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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.
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Beyond weight loss: exploring the neurological ramifications of altered gut microbiota post-bariatric surgery.
This review discusses findings related to neurological disorders, gut microbiota, and bariatric surgery, focusing on neurotransmitters, neuroendocrine, the pathophysiology of bacteria contributing to disorders, and possible therapeutic interventions. Research on neurotransmitters suggests that their levels are heavily influenced by gut microbiota, which may link them to neurological disorders such as Alzheimer's disease, Parkinson's disease, Multiple sclerosis, Depression, and Autism spectrum disorder. The pathophysiology of bacteria that reach and influence the central nervous system has been documented. Trends in microbiota are often observed in specific neurological disorders, with a prominence of pro-inflammatory bacteria and a reduction in anti-inflammatory types. Furthermore, bariatric surgery has been shown to alter microbiota profiles similar to those observed in neurological disorders. Therapeutic interventions, including fecal microbiota transplants and probiotics, have shown potential to alleviate neurological symptoms. We suggest a framework for future studies that integrates knowledge from diverse research areas, employs rigorous methodologies, and includes long-trial clinical control groups.
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Pomegranate peel polyphenols reduce chronic low-grade inflammatory responses by modulating gut microbiota and decreasing colonic tissue damage in rats fed a high-fat diet.
Recent studies have found that a high-fat diet (HFD) causes gut microbiota imbalance and colon tissue damage, resulting in increased intestinal permeability, which is one of the main reasons for the existence of constantly circulating low-grade inflammatory cytokines. Pomegranate extracts have been shown to protect from HFD-induced metabolic inflammation (e.g., colitis) and to promote the growth of beneficial bacteria in in vitro stool cultures. However, whether the beneficial effects of pomegranate extracts on the HFD-induced metabolic inflammation are achieved by acting on intestinal tissues has not yet been studied. In our present study, we found that pomegranate peel polyphenols (PPPs) alleviated HFD-induced obesity, elevated circulating pro-inflammatory cytokines, colonic tissue damage, and depressed colonic tight junction protein expression level in rats. Moreover, PPPs normalized the HFD-induced gut microbiota imbalance by increasing the abundance of beneficial bacteria in the colon. Furthermore, we also found that PPPs, punicalagin, and urolithin A (the main microbiota metabolites of pomegranate ellagitannins) all increased the LPS-induced decreased tight junction protein expression level and reversed the LPS-induced inflammatory response in Caco-2 cells. Urolithin A exhibited the best effects among the three pomegranate components. Our results suggested that the protective effects of PPPs in HFD-induced metabolic inflammation can be due to the recovery of colonic tissue damage and the regulation of gut microbiota and that urolithin A is the major component that contributes to the in vivo effects of PPPs.
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The Crosstalk between Gut Microbiota and Nervous System: A Bidirectional Interaction between Microorganisms and Metabolome.
Several studies have shown that the gut microbiota influences behavior and, in turn, changes in the immune system associated with symptoms of depression or anxiety disorder may be mirrored by corresponding changes in the gut microbiota. Although the composition/function of the intestinal microbiota appears to affect the central nervous system (CNS) activities through multiple mechanisms, accurate epidemiological evidence that clearly explains the connection between the CNS pathology and the intestinal dysbiosis is not yet available. The enteric nervous system (ENS) is a separate branch of the autonomic nervous system (ANS) and the largest part of the peripheral nervous system (PNS). It is composed of a vast and complex network of neurons which communicate via several neuromodulators and neurotransmitters, like those found in the CNS. Interestingly, despite its tight connections to both the PNS and ANS, the ENS is also capable of some independent activities. This concept, together with the suggested role played by intestinal microorganisms and the metabolome in the onset and progression of CNS neurological (neurodegenerative, autoimmune) and psychopathological (depression, anxiety disorders, autism) diseases, explains the large number of investigations exploring the functional role and the physiopathological implications of the gut microbiota/brain axis.
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Dietary supplementation with Lactobacillus rhamnosus JB-1 restores brain neurochemical balance and mitigates the progression of mood disorder in a rat model of chronic unpredictable mild stress.
Major depressive disorder is a stress-related disease associated with brain metabolic dysregulation in the glutamine-glutamate/γ-aminobutyric acid (Gln-Glu/GABA) cycle. Recent studies have demonstrated that microbiome-gut-brain interactions have the potential to influence mental health. The hypothesis of this study was that Lactobacillus rhamnosus JB-1 (LR-JB1™) dietary supplementation has a positive impact on neuro-metabolism which can be quantified in vivo using magnetic resonance spectroscopy (MRS). A rat model of depressive-like disorder, chronic unpredictable mild stress (CUMS), was used. Baseline comparisons of MRS and behavior were obtained in a control group and in a stressed group subjected to CUMS. Of the 22 metabolites measured using MRS, stressed rats had significantly lower concentrations of GABA, glutamate, glutamine + glutathione, glutamate + glutamine, total creatine, and total N-acetylaspartate (tNAA). Stressed rats were then separated into 2 groups and supplemented with either LR-JB1™ or placebo and re-evaluated after 4 weeks of continued CUMS. The LR-JB1™ microbiotic diet restored these metabolites to levels previously observed in controls, while the placebo diet resulted in further significant decrease of glutamate, total choline, and tNAA. LR-JB1™ treated animals also exhibited calmer and more relaxed behavior, as compared with placebo treated animals. In summary, significant cerebral biochemical downregulation of major brain metabolites following prolonged stress were measured in vivo using MRS, and these decreases were reversed using a microbiotic dietary supplement of LR-JB1™, even in the presence of continued stress, which also resulted in a reduction of stress-induced behavior in a rat model of depressive-like disorder.
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Copper and chlorpyrifos stress affect the gut microbiota of chironomid larvae (Propsilocerus akamusi).
Chironomids are characterized by their ubiquitous distribution, global diversity and tolerant ability to deal with environmental stressors. To our knowledge, this is the first study presenting the gut microbial structure of chironomid larvae and examining the microbial alteration induced by invading chlorpyrifos and copper with different dosages. Lethal bioassay displayed a significantly decreased percentage survival of Propsilocerus akamusi larvae exposed to 800 mg/L copper and 50 μg/L chlorpyrifos at 96 h. Larvae with deficient gut microbiota exhibited a depressed level of glutathione S-transferase activity after stressful exposure. The high-throughput 16S rRNA gene sequencing was adopted to investigate the community structure and it turned out that both copper and chlorpyrifos were able to generate distinguished variations of gut microbiota in the stressor-specific and concentration-dependent manner. Of note, the relative abundance of Comamonas, Stenotrophomonas, and Yersinia remarkably elevated in the presence of copper while chlorpyrifos exposure upregulated the prevalence of certain genera (e.g. Serratia). Flavobacterium was greatly attenuated in chlorpyrifos group with lethal dosage exhibiting more severe impacts. The predicted gene functions of the gut commensals differed between normal samples and those subjected to distinct toxins. Besides, more positive associations and limited modularity of microbial interactions were observed in stressor-challenged larvae, presenting a network with impaired complexity and stability. The appearance of either copper or chlorpyrifos exhibited strong positive correlations with genera belonging to Proteobacteria and Firmicutes. Collectively, this investigation introduces a general outline of gut microbiota obtained from chironomid individuals with latent adaptive tactics to nocuous factors (heavy metal and pesticide), which could build a fundamental basis for us to further explore the protective roles of chironomid gut bacterial colonizers in defending against aquatic contaminants.
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Fecal microbiota transplantation fails to impart the benefits of circadian-dependent intermittent fasting following ischemic stroke.
Intermittent fasting (IF) is known to induce significant ischemic tolerance. Diet is a major proponent of gut microbiota, and gut microbial dysbiosis plays a role in post-stroke brain damage. Hence, we currently evaluated whether IF-mediated ischemic tolerance is mediated by gut microbiota. Additionally, circadian cycle is known to modulate post-ischemic outcomes, and thus we further evaluated if gut microbiota would be influenced by prophylactic IF during the inactive phase (fasting during daytime; IIF) or active phase (fasting during nighttime; AIF). The AIF, but not IIF, cohort showed a significantly decreased fecal Firmicutes/Bacteroidetes ratio compared with the ad libitum (AL) cohort. Moreover, the levels of gut microbiota-derived metabolites butyrate and propionate decreased in AL cohort following focal ischemia, whereas they increased in AIF cohort. However, fecal microbiota transplantation (FMT) from IIF or AIF cohort had no significant effects on post-ischemic motor and cognitive function recovery, anxiety-, and depression-like behaviors compared with FMT from AL cohort. Furthermore, FMT from IIF or AIF cohort did not influence the post-ischemic infarct volume, atrophy volume or white matter damage. Overall, the current findings indicate that the beneficial effects of IF after focal ischemia are not mediated by the gut microbiota.
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Abnormalities in microbiota/butyrate/FFAR3 signaling in aging gut impair brain function.
Aging-related abnormalities in gut microbiota are associated with cognitive decline, depression, and anxiety, but underlying mechanisms remain unstudied. Here, our study demonstrated that transplanting old gut microbiota to young mice induced inflammation in the gut and brain coupled with cognitive decline, depression, and anxiety. We observed diminished mucin formation and increased gut permeability ("leaky gut") with a reduction in beneficial metabolites like butyrate because of decline in butyrate-producing bacteria in the aged gut microbiota. This led to suppressed expression of butyrate receptors, free fatty acid receptors 2 and 3 (FFAR2/3). Administering butyrate alleviated inflammation, restored mucin expression and gut barriers, and corrected brain dysfunction. Furthermore, young mice with intestine-specific loss of FFAR2/3 exhibited gut and brain abnormalities akin to those in older mice. Our results demonstrate that reduced butyrate-producing bacteria in aged gut microbiota result in low butyrate levels and reduced FFAR2/3 signaling, leading to suppressed mucin formation that increases gut permeability, inflammation, and brain abnormalities. These findings underscore the significance of butyrate-FFAR2/3 agonism as a potential strategy to mitigate aged gut microbiota-induced detrimental effects on gut and brain health in older adults.
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Alterations of kynurenine pathway in alcohol use disorder and abstinence: a link with gut microbiota, peripheral inflammation and psychological symptoms.
The gut-brain communication is mostly driven by the immune, metabolic and neural pathways which remained poorly explored in patients with alcohol use disorder (AUD). The metabolites arising from the tryptophan-kynurenine pathway have gained considerable attention since they are at the interface between intestinal bacteria, host immune response and brain functions. This study described the circulating levels of kynurenine metabolites in AUD patients, at the onset (T1) and end (T2) of a 3-week detoxification program, and tested correlations between those metabolites and inflammatory markers, the gut microbiota and the psychological symptoms. Increased concentration of the neurotoxic metabolite quinolinic acid (QUIN) and decreased levels of the neuroprotector metabolite kynurenic acid (KYNA) which both modulate glutamatergic neurotransmission were observed in AUD patients, particularly at T2. The inflammatory marker hsCRP was associated with several metabolic ratios of the kynurenine pathway. Tryptophan, KYNA and QUIN were correlated with depression, alcohol craving and reaction time, respectively. Analysis of gut microbiota revealed that bacteria known as short-chain fatty acid producers, as well as bacterial metabolites including butyrate and medium-chain fatty acids were associated with some metabolites of the tryptophan-kynurenine pathway. Targeting the glutamatergic neurotransmission through the modulation of the kynurenine pathway, by manipulating the gut microbiota, might represent an interesting alternative for modulating alcohol-related behavior.
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Intervening Mechanisms of Amitriptyline Combined With Domperidone on Functional Dyspepsia Rats.
OBJECTIVES: The long-term recurrent symptoms of functional dyspepsia (FD) and the prolonged course of the disease lead to varying degrees of psychological disorders in patients. The study focuses on investigating the effects of the psychological drug amitriptyline on FD rats, aiming to provide a basis for the mechanism of action in treating FD from a clinical psychological perspective. METHODS: A rat model of FD was used to assess gastric emptying, intestinal propulsion, visceral sensitivity, and behavioral states after treatment with amitriptyline, domperidone, or both drugs. The concentrations of 5-hydroxytryptamine (5-HT) and the expression of related signaling molecules were measured using ELISA, RT-qPCR, and Western blot. Gastrointestinal motility was also evaluated through muscle perfusion experiments, and the composition of gut microbiota was analyzed using 16S rRNA sequencing. RESULTS: Amitriptyline, either alone or combined with domperidone, improved FD rat behavioral scores, food intake, and mental status in FD rats. It increased 5-HT concentrations in plasma and gastrointestinal tissue, decreased visceral sensitivity, and altered the expressions of 5-HT2B receptor, phospholipase C-β2, IP3 receptor, and calcium-activated chloride channel anoctamin 1 (ANO1) in the gastrointestinal tissues. Although amitriptyline had no significant effect on in vivo gastric or intestinal transit rates, it significantly inhibited the contractile activity of isolated gastrointestinal muscle strips and exhibited anticholinergic effects. Additionally, amitriptyline either alone or combined with domperidone increased the relative abundance of Actinomycetota and specifically the Eggerthellales order in the gut microbiota. CONCLUSIONS: The combination of amitriptyline and domperidone relieves anxiety and depression, improves gastrointestinal motility by targeting the 5-HT2BR, PLCβ2, and IP3R signaling pathways, and modulates the gut microbiota. This integrated approach alleviates FD symptoms through multiple mechanisms and pathways, presenting a promising therapeutic strategy.