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Gut microbiota derived short-chain fatty acids in physiology and pathology: An update.
Short-chain fatty acids (SCFAs) are essential molecules produced by gut bacteria that fuel intestinal cells and may also influence overall health. An imbalance of SCFAs can result in various acute and chronic diseases, including diabetes, obesity and colorectal cancer (CRC). This review delves into the multifaceted roles of SCFAs, including a brief discussion on their source and various gut-residing bacteria. Primary techniques used for detection of SCFAs, including gas chromatography, high-performance gas chromatography, nuclear magnetic resonance and capillary electrophoresis are also discussed through this article. This review study also compiles various synthesis pathways of SCFAs from diverse substrates such as sugar, acetone, ethanol and amino acids. The different pathways through which SCFAs enter cells for immune response regulation are also highlighted. A major emphasis is the discussion on diseases associated with SCFA dysregulation, such as anaemia, brain development, CRC, depression, obesity and diabetes. This includes exploring the relationship between SCFA levels across ethnicities and their connection with blood pressure and CRC. In conclusion, this review highlights the critical role of SCFAs in maintaining gut health and their implications in various diseases, emphasizing the need for further research on SCFA detection, synthesis and their potential as diagnostic biomarkers. Future studies of SCFAs will pave the way for the development of novel diagnostic tools and therapeutic strategies for optimizing gut health and preventing diseases associated with SCFA dysregulation.
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Development of an Efficient and Sensitive Chemical Derivatization-Based LC-MS/MS Method for Quantifying Gut Microbiota-Derived Metabolites in Human Plasma and Its Application in Studying Cardiovascular Disease.
Recently, the gut microbiota has been found to be associated with many diseases, such as inflammatory bowel disease, depression, Parkinson's disease, cancer, metabolic syndrome, and cardiovascular disease (CVD). Among various gut microbiota-derived metabolites (GMs), short-chain fatty acids (SCFAs), bile acids (BAs), and tryptophan (TRP) metabolites are the most frequently discussed metabolites. LC-MS/MS shows advantages in quantifying the levels of metabolites with good sensitivity and selectivity; however, the poor ionization efficiency and polar characteristics of SCFAs make their analysis challenging, especially when analyzing plasma samples with low SCFA concentrations. Moreover, without characteristic fragment ions for unconjugated BAs and different detection ion modes for TRP metabolites and BAs, GM analysis is complex and time-consuming. To overcome these problems, we developed a derivatization method combined with LC-MS/MS to enhance the sensitivity and LC retention of GMs. Through derivatization with 3-nitrophenylhydrazine (3-NPH), 7 SCFAs, 9 bile acids, and 6 tryptophan metabolites can be simultaneously analyzed via separation within 14 min on a reversed-phase C18 column. For accurate quantification, 13C6-3NPH-labeled standards were used as one-to-one internal standards. This derivatization approach was optimized and then validated. We further applied this method to investigate the targeted GM profile in patients with CVD. The results showed a significant reduction in plasma butyrate levels in CVD patients compared with healthy controls, suggesting its potentially protective role in CVD. In summary, this work provides a sensitive and effective LC-MS/MS method for simultaneously quantifying gut microbiota-related metabolites in human plasma, which could benefit various future gut microbiota-related studies.
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Therapeutic potential of heat-killed Enterococcus faecalis (EC-12) para-probiotic in reversing maternal separation-triggered social deficit in mice.
Early life stress due to maternal separation (MS) disrupts the gut-brain axis (GBA), leading to long-term neurobiological and behavioral deficits, particularly social behavior impairments. Although various probiotics have shown therapeutic potential, the efficacy of heat-killed Enterococcus faecalis EC-12 (EC-12) as a para-probiotic remains largely unknown. This study aimed to evaluate the therapeutic potential of EC-12 in reversing MS-induced behavioral and molecular abnormalities in mice. Male C57BL/6 J mice were subjected to MS from postnatal days (PD) 3-20 and then divided into four groups with or without EC-12 supplementation. After five weeks of EC-12 administration, behavioral assessments were conducted, followed by prefrontal cortex transcriptomic analysis, cecal content microbiomic analysis, and serum and cecal content metabolomic analyses. EC-12 supplementation significantly restored social interaction behavior in mice with MS without affecting anxiety- or depression-like phenotypes. Transcriptome analysis revealed significant upregulation of vasopressin-related genes (Trpv4 and Ecrg4), with vasopressin secretion being the most enriched biological pathway. EC-12 also increased the levels of L-tryptophan and L-tyrosine and upregulated Tph2 gene expression. The gut microbiota composition was substantially reshaped in MS-EC-12 mice, with enrichment of beneficial genera (Blautia, Dubosiella, Romboutsia), and fecal metabolomics revealed increased levels of phenylacetic acid, glycerol 3-phosphate, and pectin, with significant activation of glycerolipid metabolism. These findings suggest that heat-killed EC-12 can mitigate early life stress-induced social deficits through microbiota- and metabolite-mediated modulation of GBA and may serve as a promising para-probiotic intervention for neurodevelopmental disorders.
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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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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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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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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.