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Safety and efficacy of Lacticaseibacillus rhamnosus LRa05, Limosilactobacillus reuteri LR08, and Lactobacillus crispatus LCr86 on hormone metabolism, body composition, and emotional regulation in overweight women: a randomized, double - blind, placebo - controlled trial.
BACKGROUND: Female obesity is linked to dysfunction of the endocrine-metabolic-gut-brain axis. Probiotics may offer therapeutic benefits, but robust evidence is limited. AIM: To investigate the effects of a 12-week multi-strain probiotic intervention on endocrine, metabolic, psychological parameters, and gut microbiota in obese women. METHODS: In a randomized, double-blind, placebo-controlled trial, 102 obese women received daily probiotics (Lacticaseibacillus rhamnosus LRa05, Limosilactobacillus reuteri LR08, and Lactobacillus crispatus LCr86) or placebo for 12 weeks. Hormones, anthropometric measures, psychological scores, and gut microbiota were assessed at baseline and endpoint. RESULTS: Probiotics selectively modulated the endocrine-metabolic axis. Compared to placebo, prolactin, adrenocorticotropic hormone, and leptin decreased, while glucagon-like peptide-1 and peptide YY increased (P < 0.05). With the probiotics group, body weight, BMI, waist and hip circumference, and body fat percentage declined significantly from baseline (P < 0.05). Anxiety and depression scores improved markedly (P < 0.001). Gut microbiota showed increased Faecalibacterium and decreased Collinsella abundance (P < 0.05). CONCLUSION: A 12-week multi-strain probiotic intervention was associated with improvements in body composition and emotional status, as well as favorable changes in appetite- and stress-related hormonal profiles and gut microbial composition in women with obesity. Clinical Trial Registration: NCT07013409 (ClinicalTrials.gov).
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Gut microbiota modulation by prednisolone in a rat kindling model of pentylenetetrazol (PTZ)-induced seizure.
The gut microbiota is a complex community composed by several microorganisms that interact in the maintenance of homeostasis and contribute to physiological processes, including brain function. The relationship of the taxonomic composition of the gut microbiota with neurological diseases such as autism, Parkinson's, Alzheimer's, anxiety, and depression is widely recognized. The immune system is an important intermediary between the gut microbiota and the central nervous system, being one of the communication routes of the gut-brain axis. Although the complexity of the relationship between inflammation and epilepsy has not yet been elucidated, inflammatory processes are similar in many ways to the consequences of dysbiosis and contribute to disease progression. This study aimed to analyze the taxonomic composition of the gut microbiota of rats treated with prednisolone in a kindling model of epilepsy. Male Wistar rats (90 days, n = 24) divided into four experimental groups: sodium chloride solution 0.9 g%, diazepam 2 mg/kg, prednisolone 1 mg/kg, and prednisolone 5 mg/kg administered intraperitoneally (i.p.) for 14 days. The kindling model was induced by pentylenetetrazole (PTZ) 25 mg/kg i.p. on alternate days. The taxonomic profile was established by applying metagenomic DNA sequencing. There was no change in alpha diversity, and the composition of the gut microbiota between prednisolone and diazepam was similar. The significant increase in Verrucomicrobia, Saccharibacteria, and Actinobacteria may be related to the protective activity against seizures and inflammatory processes that cause some cases of epilepsy. Further studies are needed to investigate the functional influence that these species have on epilepsy and the inflammatory processes that trigger it.
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Fecal microbiota transplantation from patients into animals to establish human microbiota-associated animal models: a scoping review.
BACKGROUND: Fecal microbiota transplantation (FMT) from humans with specific medical conditions to animal models can demonstrate causality by inducing or exacerbating pathophenotypes, linking the gut microbiota to health outcomes. METHODS: We conducted a scoping review searching MEDLINE, EMBASE, Scopus, and Web of Science through July 2024 to identify human noninfectious diseases studied using FMT in animal models, investigate FMT methodologies, and assess the feasibility of systematic reviews on the role of the microbiota in specific diseases. RESULTS: From 605 reports of 489 studies, we found that inflammatory bowel diseases, irritable bowel syndrome, obesity, colorectal cancer, and depression were the most commonly studied, with cancer research focusing on immunotherapy non-responsiveness. In a random sample of studies, gastrointestinal outcomes were most frequently reported, with remarkably high rates (> 80%) of successful induction of disease-specific alterations for intestinal barrier function, gastrointestinal inflammation, circulating immune parameters, and fecal metabolites. Most studies used C57BL/6 mice and oral gavage administration, with recipients being either germ-free or antibiotic-pretreated. We created tables linking conditions with publications to facilitate future systematic reviews. CONCLUSIONS: Although human-to-animal FMT studies cover diverse conditions, methodological heterogeneity and inconsistent reporting hinder comparability. Standardized protocols and guidelines are needed. For several conditions, sufficient literature exists to assess the role of the gut microbiota in human health through systematic reviews.
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The effects of chronic unpredicted mild stress on maternal negative emotions and gut microbiota and metabolites in pregnant rats.
BACKGROUND: Chronic long-term stress is associated with a range of disorders, including depression and a variety of other chronic illnesses. It is well known that maternal exposure to psychosocial stress during pregnancy significantly increases the likelihood of adverse pregnancy outcomes. The gut microbiota has been a popular topic, it is a key mediator of the gut-brain axis and plays an important role in human health; changes in the gut microbiota have been related to chronic stress-induced health impairment, however, the relationship between maternal negative emotions and abnormal gut microbiota and its metabolites during maternal exposure to chronic stress during pregnancy remains unclear. METHODS: Pregnant rats were subjected to chronic unpredicted mild stress (CUMS) to establish the rat model of chronic stress during pregnancy. The behavioral changes were recorded using sucrose preference test (SPT) and open-field test (OFT), plasma corticosterone levels were determined by radioimmunoassay, and a comprehensive method combining 16S rRNA gene sequencing and gas chromatography-mass spectrometry (GC-MS) metabolomics was used to study the effects of stress during pregnancy on the function of intestinal microbiota and its metabolites. RESULTS: Chronic stress during pregnancy not only increased maternal plasma corticosterone (P < 0.05), but also caused maternal depression-like behaviors (P < 0.05). Chronic stress during pregnancy changed the species composition at the family level of maternal gut microbiota, the species abundance of Ruminococcaceae in the stress group (23.45%) was lower than the control group (32.67%) and the species abundance of Prevotellaceae in the stress group (10.45%) was higher than the control group (0.03%) (P < 0.05). Vertical locomotion and 1% sucrose preference percentage in pregnant rats were negatively correlated with Prevotellaceae (r = - 0.90, P < 0.05). Principal component analysis with partial least squares discriminant analysis showed that the integration points of metabolic components in the stress and control groups were completely separated, indicating that there were significant differences in the metabolic patterns of the two groups, and there were seven endogenous metabolites that differed (P < 0.05). CONCLUSIONS: The negative emotional behaviors that occur in pregnant rats as a result of prenatal chronic stress may be associated with alterations in the gut microbiota and its metabolites. These findings provide a basis for future targeted metabolomics and gut flora studies on the effects of chronic stress during pregnancy on gut flora.
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Pharmacometabolomics: implications for clinical pharmacology and systems pharmacology.
Metabolomics, the study of metabolism at an "omic" level, has the potential to transform our understanding of mechanisms of drug action and the molecular basis for variation in drug response. It is now possible to define metabolic signatures of drug exposure that can identify pathways involved in both drug efficacy and adverse drug reactions. In addition, the "metabotype," the metabolic "signature" of a patient, is a unique identity that contains information about drug response and disease heterogeneity. The application of metabolomics for the study of drug effects and variation in drug response is creating "pharmacometabolomics," a discipline that will contribute to personalized drug therapy and will complement pharmacogenomics by capturing environmental and microbiome-level influences on response to drug therapy. This field has the potential to transform pharmacology and clinical pharmacology in significant ways and will contribute to efforts for personalized therapy. This overview highlights developments in the new discipline of pharmacometabolomics.
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Neurobehavioral dysfunction in non-alcoholic steatohepatitis is associated with hyperammonemia, gut dysbiosis, and metabolic and functional brain regional deficits.
Non-alcoholic steatohepatitis (NASH) is one of the most prevalent diseases worldwide. While it has been suggested to cause nervous impairment, its neurophysiological basis remains unknown. Therefore, the aim of this study is to unravel the effects of NASH, through the interrelationship of liver, gut microbiota, and nervous system, on the brain and human behavior. To this end, 40 Sprague-Dawley rats were divided into a control group that received normal chow and a NASH group that received a high-fat, high-cholesterol diet. Our results show that 14 weeks of the high-fat, high-cholesterol diet induced clinical conditions such as NASH, including steatosis and increased levels of ammonia. Rats in the NASH group also demonstrated evidence of gut dysbiosis and decreased levels of short-chain fatty acids in the gut. This may explain the deficits in cognitive ability observed in the NASH group, including their depressive-like behavior and short-term memory impairment characterized in part by deficits in social recognition and prefrontal cortex-dependent spatial working memory. We also reported the impact of this NASH-like condition on metabolic and functional processes. Brain tissue demonstrated lower levels of metabolic brain activity in the prefrontal cortex, thalamus, hippocampus, amygdala, and mammillary bodies, accompanied by a decrease in dopamine levels in the prefrontal cortex and cerebellum and a decrease in noradrenalin in the striatum. In this article, we emphasize the important role of ammonia and gut-derived bacterial toxins in liver-gut-brain neurodegeneration and discuss the metabolic and functional brain regional deficits and behavioral impairments in NASH.
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Purple sweet potato anthocyanin extract regulates redox state related to gut microbiota homeostasis in obese mice.
This study explored the advantageous effects of purple sweet potato anthocyanin extract (PSPAE) on redox state in obese mice. The normal chow diet (NCD) group, high-fat/cholesterol diet (HCD) group, and three groups based on HCD and added with low, middle, and high dose of PSPAE (PAL, PAM, and PAH) were raised for 12 weeks. High dose of PSPAE treatment decreased the elevations of the body weight by 24.7%, serum total cholesterol by 48.3%, serum triglyceride by 42.4%, and elevated serum activities of glutathione peroxidase by 53.3%, superoxide dismutase by 57.8%, catalase by 75.4%, decreased serum contents of malondialdehyde by 27.1% and lipopolysaccharides by 40.5%, as well as increased caecal total short-chain fatty acid by 2.05-fold. Additionally, PSPAE depressed toll-like receptor 4 (TLR-4), nuclear factor kappa-B (NF-κB), interleukin 6, tumor necrosis factor α, and preserved nuclear factor erythroid-2-related factor 2 (Nrf2) gene expression. Similarly, the protein expression of Nrf2 was enhanced, while TLR-4 and p-NF-κB/NF-κB were depressed by PSPAE treatment. Moreover, PSPAE administration promoted the protection of intestinal barrier function and rebuilt gut microbiota homeostasis by blooming g_Akkermansia, g_Bifidobacterium, and g_Lactobacillus. Furthermore, antibiotic interference experiments showed that the gut microbiota was indispensable for preserving the redox state of PSPAE. These results suggested that PSPAE administration could be an opportunity for improving HCD-induced obesity and the redox state related to gut dysbiosis. PRACTICAL APPLICATION: Purple sweet potato anthocyanin has diverse pharmacological properties. It is applicable for individuals to consume extracts (as pills or other forms) from raw purple sweet potato if they want to improve obesity or redox state.
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Akkermansia muciniphila Improves Depressive-Like Symptoms by Modulating the Level of 5-HT Neurotransmitters in the Gut and Brain of Mice.
Accumulating evidence has suggested that the gut microbiome plays an important role in depression. Akkermansia muciniphila (AKK), a next-generation probiotic, shows a beneficial effect on immune and metabolic homeostasis. The relative abundance of AKK was found negatively correlated with depressive symptoms in both clinical and pre-clinical studies. To evaluate the potential antidepressant effect of AKK and explore the possible mechanism, we used chronic alcohol exposure and chronic unpredictable mild stress (CUMS) to induce depressive-like behaviors in mice. We found that oral AKK administration significantly reduced the immobility time in the force swimming test (FST) and tail suspension test (TST) in the mice with chronic alcohol exposure and the CUMS mice. The sucrose preference in the mice receiving AKK was significantly increased in the sucrose preference test (SPT). More importantly, AKK implantation significantly increased the level of 5-HT in the gut and PFC of both the alcohol exposure mice and the CUMS mice. Furthermore, AKK had inhibited the expression of SERT in the gut but not in the brain for both NIAAA and the CUMS model mice. Interestingly, the expression of cFos in enteric nerves in the gut significantly decreased after AKK administration. In conclusion, our study demonstrated the antidepressant effect of AKK in mice exposed to alcohol exposure and CUMS, with the potential mechanism that AKK implantation might lead to an increased level of 5-HT and inhibited SERT expression in the gut, and might alter the gut-to-brain signal through suppression of enteric nerves activation.
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Ready-to-use blueberry extract modulates the hypothalamic-pituitary-adrenal axis and alleviates post-stress anxiety linked to antibiotic-induced gut dysbiosis.
This study investigated, for the first time, the effects of crude blueberry extracts obtained using natural deep eutectic solvent (CE-NADES) or a conventional organic solvent (CE-SORG) on anxiety- and depression-related parameters in a rat model of intestinal dysbiosis induced by antibiotics. CE-NADES is a ready-to-use extract that does not require solvent removal prior to administration, while CE-SORG was reconstituted in water after solvent removal. Oral administration of blueberry extracts (10 mg of phenolic compounds/kg b.w./day) for 11 days showed that CE-NADES significantly reduced plasma adrenocorticotropic hormone (13.2% vs. control dysbiosis; p < 0.01) and corticosterone (22.5% vs. control dysbiosis; p < 0.0001) levels, and attenuated anxiety-like behavior after acute restraint stress in the elevated plus maze test (85.1% increased time in open arms and 10.4% decreased anxiety index vs. control dysbiosis; p < 0.005). In contrast, CE-SORG reduced only corticosterone levels (15% vs. control dysbiosis; p < 0.0001) and did not produce an anxiolytic behavioral effect. These results indicate that while both extracts modulated the hypothalamic-pituitary-adrenal (HPA) axis, CE-NADES was more effective than CE-SORG. Only CE-NADES mitigated post-stress anxiety associated with antibiotic-induced gut dysbiosis, supporting an anxiolytic effect for this ready-to-use extract. NADES solvent/delivery system was a key determinant of the anxiolytic efficacy of blueberry extract, associated with HPA axis modulation at both the pituitary and adrenal levels.
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Maternal pre- and postnatal stress and maternal and infant gut microbiota features.
BACKGROUND: Maternal stress can have short and long term adverse (mental) health effects for the mother and her child. Previous evidence suggests that the gut microbiota may be a potential mediator and moderator for the effects of stress via various pathways. This study explored the maternal microbiota trajectory during pregnancy as well as the association between pre- and postnatal maternal stress and features of the maternal and infant gut microbiota during and after pregnancy. In line with previous research, we hypothesized that maternal stress would be positively related to maternal and infant microbiota volatility and that infants of highly stressed mothers would show a relative increase in Proteobacteria and a relative decrease in Bifidobacterium. METHODS: We collected maternal stool samples at 18 and 32 weeks of pregnancy and 8 months postpartum. Infant stools samples were obtained at 2, 6 and 12 weeks and 8 months postpartum. All samples were analyzed using shotgun metagenome sequencing. We also collected several measures of maternal stress (self-reported depression, anxiety, and stress, and hair cortisol and cortisone), most at the same time points as the microbiota samples. RESULTS: Our data indicated that the maternal microbiota does not undergo drastic changes from the second to the third trimester of pregnancy but that the postpartum microbiota differs significantly from the prenatal microbiota. Furthermore, we identified associations between several stress measures and maternal and infant gut microbiota features at different time points including positive and negative associations with alpha diversity, beta diversity and individual microbial phyla and species relative abundances. Also, the maternal stress composite score, the perceived stress score and the log-ratio of hair cortisol and cortisone were all positively associated with infant microbiota volatility. CONCLUSION: Our study provides evidence that maternal prenatal and postnatal stress is related to both the maternal and the infant microbiota. Collectively, this and previous studies indicate that maternal stress does not uniformly associate with most gut microbial features. Instead, the associations are highly time point specific. Regarding infant microbiota volatility, we have consistently found a positive association between stress and infant microbiota volatility. This warrants future research investigating this link in more depth.