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Circadian rhythms, gut microbiota, and diet: Possible implications for health.
AIMS: Over the past years, interest in chrono-nutrition has grown enormously as the fundamental role of circadian rhythms in regulating most physiological and metabolic processes has become clearer. Recently, the influence of circadian rhythms on the gut microbiota (GM) composition has also emerged, as more than half of the total microbial composition fluctuates rhythmically throughout the day. At the same time, other studies have observed that the GM itself synchronises the host's circadian biological clock through signals of a different nature. Therefore, it has been hypothesised that there is a two-way communication between the circadian rhythms of the host and the GM, but researchers have only just begun to identify some of its action mechanisms. The manuscript aim is, therefore, to gather and combine the latest evidence in the field of chrono-nutrition with the more recent research on the GM, in order to investigate their relationship and their potential impact on human health. DATA SYNTHESIS: Considering current evidence, a desynchronization of circadian rhythms is closely associated with an alteration in the abundance and functionality of the gut microbiota with consequent deleterious effects on health, such as increased risk of numerous pathologies, including cardiovascular disease, cancer, irritable bowel disease, and depression. A key role in maintaining the balance between circadian rhythms and GM seems to be attributed to meal-timing and diet quality, as well as to certain microbial metabolites, in particular short-chain fatty acids. CONCLUSIONS: Future studies are needed to decipher the link between the circadian rhythms and specific microbial patterns in relation to different disease frameworks.
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Extracellular Vesicles from Gram-positive and Gram-negative Probiotics Remediate Stress-Induced Depressive Behavior in Mice.
Chronic stress causes maladaptive changes in the brain that lead to depressive behavior. In the present study, we investigate whether chronic stress alters gut microbiota compositions that are related to stress-induced maladaptive changes in the brain. Mice treated with daily 2-h restraint for 14 days (CRST) exhibit depressive-like behavior. Sequence readings of 16S rRNA genes prepared from fecal samples taken from CRST-treated mice suggest that chronic stress induces gut microbiota changes that are pronounced in the post-stress period, relative to those that occur in the 14-day stress phase. The genus Lactobacillus is one such microbiota substantially changed following chronic stress. In contrast, intraperitoneal injection of extracellular vesicles (EVs) isolated from culture media of the Gram-positive probiotic Lactobacillus plantarum is sufficient to ameliorate stress-induced depressive-like behavior. Interestingly, EVs from the Gram-positive probiotic Bacillus subtilis and EVs from the Gram-negative probiotic Akkermansia muciniphila also produce anti-depressive-like effects. While chronic stress decreases the expression of MeCP2, Sirt1, and/or neurotrophic factors in the hippocampus, EVs from the three selected probiotics differentially restore stress-induced changes of these factors. These results suggest that chronic stress produces persistent changes in gut microbiota composition, whereas purified EVs of certain probiotics can be used for treatment of stress-induced depressive-like behavior.
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Longitudinal Influence of Prescribed Antidepressants on Fecal and Oral Microbiomes Among Veterans With Major Depressive Disorder.
OBJECTIVE: The purpose of this study was to evaluate the influence of a new course of antidepressant monotherapy on gut and oral microbiomes and the relationship to depressive symptoms. METHODS: Longitudinal microbiome samples obtained from 10 U.S. veterans were analyzed. Baseline samples were taken before a new course of antidepressant monotherapy (either switching from a previous treatment or starting a new treatment). Targeted genomic sequencing of the microbiome samples was used to analyze changes in taxonomy and diversity across participants, medications, and medication class. Associations between these changes and Patient Health Questionnaire-9 (PHQ-9) scores were analyzed. RESULTS: Taxonomic variability was observed across participants, with the individual being the main microbial community driver. In terms of the fecal microbiome, antidepressants were associated with shifts toward Bacteroides being less abundant and Blautia, Pseudomonas, or Faecalibacterium being more abundant. Likewise, the composition of the oral microbiome was variable, with individual participants being the primary drivers of community composition. In the oral samples, the relative abundance of Haemophilus decreased after antidepressants were started. Increases in Blautia and decreases in Bacteroides were associated with lower PHQ-9 scores. CONCLUSIONS: Antidepressants were found to influence fecal and oral microbiomes such that a new course of antidepressant monotherapy was associated with taxonomic alterations toward healthier states in both fecal and oral microbiomes, which were associated with decreases in depressive symptoms. Additional longitudinal research is required to increase understanding of microbiomes and symptom-based changes, with a particular focus on potential differences between medication classes and underlying mechanisms.
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Feasibility, Acceptability, and Safety of Faecal Microbiota Transplantation in the Treatment of Major Depressive Disorder: A Pilot Randomized Controlled Trial.
OBJECTIVES: Perturbations of the intestinal microbiota have been associated with mental health disorders, including major depressive disorder (MDD). Therefore, faecal microbiota transplantation (FMT) holds promise as a microbiota-modulating treatment for MDD. Yet, to date, there are no published controlled studies evaluating the use of FMT for MDD. This study aimed to address this gap by evaluating the feasibility, acceptability, and safety of FMT for MDD. METHODS: The study was an 8-week, double-blind, 2:1 parallel group, randomized controlled pilot trial (n = 15) of enema-delivered FMT (n = 10) compared with a placebo enema (n = 5) in adults with moderate-to-severe MDD. RESULTS: Recruitment was completed within 2 months, with 0% attrition and 100% attendance at key study appointments. There were no major protocol deviations. The placebo and blinding strategies were considered successful; nurses and participants correctly guessing their treatment allocation at a rate similar to that anticipated by chance. No serious or severe adverse events were reported in either group, and there were no significant differences in mild-to-moderate adverse events between groups (median of 2 adverse events per participant reported in both groups). Furthermore, the 12/15 participants who completed the Week 2 participant satisfaction survey agreed or strongly agreed that the enema delivery was tolerable and that they would have the treatment again if required. Whilst the study was not designed to measure clinical outcomes, exploratory data also suggested that the active FMT treatment may lead to improvements in gastrointestinal symptoms and quality of life in this population, noting that irritable bowel syndrome is commonly comorbid with MDD. CONCLUSIONS: All feasibility targets were met or exceeded. This study found that enema-delivered FMT is feasible, acceptable, well-tolerated, and safe in patients with MDD. The findings of this study support further research to evaluate clinical efficacy, and the use of this protocol is supported.
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Design of functional glucomannan via acetylation for targeting regulation of gut microbiota.
In this study, konjac glucomannan (KGM) was acetylated, followed by the investigation of its corresponding structural and physicochemical properties. Spectroscopic analyses, including FTIR and NMR, confirmed the introduction of acetyl groups. Rheological measurements found a decrease in both viscosity and gel strength of the acetylated KGM (AKGM), attributing to weaker intermolecular interactions. The current study also revealed that the acetylation of KGM led to reduced gut microbiota fermentation kinetics, followed by a lower short-chain fatty acids (SCFAs) generation, which may be due to the stearic hindrance raised from the introduction of acetyl groups onto its macromolecules. Interesting, although both two types of polysaccharides (before and after acetylation) improved gut microbiota profile in term of enriched probiotics profile, AKGM even generated a lower ratio of Firmicutes/Bacteroidota compared to that of KGM, which was negatively correlated with the degree of acetylation of KGM. Importantly, this was the first time to reveal that Prevotella_9 was selectively promoted in AKGM, followed by a greatly depressed growth of pathogens, such as Escherichia-Shigella compared to KGM. Nevertheless, this study demonstrated that the change in the molecular structure of the polysaccharides targets the promotion of specific bacteria, which may highlight their potent application for individual healthy intervention.
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The intestinal barrier in disorders of the central nervous system.
The intestinal barrier, which primarily consists of a mucus layer, an epithelial barrier, and a gut vascular barrier, has a crucial role in health and disease by facilitating nutrient absorption and preventing the entry of pathogens. The intestinal barrier is in close contact with gut microbiota on its luminal side and with enteric neurons and glial cells on its tissue side. Mounting evidence now suggests that the intestinal barrier is compromised not only in digestive disorders, but also in disorders of the central nervous system (CNS), such as Parkinson's disease, autism spectrum disorder, depression, multiple sclerosis, and Alzheimer's disease. After providing an overview of the structure and functions of the intestinal barrier, we review existing preclinical and clinical studies supporting the notion that intestinal barrier dysfunction is present in neurological, neurodevelopmental, and psychiatric disorders. On the basis of this evidence, we discuss the mechanisms that possibly link gut barrier dysfunction and CNS disorders and the potential impact that evaluating enteric barriers in brain disorders could have on clinical practice, in terms of novel diagnostic and therapeutic strategies, in the near future.
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Modulating stress responses via the microbiota-gut-brain axis: a pathway-focused review of GABA, 5-HT, and kynurenine metabolites.
Stress is a major risk factor for human anxiety, depression, and other neuropsychiatric disorders, yet nutritional strategies that target upstream biological mechanisms remain insufficiently developed. Growing evidence indicates that host-microbiota co-regulated metabolites act as functional mediators within the microbiota-gut-brain axis, shaping individual vulnerability or resilience to stress. In this review, we synthesize current preclinical and human evidence with a focus on three metabolite systems of high mechanistic relevance-γ-aminobutyric acid, serotonin, and kynurenine-pathway metabolites. We discuss how microbial activity, host metabolism, and dietary inputs interact to modulate brain-relevant signaling under stress. We highlight neuroendocrine, neuroimmune, and neural pathways through which these systems may act, including stress-induced disruptions in intestinal and blood-brain barrier integrity and amplification of inflammatory signaling. Evidence across models suggests that stress-associated dysbiosis alters GABAergic and serotonergic signaling and shifts tryptophan metabolism toward neuroactive kynurenines, thereby biasing neural excitability, synaptic plasticity, and affect-related behaviors. We further evaluate food-based psychobiotic strategies-such as targeted whole-food matrices, fermented foods, and selected probiotic strains-that can reprogram microbial metabolism to restore neurotransmitter balance and attenuate inflammation. Finally, we propose a translational framework emphasizing strain- and pathway-specific mechanisms, standardized metabolite quantification, and biomarker-guided personalization to advance microbiome-metabolite interventions for stress-related brain dysfunction.
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Cannabis and cannabinoid-microbiome interactions in varied clinical contexts: A comprehensive systematic review.
With legalisation of cannabis for both medicinal and recreational use expanding to more world nations, grasping its effects on the human body is vital. The microbiome is critical to human health and disease, and accumulating data suggests that it is influenced by a variety of external variables, including marijuana/cannabis and cannabinoids. We therefore conducted a comprehensive assessment of the literature to analyse cannabis and cannabinoid effects on the human microbiota. We searched PubMed, Embase and Cochrane Library CENTRAL databases for studies involving the use of marijuana, medical cannabis, cannabinoids and cannabinoid-like lipid mediators on microbiota, across all clinical conditions. Nine studies were identified: 2 clinical trials and 7 observational studies examining cannabis and cannabinoid impact on oral, gastrointestinal, faecal and vaginal microbial abundance and diversity. Outcomes illustrated positive and negative impacts of cannabis use/cannabinoid actions on microbiota in adults with cognitive deficiency, depression, HIV infection, inflammation/pain, oral disease or obesity. Changes in alpha diversity were identified with cannabis/cannabinoid use, although this varied depending on the clinical context. A positive association exists between serum endocannabinoids and gut microbiota, via elevation in SCFAs and anti-inflammatory actions, beneficial for musculoskeletal pain relief and to counter obesity. Marijuana use in HIV patients showed protective effects by decreasing abundance of pro-inflammatory Prevotella, though excessive consumption leads to reduced microbiome richness and diversity, and increased systemic inflammation. Overall, this review underscores the need for further exploration in understanding the complex effects of cannabis, cannabinoids and cannabinoid-like mediators on composition and metabolic activity of the human microbiota.
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Role of Gut Microbiota in the Pathophysiology of Stress-Related Disorders: Evidence from Neuroimaging Studies.
BACKGROUND: The brain and gut communicate bidirectionally via immune, neurological, and endocrine pathways, which is termed the "brain-gut interaction." Recent studies of gut microbiota as a mediator of this interaction have provided a growing body of scientific evidence that suggests that the gut microbiota influences stress and emotional responses and stress-related disorders. SUMMARY: Major advances in analytical methods have led to an increased number of studies that combine gut microbiota and neuroimaging, mainly magnetic resonance imaging, to elucidate the mechanisms. Observational studies have been done to examine brain characteristics related to gut microbiota profiles, and intervention studies have examined brain changes related to probiotic intake. Studies of healthy subjects using negative emotional stimuli have shown that the pattern of emotional response differs depending on the gut microbiota profile and that probiotic intervention can modulate emotional response and be a buffer against the negative effects of stress. In studies on irritable bowel syndrome (IBS), a typical psychosomatic disorder, IBS-specific gut microbiota were reported to contribute to visceral irritability and pain by affecting the subcortical regions. Studies on psychiatric disorders revealed that a relative abundance of Bacteroides that produce γ-aminobutyric acid in feces was associated with a change in brain function specific to depression and that gut microbiota have an influence on abnormalities in the reward system of attention-deficit/hyperactivity disorder.
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Neuropharmacological insights into Gardenia jasminoides Ellis: Harnessing therapeutic potential for central nervous system disorders.
BACKGROUND: In China, Gardenia jasminoides Ellis (GJE) has a longstanding history of application. The Ministry of Health has listed it as one of the first pharmaceutical or food resources. In ethnic, traditional, and folk medicine, GJE has been used to treat fever and cold and relieve nervous anxiety. Recent studies have confirmed the significant efficacy of GJE for treating central nervous system (CNS) disorders, including Alzheimer's disease, Parkinson's disease, and major depressive disorder; however, GJE has not been systematically evaluated. PURPOSE: This research systematically summarizes global studies on the use of GJE for treating CNS disorders and explores the potential applications and underlying mechanisms via intestinal flora analysis and network pharmacology, aiming to establish a scientific basis for innovative CNS disorder treatment with GJE. METHODS: The PRISMA guidelines were used, and electronic databases such as the Web of Science, PubMed, and China National Knowledge Infrastructure were searched using the following search terms: "Gardenia jasminoides Ellis" with "central nervous system disease," "neuroprotection," "Alzheimer's disease," "Parkinson's disease," "ischemic stroke," "Epilepsy," and "major depressive disorder." The published literature up to September 2023 was searched to obtain relevant information on the application of GJE for treating CNS disorders. RESULTS: There has been an increase in research on the material formulation and mechanisms of action of GJE for treating CNS disorders, with marked effects on CNS disorder treatment in different countries and regions. We summarized the research results related to the role of GJE in vitro and in vivo via multitargeted interventions in response to the complex mechanisms of action of CNS disorders. CONCLUSION: We systematically reviewed the research progress on traditional treatment for GJE and preclinical mechanisms of CNS disorders and explored the potential of optimizing network pharmacology strategies and intestinal flora analysis to elucidate the mechanisms of action of GJE. The remarkable therapeutic efficacy of GJE, an important resource in traditional medicine, has been well documented in the literature, highlighting its significant medicinal potential.