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Sex-dependent and long-lasting effects of adolescent sleep deprivation on social behaviors in adult mice.
Increasing evidence indicates that sleep deprivation (SD) can exert multiple negative effects on neuronal circuits, resulting in memory impairment, depression, and anxiety, among other consequences. The long-term effects of SD during early life on behavioral phenotypes in adulthood are still poorly understood. In this study, we investigated the long-lasting effects of SD in adolescence on social behaviors, including empathic ability and social dominance, and the role of the gut microbiota in these processes, using a series of behavioral paradigms in mice combined with 16S rRNA gene pyrosequencing. Behavioral assay results showed that SD in adolescence significantly reduced the frequency of licking, the total time spent licking, and the time spent sniffing during the emotional contagion test in male mice, effects that were not observed in female mice. These findings indicated that SD in adolescence exerts long-term, negative effects on empathic ability in mice and that this effect is sex-dependent. In contrast, SD in adolescence had no significant effect on locomotor activities, social dominance but decreased social interaction in male mice in adulthood. Meanwhile, 16S rRNA gene pyrosequencing results showed that gut microbial richness and diversity were significantly altered in adult male mice subjected to SD in adolescence. Our data provide direct evidence that SD in youth can induce alterations in empathic ability in adult male mice, which may be associated with changes in the gut microbiota. These findings highlight the long-lasting effects of sleep loss in adolescence on social behaviors in adulthood and the role played by the brain-gut axis.
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Changes in brain kynurenine levels via gut microbiota and gut-barrier disruption induced by chronic ethanol exposure in mice.
Inflammatory processes have been shown to modify tryptophan (Trp) metabolism. Gut microbiota appears to play a significant role in the induction of peripheral and central inflammation. Ethanol (EtOH) exposure alters gut permeability, but its effects on Trp metabolism and the involvement of gut microbiota have not been studied. We analyzed several parameters of gut-barrier and of peripheral and central Trp metabolism following 2 different EtOH consumption patterns in mice, the binge model, drinking in the dark (DID), and the chronic intermittent (CI) consumption paradigm. Antibiotic treatment was used to evaluate gut microbiota involvement in the CI model. Mice exposed to CI EtOH intake, but not DID, show bacterial translocation and increased plasma LPS immediately after EtOH removal. Gut-barrier permeability to FITC-dextran is increased by CI, and, furthermore, intestinal epithelial tight-junction (TJ) disruption is observed (decreased expression of zonula occludens 1 and occludin) associated with increased matrix metalloproteinase (MMP)-9 activity and iNOS expression. CI EtOH, but not DID, increases kynurenine (Kyn) levels in plasma and limbic forebrain. Intestinal bacterial decontamination prevents the LPS increase but not the permeability to FITC-dextran, TJ disruption, or the increase in MMP-9 activity and iNOS expression. Although plasma Kyn levels are not affected by antibiotic treatment, the elevation of Kyn in brain is prevented, pointing to an involvement of microbiota in CI EtOH-induced changes in brain Trp metabolism. Additionally, CI EtOH produces depressive-like symptoms of anhedonia, which are prevented by the antibiotic treatment thus pointing to an association between anhedonia and the increase in brain Kyn and to the involvement of gut microbiota.-Giménez-Gómez, P., Pérez-Hernández, M., O'Shea, E., Caso, J. R., Martín-Hernández, D., Cervera, L. A., Centelles. M. L. G.-L., Gutiérrez-Lopez, M. D., Colado, M. I. Changes in brain kynurenine levels via gut microbiota and gut-barrier disruption induced by chronic ethanol exposure in mice.
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Evaluation of a natural S-equol supplement in treating premenstrual symptoms and the effect of the gut microbiota: An open-label pilot study.
AIM: Premenstrual syndrome causes disturbances in many women's daily activities. Isoflavones might cause changes in the estrogen cycle by their selective estrogen receptor modulator-like activities. Equol, which is a metabolite of a soy isoflavone, has greater biological activity than other soy isoflavones. In this preliminary study, we aimed to examine the effect of a natural S-equol supplement (SE5-OH) on premenstrual symptoms. The gut microbiota has recently been suggested to play an important role in brain function in psychiatric disease, such as depression. Therefore, we further aimed to evaluate the relationship of the effect of SE5-OH and the gut microbiota at preintervention. METHODS: Twenty women who showed premenstrual symptoms and were nonequol producers were enrolled in an open-label, single-arm, clinical study in which they received oral SE5-OH for two period cycles. The Daily Record of Severity of Problems (DRSP) total score was evaluated during the intervention cycles. Before taking SE5-OH, fecal samples were obtained and subjected to terminal restriction fragment length polymorphism analysis. RESULTS: The response rate to treatment (≥50% reduction from baseline in the DRSP total score) was 10.5%. Post hoc analysis showed a significant improvement in the change in the DRSP total score (P = .008) and DRSP scores for four core premenstrual dysphoric disorder symptoms. Multiple regression analysis showed that the percentage improvement of the DRSP total score was positively related to Bifidobacterium and negatively related to Clostridium cluster IV. CONCLUSION: SE5-OH supplementation may be an acceptable treatment for premenstrual symptoms. The intestinal microbiota may have an effect on SE5-OH.
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The gut microbiota metabolite indole increases emotional responses and adrenal medulla activity in chronically stressed male mice.
BACKGROUND AND AIMS: The gut microbiota produces metabolites that are an integral part of the metabolome and, as such, of the host physiology. Changes in gut microbiota metabolism could therefore contribute to pathophysiological processes. We showed previously that a chronic and moderate overproduction of indole from tryptophan in male individuals of the highly stress-sensitive F344 rat strain induced anxiety-like and helplessness behaviors. The aim of the present study was to extend the scope of these findings by investigating whether emotional behaviors of male mice that are moderately stress-sensitive but chronically exposed to environmental stressors would also be affected by indole. METHODS: We colonized germ-free male C3H/HeN mice with a wild-type indole-producing Escherichia coli strain, or with the non-indole producing mutant. Gnotobiotic mice were subjected to an unpredictable chronic mild stress procedure, then to a set of tests aimed at assessing anxiety-like (novelty and elevated plus maze tests) and depression-like behaviors (coat state, splash, nesting, tail suspension and sucrose tests). Results of the individual tests were aggregated into a common z-score to estimate the overall emotional response to chronic mild stress and chronic indole production. We also carried out biochemical and molecular analyses in gut mucosa, plasma, brain hippocampus and striatum, and adrenal glands, to examine biological correlates that are usually associated with stress, anxiety and depression. RESULTS: Chronic mild stress caused coat state degradation and anhedonia in both indole-producing and non-indole producing mice, but it did not influence behaviors in the other tests. Chronic indole production did not influence mice behavior when tests were considered individually, but it increased the overall emotionality z-score, specifically in mice under chronic mild stress. Interestingly, in the same mice, indole induced a dramatic increase of the expression of the adrenomedullary Pnmt gene, which is involved in catecholamine biosynthesis. By contrast, systemic tryptophan bioavailability, brain serotonin and dopamine levels and turnover, as well as expression of gut and brain genes involved in cytokine production and tryptophan metabolism along the serotonin and kynurenine pathways, remained similar in all mice. CONCLUSIONS: Chronic indole production by the gut microbiota increased the vulnerability of male mice to the adverse effects of chronic mild stress on emotional behaviors. It also targeted catecholamine biosynthetic pathway of the adrenal medulla, which plays a pivotal role in body's physiological adaptation to stressful events. Future studies will aim to investigate the action mechanisms responsible for these effects.
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PROMISE: a PROspective randomised double-blind parallel group placebo-controlled multicentre trial of faecal MIcrobiota tranSplantation to improve outcomEs in patients with cirrhosis over 24 months-study protocol for a clinical trial.
BACKGROUND: Patients with cirrhosis have reduced gut bacterial diversity and a gut microbiota dominated by pathobionts. These changes, coupled with increased gut permeability and bacterial translocation, increase susceptibility to infection and death. There is also considerable concern that high antimicrobial exposure in the cirrhotic population drives the development of antimicrobial resistance (AMR). We previously performed a randomised feasibility trial of endoscopically administered jejunal faecal microbiota transplant (FMT) slurry derived from stringently screened donors, and showed it to be safe and well-tolerated in patients with cirrhosis (PROFIT Trial: NCT02862249). FMT was associated with reduced enteropathogenic bacteria in the gut, augmented ammonia excretion, ameliorated systemic inflammation, and enhanced innate immune responses to pathogen challenge. The trial was not powered to detect differences in clinical outcomes. The PROMISE study will evaluate the efficacy of lyophilised encapsulated FMT to reduce infection, decompensating events and mortality in patients with cirrhosis secondary to alcohol-related liver disease (ALD), metabolic dysfunction-associated steatotic liver disease (MASLD) cirrhosis and metabolic dysfunction and alcohol-related liver disease (MetALD). METHODS: The PROMISE study is a phase 3 multicentre, randomised, double-blinded, placebo-controlled trial that will evaluate encapsulated lyophilised FMT in 300 participants with ALD, MetALD or MASLD cirrhosis (Model for End-Stage Liver Disease Sodium (MELD-Na) score 8-16). Participants will be randomly allocated (1:1) to receive FMT or matched placebo capsules every 91 days for 21 months, with 24-month follow-up. The primary endpoint is time-to-infection or decompensating event resulting in presentation to the emergency department or hospitalisation. Secondary endpoints include all hepatic decompensation, all-cause infection, antibiotic usage, incidence of AMR, hospitalisation rates, liver disease severity scores, quality of life scores, Hospital Anxiety and Depression Scale score (HADS), alcohol use, and mortality. Mechanistic endpoints include quantification of plasma bacterial DNA, plasma and faecal cytokines/biomarkers, plasma and faecal metabolome, faecal proteome, faecal microbiome composition and diversity (including resistome) and monocyte and mucosal-associated invariant T (MAIT) cell frequency, phenotype and function. Recruitment commenced in June 2023. Results will be disseminated via peer-reviewed journals, international conferences and patient support groups. DISCUSSION: The PROMISE study will assess the efficacy and evaluate the mechanisms of action of FMT in patients with ALD, MASLD and MetALD cirrhosis. FMT may provide an alternative non-antibiotic treatment for these patients through ecological reconstitution of microbial balance. TRIAL REGISTRATION: ISRCTN, ISRCTN17863382. Registered on 25th March 2022, https://www.isrctn.com/ISRCTNISRCTN17863382 . CLINICALTRIALS: gov NCT06461208. Registered on 4th June 2024, https://clinicaltrials.gov/study/NCT06461208#study-overview .
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Colitis-associated intestinal microbiota regulates brain glycine and host behavior in mice.
Inflammatory bowel diseases (IBD) are chronic and relapsing inflammatory disorders of the gastrointestinal tract with complex etiology and no strategies for complete cure. IBD are often complicated by mental disorders like anxiety and depression, indicating substantial shifts in the microbiota gut-brain axis. However, the mechanisms connecting IBD to mental diseases are still under debate. Here we use Muc2 knockout mouse model of chronic colitis to uncouple the effects of the intestinal microbiota on host behavior from chronic inflammation in the gut. Muc2 knockout male mice exhibit high exploratory activity, reduced anxiety-related behaviors, impaired sensorimotor gating, and altered social preference towards males and females. Microbial transfer to wild-type mice via littermate co-housing shows that colitis-associated microbiota rather than inflammation per se defines behavioral features in Muc2 colitis model. Metagenomic profiling and combination of antibiotic treatments revealed that bacterial species Akkermansia muciniphila is associated with the behavioral phenotype in mutants, and that its intestinal abundance correlates with social preference towards males. Metabolomic analysis together with pharmacological inhibition of Gly and NMDA receptors helped us to determine that brain glycine is responsible for the behavioral phenotype in Muc2 mice. Blood and brain metabolic profiles suggest that microbiota-dependent changes in choline metabolism might be involved in regulation of central glycine neurotransmission. Taken together, our data demonstrates that colitis-associated microbiota controls anxiety, sensorimotor gating and social behavior via metabolic regulation of the brain glycinergic system, providing new venues to combat neurological complications of IBD.
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Impact of polypropylene microplastics and chemical pollutants on European sea bass (Dicentrarchus labrax) gut microbiota and health.
Plastic pollution has become a global problem for marine ecosystems. Microplastics (MPs) are consumed by several marine organisms, including benthic and pelagic fish species that confuse them with food sources, thus contributing to bioaccumulation along the food chain. In addition to structural intestinal damage, ingestion of MPs represents a pathway for fish exposure to potentially hazardous chemicals, too. Most of them are endocrine disrupters, genotoxic or induce immune depression in fish. Accordingly, we assessed the combined toxicological effects of microplastics (MPs) and adsorbed pollutants by adding them to marine fish diet. European sea bass (Dicentrarchus labrax) juveniles were fed for 60 days with feeds containing polypropylene MPs, either virgin or contaminated with chemical pollutants (a blend of dichlorodiphenyldichloroethylene, chlorpyrifos, and benzophenone-3). The data demonstrated a synergic action of MPs and chemical pollutants to induce an inflammatory-like response in distal intestine of sea bass as shown by the up regulation of cytokine il-6 and tnf-α expression. Morphological analysis detected the presence of a focus of lymphocytes in anterior and posterior intestinal segments of fish fed with contaminants in the diet. With regard to microbiota, significant changes in bacterial species richness, beta diversity, and composition of gut microbiota were observed as a consequence of both pollutants and polluted MPs ingestion. These perturbations in gut microbial communities, including the reduction of beneficial lactic acid bacteria and the increase in potential pathogenic microorganism (Proteobacteria and Vibrionales), were undeniable signs of intestinal dysbiosis, which in turn confirmed the signs of inflammation caused by pollutants, especially when combined with MPs. The results obtained in this study provide, therefore, new insights into the potential risks of ingesting MPs as pollutant carriers in marine fish.
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High-fat diet and age disrupt a Muribaculaceae-associated SCFA network linked to gut barrier and cognitive deficits.
Both diet and aging shape the gut microbiota, yet how their combined remodeling propagates across microbial function to host barrier and brain outcomes remains poorly understood. Despite abundant links between Short-chain fatty acids (SCFAs) and intestinal health, integrative studies that connect community ecology with SCFA linked metabolism, epithelial signaling, systemic inflammation, behavior, and test causal reversibility are limited. In this study, we assessed gut microbiota and function alongside host tissues and behavior. In mice fed a high-fat diet (HFD), particularly in the 12-month-old cohort, we observed hippocampal-dependent cognitive and locomotor deficits (longer escape latency, fewer platform crossings, reduced target-quadrant time; lower distance, speed and center time), accompanied by systemic inflammation, with serum lipopolysaccharide (LPS) and cytokines (IL-6 and TNF-α) elevated and associated with adiposity. We then profiled the gut microbiota and its functions alongside host tissues and behavior, finding that HFD and age reduced α-diversity and shifted β-diversity, with a selective depletion of Muribaculaceae and depressed SCFA-linked pathways. Muribaculaceae abundance positively correlated with predicted SCFA-related pathways, while qRT-PCR of microbial fermentation genes supported concurrent functional alterations. In the colon, ELISA-measured butyrate level, SCFA receptors Ffar2, Ffar3 and tight-junction genes Tjp1 and Ocln were downregulated, with ZO-1 and occludin mislocalization, while serum LPS and inflammatory cytokines increased and associated with adiposity. Notably, an intervention arm showed that sodium butyrate supplementation attenuated cytokinemia, restored Ffar2, Ffar3 and tight-junction expression, improved ZO-1 and occludin integrity, and rescued behavioral performance. Collectively, these findings support an association between Muribaculaceae depletion, reduced SCFA-related functional signatures, impaired barrier associated markers, systemic inflammation, and behavioral deficits under HFD and age-associated conditions. In an intervention setting, butyrate supplementation partially ameliorated inflammatory and barrier-related readouts and improved behavioral performance.
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Gut bacteria convert glucocorticoids into progestins in the presence of hydrogen gas.
Recent studies suggest that human-associated bacteria interact with host-produced steroids, but the mechanisms and physiological impact of such interactions remain unclear. Here, we show that the human gut bacteria Gordonibacter pamelaeae and Eggerthella lenta convert abundant biliary corticoids into progestins through 21-dehydroxylation, thereby transforming a class of immuno- and metabo-regulatory steroids into a class of sex hormones and neurosteroids. Using comparative genomics, homologous expression, and heterologous expression, we identify a bacterial gene cluster that performs 21-dehydroxylation. We also uncover an unexpected role for hydrogen gas production by gut commensals in promoting 21-dehydroxylation, suggesting that hydrogen modulates secondary metabolism in the gut. Levels of certain bacterial progestins, including allopregnanolone, better known as brexanolone, an FDA-approved drug for postpartum depression, are substantially increased in feces from pregnant humans. Thus, bacterial conversion of corticoids into progestins may affect host physiology, particularly in the context of pregnancy and women's health.
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Non-traditional risk factors for atrial fibrillation: epidemiology, mechanisms, and strategies.
Atrial fibrillation (AF) has become the pre-dominant arrhythmia worldwide and is associated with high morbidity and mortality. Its pathogenesis is intricately linked to the deleterious impact of cardiovascular risk factors, emphasizing the pivotal imperative for early detection and mitigation strategies targeting these factors for the prevention of primary AF. While traditional risk factors are well recognized, an increasing number of novel risk factors have been identified in recent decades. This review explores the emerging non-traditional risk factors for the primary prevention of AF, including unhealthy lifestyle factors in current society (sleep, night shift work, and diet), biomarkers (gut microbiota, hyperuricaemia, and homocysteine), adverse conditions or diseases (depression, epilepsy, clonal haematopoiesis of indeterminate potential, infections, and asthma), and environmental factors (acoustic pollution and other environmental factors). Unlike traditional risk factors, individuals have limited control over many of these non-traditional risk factors, posing challenges to conventional prevention strategies. The purpose of this review is to outline the current evidence on the associations of non-traditional risk factors with new-onset AF and the potential mechanisms related to these risk factors. Furthermore, this review aims to explore potential interventions targeting these risk factors at both the individual and societal levels to mitigate the growing burden of AF, suggesting guideline updates for primary AF prevention.