbiota of IBS patients. Therefore, FMT delivered by a single infusion via colonoscopy cannot be recommended as a treatment for IBS in clinical practice. ClinicalTrials.Org, Trial registration number: NCT03561519.
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Rumen microbial abundance and fermentation profile during severe subacute ruminal acidosis and its modulation by plant derived alkaloids in vitro.
Rumen microbiota have important metabolic functions for the host animal. This study aimed at characterizing changes in rumen microbial abundances and fermentation profiles using a severe subacute ruminal acidosis (SARA) in vitro model, and to evaluate a potential modulatory role of plant derived alkaloids (PDA), containing quaternary benzophenanthridine and protopine alkaloids, of which sanguinarine and chelerythrine were the major bioactive compounds. Induction of severe SARA strongly affected the rumen microbial composition and fermentation variables without suppressing the abundance of total bacteria. Protozoa and fungi were more sensitive to the low ruminal pH condition than bacteria. Induction of severe SARA clearly depressed degradation of fiber (P < 0.001), which came along with a decreased relative abundance of fibrolytic Ruminococcus albus and Fibrobacter succinogenes (P < 0.001). Under severe SARA conditions, the genus Prevotella, Lactobacillus group, Megasphaera elsdenii, and Entodinium spp. (P < 0.001) were more abundant, whereas Ruminobacter amylophilus was less abundant. SARA largely suppressed methane formation (-70%, P < 0.001), although total methanogenic 16S rRNA gene abundance was not affected. According to principal component analysis, Methanobrevibacter spp. correlated to methane concentration. Addition of PDA modulated ruminal fermentation under normal conditions such as enhanced (P < 0.05) concentration of total SCFA, propionate and valerate, and increased (P < 0.05) degradation of crude protein compared with the unsupplemented control diet. Our results indicate strong shifts in the microbial community during severe SARA compared to normal conditions. Supplementation of PDA positively modulates ruminal fermentation under normal ruminal pH conditions.
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Molecular mechanisms and therapeutic potential of tryptophan metabolism in gut-brain signaling transduction: a narrative review.
As an essential amino acid, tryptophan (Trp) serves as a pivotal mediator in gut-brain axis (GBA) communication through three primary metabolic pathways: kynurenine (Kyn), indole, and serotonin (5-HT), which together regulate neuroimmune and neuroendocrine homeostasis via the vagus and spinal afferent nerves, circulatory system, and hypothalamic-pituitary-adrenal (HPA) axis. This review systematically examines Trp metabolism’s critical roles in GBA, emphasizing molecular pathways, rate-limiting enzymes, and receptor-mediated signaling. We discuss the bidirectional interplay between gut microbiota and host Trp metabolism, encompassing microbial modulation of host enzyme activities such as indoleamine 2,3-dioxygenase and direct production of bioactive indole derivatives like indole-3-propionic acid. Characteristic disruptions in Trp metabolism patterns are identified across GBA-associated disorders including irritable bowel syndrome, inflammatory bowel disease, depression, Alzheimer’s disease, schizophrenia and Parkinson’s disease, marked by aberrant neurotoxic to neuroprotective metabolite ratios and enzymatic dysregulation. The aryl hydrocarbon receptor (AhR) emerges as a molecular hub connecting Trp metabolites to GBA functions, with distinct metabolites eliciting opposing effects through AhR activation. Therapeutic strategies targeting Trp metabolism are critically evaluated, including fecal microbiota transplantation, probiotic supplementation, metabolite administration, and enzyme inhibitors. Future research directions address mechanistic gaps and translational challenges in restoring GBA homeostasis via Trp pathway modulation.
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Gut bacteria-derived metabolites and their implications in mental health and neurological diseases.
Gut bacteria generate various metabolites that can significantly affect brain function and behavior through the microbiota–gut–brain axis. This article highlights the role of short-chain fatty acids, tryptophan derivatives, bile acids, and neurotransmitter-like metabolites in regulating neuroinflammation, synaptic plasticity, and neuronal signaling. The article also explores the potential mechanistic pathways through which these chemical signals act on the central nervous system, such as vagus nerve signaling, immune modulation, and blood–brain barrier integrity. The emerging studies suggested that the alterations to metabolites are linked to mental health disorders, including depression, anxiety, and autism spectrum disorders, and neurodegenerative diseases such as Alzheimer’s disease and Parkinson’s disease. Although preclinical and clinical studies provide early promise and insight into the relevance of metabolites in the brain, substantial gaps remain concerning the effects induced by metabolites at the mechanistic level, how the effect is dependent on the context, and how it varies between individuals. The article also highlights and focuses on the translational potential of clinical research, targeting the utilization of microbial metabolites for diagnostics and treatments, including methodological limitations on biomarkers, interventional reliability, and personalized interventions. The review illustrates both the potential and the shortcomings of metabolite-centric research in neuropsychiatric and neurological disorders. Future investigations should prioritize integrative approaches that combine metabolomics, neuroimaging, and clinical outcomes to infer causality and clinical relevance. Overall, metabolites derived from gut bacteria represent an attractive but underappreciated territory for advancing precision medicine for mental health and neurology.