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Contribution of hippocampal BDNF/CREB signaling pathway and gut microbiota to emotional behavior impairment induced by chronic unpredictable mild stress during pregnancy in rats offspring.
BACKGROUND: Numerous studies have shown that exposure to prenatal maternal stress (PMS) is associated with various psychopathological outcomes of offspring. The accumulating evidence linking bacteria in the gut and neurons in the brain (the microbiota-gut-brain axis) has been aconsensus; however, there is a lack of research on the involvement mechanism of gut microbiota in the regulation of the BDNF/CREB signaling pathway in the hippocampus of prenatally stressed offspring. METHODS: Pregnant rats were subjected to chronic unpredictable mild stress (CUMS) to establish the prenatal maternal stress model. The body weight was measured and the behavioral changes were recorded. Offspring were tested to determine emotional state using sucrose preference test (SPT), open-field test (OFT) and suspended tail test (STT). Gut microbiota was evaluated by sequencing the microbial 16S rRNA V3-V4 region, and the interactive analysis of bacterial community structure and diversity was carried out. The expression of hippocampal BDNF, TrkB and CREB mRNA and proteins were respectively measured using RT-PCR and Western blotting. RESULTS: Prenatal maternal stress increased maternal plasma corticosterone levels, slowed maternal weight gain and caused depression-like behaviors (all P < 0.05). In offspring, prenatal maternal stress increased plasma corticosterone levels (P < 0.05) and emotional behavior changes (depression-like state) were observed (P < 0.05). The species abundance, diversity and composition of the offspring's gut microbiota changed after the maternal stress during pregnancy (P < 0.05). Compared with the control group's offspring, the species abundance of Lactobacillaceae was dropped, while the abundance of the Muribaculaceae species abundance was risen. Concurrent, changes in the hippocampal structure of the offspring and decreases in expression of BDNF/CREB signaling were noted (P < 0.05). CONCLUSIONS: Prenatal maternal stress leads to high corticosterone status and abnormal emotion behavior of offspring, which may be associated with the abnormal BDNF/CREB signaling in hippocampus of offspring caused by the change of gut microbiota composition.
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Puerarin alleviates bisphenol S induced neurobehavioral impairments via remodeling the gut-brain axis and activating the BDNF/TrkB/CREB pathway.
Bisphenol S (BPS), broadly used in consumer products and food packaging, raises mounting toxicological concerns. Puerarin (PUE), a neuroprotective antioxidant from pueraria lobata, is largely uncharacterized for its efficacy in mitigating BPS-triggered neurotoxicity. This study investigates how BPS impairs the intestinal mucosal barrier, induces inflammation and gut dysbiosis to elicit neurotoxicity, and evaluates the protective effects of PUE on these gut-mediated damages. Thirty-six male mice were randomly divided into four groups (control, BPS (50 mg/kg bw), BPS + PUE(150 mg/kg bw). The Open field test and Morris water maze were adopted to evaluate learning, memory and spontaneous behaviors. H&E and PAS staining were performed to assess pathological lesions in colon and hippocampal tissues. 16S rRNA sequencing and gas chromatography were used to profile gut microbiota composition and short-chain fatty acids (SCFAs) levels, respectively. ELISA, RT-qPCR, Western blotting, and immunohistochemistry were further applied to detect the expression levels of associated molecules in intestinal and brain tissues. Behavioral testing revealed that PUE rescued BPS-induced spatial memory deficits, depressive-like behaviors and synaptic damage. PUE also alleviated gut microbial dysbiosis and restored BPS-mediated reduction of SCFAs Moreover, PUE mitigated colitis and preserved colonic mucosal integrity and tight junction proteins (ZO-1, OCLN, MUC2 and CLDN1) disrupted by BPS. BPS exposure suppressed synaptic architecture and inhibited the Brain-derived neurotrophic factor (BDNF)/tropomyosin receptor kinase B (TrkB)/cAMP response element-binding protein (CREB) signaling cascade; these adverse changes were significantly reversed by PUE supplementation. Collectively, these findings highlighted that PUE ameliorates BPS-triggered neurobehavioral dysfunction by remodeling gut microbiota and microbial metabolism via the gut-brain axis, and the BDNF/TrkB/CREB pathway participates in this neuroprotective process.
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Probiotic enhanced immunity and mental wellbeing of generally healthy women: a randomised, placebo-controlled and double-blind study.
The elucidation of the gut-brain axis underscores the critical role of probiotics in enhancing mental wellbeing through immunomodulatory mechanisms. We thus aimed to investigate the effects of a probiotic Lactiplantibacillus plantarum Probio87 (orally administered one sachet/day; 9 log cfu/sachet) or placebo for 12-weeks, on immunity and brain health, via possible mechanisms of inflammation and neurotransmitter functions in a generally healthy women population. A parallel, randomised, double-blind and placebo-controlled study was performed in generally healthy women (n = 112). Women were randomised to either the probiotic (n = 58, mean age 38.38 ± 0.85 years) or placebo (n = 54, mean age 38.91 ± 0.98 years) for 12-weeks. Immunity and mental wellbeing profiles were evaluated via questionnaires and blood gene expression profiles. Over the study period, the Probio87 group demonstrated a better impact on general women's health as compared to the control group, as measured by the Women's Health Questionnaire (WHQ), particularly in domains related to depressed mood, somatic symptoms, anxiety, sexual health, sleep, and menstrual health. The probiotic effects were exhibited later, typically after 6-weeks of intervention, taking over placebo effects that primarily faded off during early stages of the intervention. Regarding immunity, women in the Probio87 group exhibited upregulation of more immunity-related genes than those in the placebo group, primarily associated with NK cells and anti-inflammatory effects via IL-10. Additionally, Probio87 provided gut-brain axis benefits by enhancing the actions of neurotransmitters serotonin and GABA, while also balancing hunger and satiety. The probiotic Lactiplantibacillus plantarum Probio87 significantly improved general health, mood, anxiety, and sleep in a generally healthy women population over 12 weeks. It enhanced immune function through increased expression of immunity-related genes and positively modulated neurotransmitters involved in brain health. All these findings supported from our WHQ data, where the administration of probiotic improved domains related to depressed mood, anxiety, sexual behaviour and sleep problems. The study is registered at ClinicalTrials.gov under identifier number: NCT05302687.
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Inhibitory effect of the gut microbial linoleic acid metabolites, 10-oxo-trans-11-octadecenoic acid and 10-hydroxy-cis-12-octadecenoic acid, on BV-2 microglial cell activation.
10-oxo-trans-11-octadecenoic acid (KetoC) and 10-hydroxy-cis-12-octadecenoic acid (HYA) are long-chain fatty acids generated from linoleic acid by the gut lactic acid bacterium Lactobacillus plantarum. These fatty acids have been reported to have anti-inflammatory activity in the intestine. However, little is known about their effects in the brain. In this study, we aimed to investigate the effects of these fatty acids on lipopolysaccharide (LPS)-induced inflammatory processes in mouse microglial cells (BV-2 cells). KetoC and HYA inhibited LPS-induced nitric oxide (NO) production and suppressed the expression of inducible NO synthase in BV-2 cells. NO changes in these inhibitory effects were observed with AH7614, a G-protein coupled receptor 120 antagonist, or the peroxisome proliferator-activated receptors antagonists, GW6471 and GW9662. In addition, KetoC and HYA did not inhibit translocation of p65, a subunit of NF-κB, or IκB degradation. Similarly, no effect on p38 or JNK phosphorylation was observed. However, KetoC and HYA were found to inhibit ERK phosphorylation induced by LPS, suggesting that these fatty acids may exert their anti-inflammatory effects through the inhibition of ERK activation in microglial cells.
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Journey through the gut-inflammation axis in polycystic ovary syndrome: the microbiota's role in shaping inflammatory pathways.
Polycystic ovary syndrome (PCOS) is a prevalent endocrine disease in women in their reproductive phase of life. It could be characterized by irregularity in menstrual cycles, abnormal levels of androgen, and multiple cyst formations in the ovaries. It involves a complex and multifaceted pathophysiology including endocrine and metabolic irregularity, genetic and epigenetic abnormality, inflammation, and gut microbiota dysbiosis. PCOS interferes with the fertility of the patient directly due to irregular ovulation caused by hormonal imbalances. Further, this condition is also associated with increased risk for other health conditions such as type2 diabetes and cardiovascular disease, as well as psychological conditions such as anxiety and depression. Among various other factors, metabolic profiles and gut health also play a crucial role in PCOS pathogenesis. Various recent studies have reported an association of gut microbiota dysbiosis with PCOS. gut microbiota: The microbial population residing in the host organism influences our health status, and their diversity and balance are crucial to maintaining the healthy status of the body. There is growing evidence of the involvement of gut microbe dysbiosis in different diseases, including PCOS. Further inflammation is another key hallmark of PCOS. The inflammatory status of the host body depends on various factors; gut microbe dysbiosis is one such factor that can modulate the inflammatory status and thus contribute to various health conditions such as PCOS. In the present article, we have thoroughly reviewed the current status of research on the involvement of gut microbiota dysbiosis in PCOS pathogenesis and the inflammatory mechanism by which it leads to PCOS, including MCP-1/IL-2 mediated cytokine signaling, LPS-induced leaky gut inflammation, JNK/NF-KB and IKK pathways, tight junction disruption, and oxidative stress. Further, we have also discussed the factors affecting gut microbe dysbiosis and the current status of therapeutic interventions targeting gut dysbiosis in PCOS. These insights emphasize the clinical potential of targeting gut dysbiosis and associated inflammatory pathways to improve the metabolic, reproductive, and psychological outcomes in women with PCOS.
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Alcohol Addiction, Gut Microbiota, and Alcoholism Treatment: A Review.
Alcohol addiction is a leading risk factor for personal death and disability. In 2016, alcohol use caused 2.2% of female deaths and 6.8% of male deaths, and disability-adjusted life years (DALYs) were 2.3% in female and 8.9% in male. Individuals with alcohol use disorder are at high risk of anxiety, depression, impaired cognition performance, and illicit drug use and are comorbid with liver disease, such as alcoholic hepatitis and liver cirrhosis, which is a major cause of personal death and disability worldwide. Psychological interventions, such as cognitive behavior therapy and motivational interviewing, as well as medical treatments, such as disulfiram, naltrexone, acamprosate, and nalmefene, are used for the treatment of alcohol addiction in Europe and the United States. However, the effect of current interventions is limited, and the need for additional interventions is substantial. Alcohol use impairs the intestinal barrier and causes changes to the intestinal permeability as well as the gut microbiota composition. Emerging studies have tried to reveal the role of the gut-brain axis among individuals with alcohol use disorder with or without alcohol liver disease. Bacterial products penetrate the impaired intestinal barrier and cause central inflammation; changes to the gut microbiota impair enterohepatic circulation of bile acids; alcohol abuse causes shortage of vital nutrients such as thiamine. Several studies have suggested that probiotics, through either oral administration or fecal microbiota transplantation, increased intestinal levels of potentially beneficial bacteria such as bifidobacteria and lactobacilli, improving the levels of liver-associated enzymes in patients with mild alcoholic hepatitis, and demonstrating beneficial psychotropic effects on anxiety and depression. In addition to medications for alcohol addiction, gene editing therapy such as clustered regularly interspaced short palindromic repeats (CRISPRs) may be another potential research target. Alcohol dehydrogenase (ADH) and aldehyde dehydrogenase (ALDH), which are associated with ADH and ALDH genes, are major enzymes involved in alcohol metabolism, and gene editing approaches may have the potential to directly modify specific genes to treat alcoholism caused by genetic defects. Further research is needed to study the effect of the combined treatment for alcohol addiction.
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Saikosaponin D Improves Diarrhea-Predominant Irritable Bowel Syndrome by Regulating the Brain-Gut Axis: Based on Changes in the Gut HMGB1-TLR4/NF-κB Pathway and Hypothalamic HPA Axis.
BACKGROUND: Diarrhea-predominant irritable bowel syndrome (IBS-D) is characterized by diarrhea and is often accompanied by depression, abdominal symptoms, and emotional comorbidities. Preclinical and clinical studies have shown that dysfunction of the brain-gut axis is a key pathogenic factor in IBS-D, yet the specific mechanisms remain unclear. Saikosaponin D (SSD), a major bioactive component of Bupleurum chinense DC., exhibits anti-inflammatory, antidepressant, and antitumor activities, with multi-target and multi-pathway interactions. METHODS: Acetic acid and restraint stress induced an IBS-D mouse model. SSD (purity ≥ 98%, Macklin Inc.) was administered orally at low, medium, and high doses (5, 10, 20 mg/kg). Visceral sensitivity, inflammatory status, intestinal barrier function, HPA axis activity, and gut microbiota composition were systematically evaluated using behavioral tests, Western blot, qRT-PCR, and 16S rRNA sequencing. RESULTS: SSD significantly alleviated visceral hypersensitivity and depression-like behavior, inhibited the peripheral HMGB1-TLR4/NF-κB inflammatory pathway, and restored intestinal barrier integrity. SSD also downregulated hypothalamic Nesfatin-1/CRH/p-CREB expression, suppressed hyperactivation of the stress-related HPA neuroendocrine axis, and reshaped the gut microbial community structure (β-diversity). Network pharmacology analysis suggested that SSD targets were significantly enriched in brain-gut axis-related pathways. CONCLUSION: The present results indicate that SSD could ameliorate IBS-D by synergistically regulating peripheral inflammation, central stress, and intestinal microbes via the brain-gut-microbiota axis, providing experimental evidence for its potential application in TCM-based treatment.
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Intestinal permeability and low-grade chronic inflammation in schizophrenia: A multicentre study on biomarkers. Rationale, objectives, protocol and preliminary results.
BACKGROUND: Altered intestinal permeability and low-grade chronic inflammation disrupt the integrity of the blood-brain barrier (microbiota-gut-brain axis), probably playing a role in the pathophysiology of schizophrenia-spectrum disorders. However, studies assessing the microbiota-gut-brain axis are inconsistent. This article describes the rationale, objectives, protocol, and presents descriptive results for a new project. METHODS: The sample of this study came from an observational, cross-sectional and multisite study including four centers in Spain (PI17/00246) recruiting adult patients with DSM-5 schizophrenia-spectrum disorders at any stage of the disease. The aims of the project are to assess the interrelation between intestinal permeability and low-grade chronic inflammation in schizophrenia-spectrum disorders and the role of peripheral biomarkers, diet, exercise, metabolic syndrome, disease severity and functioning as well as cognition. Assessments included the following variables: (1) anthropometric, (2) intestinal permeability, diet, and physical exercise, (3) clinical and functional, (4) neuropsychological and cognitive reserve, and (5) peripheral biomarkers from blood. RESULTS: A total of 646 patients were enrolled (257, 39.7% female). Mean age was 43.2±13.6 years, illness duration 15.1±11.5 years. 55.8% consumed tobacco. Positive PANSS score was 13.68±6.55, and 20.38±8.69 in the negative symptoms. CGI was 4.16±2.22 and GAF was 60.00±14.84. CONCLUSION: The results obtained by this project are expected to contribute toward the understanding of the physiopathology of schizophrenia-spectrum disorders. This will likely aid to personalize treatments in real-world clinical practice, potentially including variables related to intestinal permeability and inflammation.
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Nutrition program, physical activity and gut microbiota modulation: a randomized controlled trial to promote a healthy lifestyle in students with vitamin D3 deficiency.
BACKGROUND: University students are a high-risk group for stress, consumption of junk food and significant weight gain over a short period. Inadequate vitamin D intake has been linked to many health issues, including chronic headache, apathy, aggression and depression. Furthermore, vitamin D deficiency led to dysbiosis of the gut microbiota. The purpose of our study was to estimate the effect of 90-days healthy lifestyle programs along with gut microbiota modulation in university students with vitamin D<inf>3</inf> deficiency. METHODS: In this randomized controlled trial, 130 students (18-25 years old) with vitamin D deficiency were recruited. Both the standard care group (N.=65) and the intervention group (N.=65) received a 3-months course of individually selected nutrition program and physical activity (8000-10,000 steps daily). The intervention group received an additional treatment with synbiotic Acidolac and vitamin D<inf>3</inf> for 3 months. The psycho-emotional status of the participants was assessed by a validated questionnaire that examined situational anxiety. In all students, blood pressure, anthropometric variables, as well as laboratory metabolic parameters, were recorded. RESULTS: In both groups, vitamin D<inf>3</inf> deficiency was associated with instability and lability of mental processes, mood swings, bad sleep, high rates of stuck and agitation for any problem. Combined therapy (diet, physical activity and synbiotic) induced a significant improvement in the psycho-emotional state of students. The 90-days therapy vitamin D<inf>3</inf> increased the level of vitamin D<inf>3</inf> in serum in the intervention group. Lastly, we observed a decrease in the body weight, body mass index, waist circumference and fatty mass, only in students included in the interventional group. CONCLUSIONS: Nutrition program, physical activity, vitamin D<inf>3</inf> intake and gut microbiota modulation led to both the improvement in vitamin D levels in serum and emotional harmonization.
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Aerobic exercise remodels gut microbiota to alleviate cerebral ischemia-reperfusion injury.
Aerobic exercise exhibits a neuroprotective role against cerebral ischemia-reperfusion (I/R) injury, and the present study explored the underlying mechanisms. Adult Sprague-Dawley rats (n=87) were used in the study, and cerebral I/R injury in rats was modeled using middle cerebral artery occlusion and reperfusion (MCAOR), followed by interval aerobic exercise training at a moderate intensity. Colonization with gut microbiota from the trained rats was performed on MCAOR rats. Neurobehavioral assessments were performed. Cerebral infarction and neuronal damage were detected by tissue staining and molecular experiments. Gut microbiota composition was analyzed by 16S rRNA gene sequencing. Neuroinflammation was detected using an enzyme-linked immunosorbent assay. Aerobic exercise ameliorated neurological deficit, spontaneous locomotor activity, and spatial learning and memory impairment in MCAOR rats (p<0.001). Further, aerobic exercise decreased infarct volume, attenuated neuronal damage, increased SYN1 and PSD95 expression, as well as reduced neuroinflammation by upregulating IL-10 and downregulating IL-6, TNF-α, IL-17, and TGF-β in MCAOR rats (p<0.05). Aerobic exercise altered gut microbiota composition in MCAOR rats. Gut microbiota colonization in rats alleviated cerebral I/R injury by reducing neurological deficit scores, promoting spontaneous locomotor activity, decreasing infarct volume, elevating SYN1 and PSD95 expression, and improving neuroinflammation (p<0.05). In conclusion, aerobic exercise remodeled the gut microbiota in rats to attenuate cognitive dysfunction and neuroinflammation after cerebral I/R.