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Methanogen Levels Are Significantly Associated with Fecal Microbiota Composition and Alpha Diversity in Healthy Adults and Irritable Bowel Syndrome Patients.
Hydrogenotrophic microbes, primarily including the three functional groups methanogens, sulfate-reducing bacteria, and reductive acetogens, use hydrogen as an energy source and play an important role in maintaining the hydrogen balance in gut ecosystems. A distorted hydrogen balance has been associated with irritable bowel syndrome (IBS). However, the role of hydrogenotrophic microbes in overall microbiota composition and function remains largely unknown. This study aims to assess the distribution and stability of hydrogenotrophic functional groups in healthy adults (HAs) and IBS patients and their association with overall microbiota composition and IBS symptoms. A two-time-point study with 4 weeks in between was performed with 27 HAs and 55 IBS patients included. Our observations revealed that methanogens showed a bimodal distribution across samples. A high-level methanogen microbiota was consistently associated with higher alpha diversity, and its composition was significantly different from that of individuals with a low-level methanogen microbiota. In general, these associations were more pronounced in IBS patients than in HAs. The differences in the copy numbers of genes indicative of total bacteria and acetogens between HAs and IBS patients and their correlations with IBS symptom severity, anxiety, depression, and quality of life (QoL) were sampling time dependent. Hydrogenotrophic functional groups did not show negative abundance correlations with each other in HAs and IBS patients. These findings suggest that methanogen levels in the gut have a pronounced association with microbiota alpha diversity and composition, and the interactions between hydrogenotrophic functional groups are complex in gut ecosystems. IMPORTANCE Hydrogenotrophic microbes play an essential role in the disposal of hydrogen and the maintenance of the hydrogen balance in gut ecosystems. Their abundances vary between individuals and have been reported to be associated with human gut disorders such as irritable bowel disease. This study confirms that methanogen levels show a bimodal distribution. Moreover, a high-level methanogen microbiota was associated with higher alpha diversity, and its composition was different from that of individuals with a low-level methanogen microbiota. These associations are more pronounced in IBS patients than in healthy subjects. In addition, associations between hydrogenotrophic microbes and IBS symptom scores vary over time, which argues for the use of longitudinal study designs. Last but not least, this study suggests that the different hydrogenotrophic microbes coexist with each other and do not necessarily compete for hydrogen in the gut. The findings in this study highlight the impact of methanogens on overall microbiota composition and function.
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Co-occurrence of gut microbiota dysbiosis and bile acid metabolism alteration is associated with psychological disorders in Crohn's disease.
This study aims to elucidate the relationships between gut microbiota, bile acid metabolism, and psychological comorbidity in Crohn's disease (CD). We profiled the fecal microbiota composition and quantified the bile acid pool of 39 CD patients and 14 healthy controls using 16S rRNA gene sequencing and liquid chromatography-tandem mass spectrometry, respectively. Significant reductions in the secondary bile acids, LCA and DCA, were found in both the feces and serum samples of CD patients, while the concentration of 7-DHCA was particularly higher in the serum of CD patients with psychological disorders. The fecal levels of HDCA and 12-DHCA of the CD patients were inversely correlated with their Self-Rated Depression Scale (SDS) scores, whereas the serum level of 7-DHCA was positively correlated with the SDS scores. In addition, the fecal levels of TDCA, TLCA, and TβMCA showed a positive correlation with the Self-Rated Anxiety Scale (SAS) scores. The fecal microbiota biodiversity was particularly declined in CD patients with psychological disorders. An enrichment of Ruminococcus gnavus in CD patients may cause psychological disorders by affecting the microbiota-gut-brain axis via its ability to degrade the gut barrier, regulate the tryptophan-kynurenine metabolism, and modulate bile acid metabolism. In addition, the overabundant Enterobacteriaceae and Lachnospiraceae in CD patients may contribute to psychological comorbidity via dysregulating their bile acids metabolism. Taken together, changes in the gut microbiota composition may cooperate with alterations in the bile acid metabolism that are involved in the development of psychological disorders in CD.
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Limosilactobacillus reuteri NCU-37 alleviates leuprorelin-induced perimenopausal syndrome in infertile women by modulating the gut microbiota: a randomized controlled trial.
Leuprorelin-induced perimenopausal syndrome (LIPS) represents a common challenge faced by infertile women undergoing assisted reproductive procedures, characterized primarily by hot flashes, night sweats, and mood swings. Currently, there is a shortage of safe approaches that can effectively alleviate these symptoms without compromising the therapeutic outcomes of pregnancy. In this study, 100 infertile women with LIPS (placebo group, MP group; probiotic group, ML group) and 50 healthy women were enrolled to evaluate the therapeutic effects of Limosilactobacillus reuteri NCU-37 on LIPS. The results showed that, compared to the MP group, NCU-37 significantly reduced the Modified Kupperman Index (MKI) scores (MP vs. ML = 15.00 vs. 8.00, p < 0.01), Hamilton Anxiety Scale (HAMA) scores (11.50 vs. 7.00, p < 0.01), Hamilton Depression Scale (HAMD) scores (9.00 vs. 7.00, p < 0.01), and Athens Insomnia Scale (AIS) scores (7.50 vs. 5.00, p < 0.05). Additionally, NCU-37 significantly increased serum hormone levels, including anti-Müllerian hormone (AMH), estradiol (E2), follicle-stimulating hormone (FSH), and luteinizing hormone (LH), compared to the placebo group (p < 0.05). These results indicate that NCU-37 effectively improves perimenopausal symptoms, mood disorders, and hormone levels. Meanwhile, NCU-37 altered the composition and diversity of the gut microbiota in LIPS patients, resulting in a significant increase in beneficial bacteria (Blautia) and a reduction in pathogenic bacteria (Bacteroides). Interestingly, NCU-37 increased the pregnancy rate in LIPS patients. In conclusion, this study demonstrates for the first time that the probiotic NCU-37 alleviates LIPS by improving perimenopausal symptoms, mood disorders, hormone levels, and the gut microbiota, thereby providing data to support its clinical application.
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Influence of cecotrophy on fat metabolism mediated by caecal microorganisms in New Zealand white rabbits.
Cecotrophy is a special behaviour of rabbits. Eating soft faeces can improve feed efficiency and maintain gut flora in rabbits. In our previous study, we found that fasting from soft faeces significantly reduced growth rate and total cholesterol (TC) in New Zealand white rabbits (NZW rabbits), thereby resulting in lower values for body weight and fat deposition in the soft faeces fasting group than in the control group. However, it has not been demonstrated whether cecotrophy by NZW rabbits can regulate lipid metabolism by changing the diversity of caecal microorganisms. In this study, thirty-six 28-day-old weaned NZW female rabbits were randomly divided into two groups (the soft faeces fasting group and the control group) and fed to 90 days. Rabbits in the experimental group were treated with an Elizabeth circle to prevent them from eating their soft faeces. Then, the caecal contents of three rabbits from the soft faeces fasting group and three rabbits from the control group were collected for metagenomic sequencing. We found that the abundance of Bacteroides increased, while Ruminococcus decreased, compared with the control group after fasting from soft faeces. Relative abundance was depressed for genes related to metabolic pathways such as ascorbate and aldarate metabolism, riboflavin metabolism and bile secretion. Moreover, there was a general correlation between variation in microbial diversity and fat deposition. Bacteroides affects body weight and TC by participating in the riboflavin metabolism pathway. By investigating the effect of cecotrophy on caecal microorganisms of rabbits, we identified the key microorganisms that regulate the rapid growth performance of NZW rabbits, which may provide useful reference for the future research and development of microecological preparations for NZW rabbits.
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Randomised controlled trial: nutritional supplements to relieve irritable bowel syndrome symptoms by targeting the gut microbiota.
In individuals with irritable bowel syndrome (IBS), eliminating dietary triggers can alleviate symptoms but may lead to nutrient deficiencies and overall health decline. Although various nutritional supplements show promising results in relieving IBS symptoms due to their potential to alter the microbiome, conclusive scientific evidence remains lacking. This exploratory study aims to assess the bifidogenic properties of four nutritional supplement interventions and their impact on IBS-symptoms, faecal microbiota composition, faecal short-chain fatty acid (SCFA) concentrations, stool pattern, and quality of life (QoL), compared to a placebo control. Seventy subjects with IBS, meeting the ROME IV criteria, participated in this randomised, double-blind, placebo-controlled parallel intervention study. Subjects were assigned to one of the four treatment groups, receiving either resistant starch, pea fibre, chondroitin sulfate, protein hydrolysate, or placebo daily for four weeks. Daily reports on stool pattern and gastrointestinal complaints were collected. Stool samples and questionnaires on dietary intake, symptom severity, QoL, and anxiety and depression were collected at baseline and after the 4-week intervention. The results show no significant increase in Bifidobacterium abundance or faecal SCFA levels after the 4-week intervention with any of the four nutritional supplement interventions. While some improvements in symptom severity and QoL were observed within-groups, these were not significantly different from changes observed with placebo. In conclusion, the tested nutritional supplements did not increase Bifidobacterium abundance in subjects with IBS within four weeks. Furthermore, we conclude that future studies should consider a run-in period and a larger sample size to study improvements in IBS symptoms.
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Gut microbiota composition links to variation in functional domains across psychiatric disorders.
OBJECTIVE: Changes in microbial composition are observed in various psychiatric disorders, but their specificity to certain symptoms or processes remains unclear. This study explores the associations between the gut microbiota composition and the Research Domain Criteria (RDoC) domains of functioning, representing symptom domains, specifically focusing on stress-related and neurodevelopmental disorders in patients with and without psychiatric comorbidity. METHODS: The gut microbiota was analyzed in 369 participants, comprising 272 individuals diagnosed with a mood disorder, anxiety disorder, attention deficit/hyperactivity disorder, autism spectrum disorder, and/or substance use disorder, as well as 97 psychiatrically unaffected individuals. The RDoC domains were estimated using principal component analysis (PCA) with oblique rotation on a range of psychiatric, psychological, and personality measures. Associations between the gut microbiota and the functional domains were assessed using multiple linear regression and permanova, adjusted for age, sex, diet, smoking, medication use and comorbidity status. RESULTS: Four functional domains, aligning with RDoC's negative valence, social processes, cognitive systems, and arousal/regulatory systems domains, were identified. Significant associations were found between these domains and eight microbial genera, including associations of negative valence with the abundance of the genera Sellimonas, CHKCI001, Clostridium sensu stricto 1, Oscillibacter, and Flavonifractor; social processes with Sellimonas; cognitive systems with Sporobacter and Hungatella; and arousal/regulatory systems with Ruminococcus torques (all pFDR < 0.05). CONCLUSION: Our findings demonstrate associations between the gut microbiota and the domains of functioning across patients and unaffected individuals, potentially mediated by immune-related processes. These results open avenues for microbiota-focused personalized interventions, considering psychiatric comorbidity. However, further research is warranted to establish causality and elucidate mechanistic pathways.
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Investigating the Impact of Nutrition and Oxidative Stress on Attention Deficit Hyperactivity Disorder.
Background/Objectives: Attention deficit hyperactivity disorder (ADHD) is the most common childhood-onset neurodevelopmental disorder, characterized by difficulty maintaining attention, impulsivity, and hyperactivity. While the cause of this disorder is still unclear, recent studies have stated that heredity is important in the development of ADHD. This is linked to a few comorbidities, including depression, criminal behavior, and anxiety. Although genetic factors influence ADHD symptoms, there are also non-genetic factors, one of which is oxidative stress (OS), which plays a role in the pathogenesis and symptoms of ADHD. This review aims to explore the role of OS in ADHD and its connection to antioxidant enzyme levels, as well as the gut-brain axis (GBA), focusing on diet and its influence on ADHD symptoms, particularly in adults with comorbid conditions. Methods: The literature search included the main available databases (e.g., Science Direct, PubMed, and Google Scholar). Articles in the English language were taken into consideration and our screening was conducted based on several words such as "ADHD", "oxidative stress", "diet", "gut-brain axis", and "gut microbiota." The review focused on studies examining the link between oxidative stress and ADHD, the role of the gut-brain axis, and the potential impact of dietary interventions. Results: Oxidative stress plays a critical role in the development and manifestation of ADHD symptoms. Studies have shown that individuals with ADHD exhibit reduced levels of key antioxidant enzymes, including glutathione peroxidase (GPx), catalase (CAT), and superoxide dismutase (SOD), as well as a diminished total antioxidant status (TOS) compared to healthy controls. Additionally, there is evidence of a close bidirectional interaction between the nervous system and gut microbiota, mediated by the gut-brain axis. This relationship suggests that dietary interventions targeting gut health may influence ADHD symptoms and related comorbidities. Conclusions: Oxidative stress and the gut-brain axis are key factors in the pathogenesis of ADHD, particularly in adults with comorbid conditions. A better understanding of these mechanisms could lead to more targeted treatments, including dietary interventions, to mitigate ADHD symptoms. Further research is required to explore the therapeutic potential of modulating oxidative stress and gut microbiota in the management of ADHD.
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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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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 .