-
Biomedicine & Pharmacotherapy =... Jun 2024The interaction between the gut microbiota and mercaptopurine (6-MP), a crucial drug used in pediatric acute lymphoblastic leukemia (ALL) treatment, has not been...
The interaction between the gut microbiota and mercaptopurine (6-MP), a crucial drug used in pediatric acute lymphoblastic leukemia (ALL) treatment, has not been extensively studied. Here we reveal the significant perturbation of gut microbiota after 2-week 6-MP treatment in beagles and mice followed by the functional prediction that showed impairment of SCFAs production and altered amino acid synthesis. And the targeted metabolomics in plasma also showed changes in amino acids. Additionally, targeted metabolomics analysis of feces showed changes in amino acids and SCFAs. Furthermore, ablating the intestinal microbiota by broad-spectrum antibiotics exacerbated the imbalance of amino acids, particularly leading to a significant decrease in the concentration of S-adenosylmethionine (SAM). Importantly, the depletion of gut microbiota worsened the damage of small intestine caused by 6-MP, resulting in increased intestinal permeability. Considering the relationship between toxicity and 6-MP metabolites, we conducted a pharmacokinetic study in pseudo germ-free rats to confirm that gut microbiota depletion altered the methylation metabolites of 6-MP. Specifically, the concentration of MeTINs, a secondary methylation metabolite, showed a negative correlation with SAM, the pivotal methyl donor. Additionally, we observed a strong correlation between Alistipes and SAM levels in both feces and plasma. In conclusion, our study demonstrates that 6-MP disrupts the gut microbiota, and depleting the gut microbiota exacerbates 6-MP-induced intestinal toxicity. Moreover, SAM derived from microbiota plays a crucial role in influencing plasma SAM and the methylation of 6-MP. These findings underscore the importance of comprehending the role of the gut microbiota in 6-MP metabolism and toxicity.
PubMed: 38925017
DOI: 10.1016/j.biopha.2024.116975 -
International Journal of Biological... Jun 2024Paecilomyces hepiali is a precious health-care edible medicinal fungus with rich polysaccharides and exhibits various biological activities. Polysaccharides from P....
Paecilomyces hepiali is a precious health-care edible medicinal fungus with rich polysaccharides and exhibits various biological activities. Polysaccharides from P. hepiali fermentation broth (PHP) exhibits good immunomodulatory activity; however, the mechanism underlying PHP-mediated regulation of immunity and gut microbiota remains unclear. To reveal the mechanisms, PHP of different doses were used to intervene cyclophosphamide (CTX)-induced immunosuppressive model mice. The results revealed that PHP facilitated the secretion of serum cytokines, increased the mRNA and protein expression of TLR4/NF-κB signaling pathway. Furthermore, it improved the physical barrier function of the intestine by upregulating the expression of tight junction proteins. PHP increased the proliferation of beneficial bacteria, including, Actinobacteriota, Alistipes, Candidatus_Saccharimonas and unclassified_Clostridia_vadinBB60_group, and reduced the abundance of Proteobacteria, Deferribacterota, Mucispirillum and Escherichia_Shigella, promoted the production of short-chain fatty acids, which were positively associated with immune traits. Thus, as an immune enhancer, PHP has the potential to regulate the intestinal immune response in immunosuppressed mice through modulating gut microbiota.
PubMed: 38917915
DOI: 10.1016/j.ijbiomac.2024.133390 -
Clinical Nutrition ESPEN Aug 2024Previous studies have shown a strong correlation between gut microbiota and diabetes and its associated complications. We aimed to evaluate the causal relationships...
BACKGROUND
Previous studies have shown a strong correlation between gut microbiota and diabetes and its associated complications. We aimed to evaluate the causal relationships between the gut microbiota, gut metabolites, and diabetic neuropathy.
METHODS
Summary statistics of 211 gut microbiota and 12 gut-related metabolites (β-hydroxybutyric acid, betaine, trimethylamine-N-oxide, carnitine, choline, glutamate, kynurenine, phenylalanine, propionic acid, serotonin, tryptophan, and tyrosine) were obtained from previous genome-wide association studies (GWAS). A two-sample Mendelian randomization (MR) design was used to estimate the effects of gut microbiota and gut metabolites on the risk of diabetic neuropathy based on FinnGen GWAS.
RESULTS
Higher levels of Acidaminococcaceae (OR = 0.62; 95%CI = 0.46 to 0.84; P = 0.002), Peptococcaceae (OR = 0.70; 95%CI = 0.54 to 0.90; P = 0.006), and Eubacterium coprostanoligenes group (OR = 0.68; 95%CI = 0.50 to 0.93; P = 0.016) are genetically determined to provide protection against diabetic neuropathy. Conversely, the presence of Alistipes (OR = 1.65; 95%CI = 1.18 to 2.31; P = 0.003), ChristensenellaceaeR7 group (OR = 1.52; 95%CI = 1.03 to 2.23; P = 0.033), Eggerthella (OR = 1.28; 95%CI = 1.05 to 1.55; P = 0.014), RuminococcaceaeUCG013 (OR = 1.35; 95%CI = 1.01 to 1.82; P = 0.046), and Firmicutes (OR = 1.42; 95%CI = 1.05 to 1.93; P = 0.023) increases the risk of diabetic neuropathy. Moreover, a correlation has been identified between diabetic neuropathy and two gut metabolites: betaine (OR = 0.95; 95%CI = 0.90 to 1.00; P = 0.033) and tyrosine (OR = 1.03; 95%CI = 1.01 to 1.06; P = 0.019). Sensitivity analysis indicated robust results with no sign of heterogeneity or pleiotropy.
CONCLUSION
The present study elucidated the impact of specific gut microbiota and gut metabolites on the susceptibility to diabetic neuropathy. Interventions targeting the improvement of the gut microbiota diversity and composition hold considerable promise as a potential strategy.
Topics: Gastrointestinal Microbiome; Humans; Mendelian Randomization Analysis; Diabetic Neuropathies; Genome-Wide Association Study
PubMed: 38901934
DOI: 10.1016/j.clnesp.2024.04.019 -
Gualou-Xiebai-Banxia-Tang regulates liver-gut axis to ameliorate Metabolic Syndrome in HFD-fed mice.Phytomedicine : International Journal... Jan 2024Metabolic syndrome (MetS), characterized by obesity, hyperglycemia, and abnormal blood lipid levels, is the pathological basis of many cardiovascular diseases....
BACKGROUND
Metabolic syndrome (MetS), characterized by obesity, hyperglycemia, and abnormal blood lipid levels, is the pathological basis of many cardiovascular diseases. Gualou-Xiebai-Banxia-Tang decoction (GT) was first described in the Synopsis of the Golden Chamber, the earliest traditional Chinese medicine (TCM) monograph on diagnosis and treatment of miscellaneous diseases in China. According to TCM precepts, based on its ability to activate yang to release stagnation, activate qi to reduce depression, remove phlegm, and broaden the chest, GT has been used for more than 2,000 years to treat cardiovascular ailments. However, the molecular bases of its therapeutic mechanisms remain unclear.
PURPOSE
The aim of this study was to identify lipid- and glucose-related hepatic genes differentially regulated by GT, and to assess GT impact on gut microbiota composition, in mice with high-fat diet (HFD)-induced MetS.
STUDY DESIGN AND METHODS
ApoE/ mice were fed with an HFD for 24 weeks, with or without concurrent GT supplementation, to induce MetS. At the study's end, body weight, visceral fat weight, blood lipid levels, and insulin sensitivity were measured, and histopathological staining was used to evaluate hepatosteatosis and intestinal barrier integrity. Liver transcriptomics was used for analysis of differentially expressed genes in liver and prediction of relevant regulatory pathways. Hepatic lipid/glucose metabolism-related genes and proteins were detected by RT-qPCR and western blotting. Gut microbial composition was determined by 16S rRNA gene sequencing.
RESULTS
GT administration reduced MetS-related liver steatosis and weight gain, promoted insulin sensitivity and lipid metabolism, and beneficially modulated gut microbiota composition by decreasing the relative abundance of g_Lachnospiraceae_NK4A136_group and increasing the relative abundance of g_Alistipes. Liver transcriptomics revealed that GT regulated the expression of genes related to lipid and glucose metabolism (Pparγ, Igf1, Gpnmb, and Trem2) and of genes encoding chemokines/chemokine receptors (e.g. Cxcl9 and Cx3cr1). Significant, positive correlations were found for Ccr2, Ccl4, Ccr1, and Cx3cr1 and the g_Lachnospiraceae_NK4A136_group, and between Cxcl9, Ccr2, Ccl4, and Cx3cr1 and g_Desulfovibrio. GT treatment downregulated the protein expressions of SCD1 and CX3CR1 and upregulated the expression of PCK1 protein.
CONCLUSION
GT supplementation alleviates HFD-induced MetS in mice by improving hepatic lipid and glucose metabolism. The anti-metabolic syndrome effects of GT may be related to the regulation of the gut-liver axis.
PubMed: 38901285
DOI: 10.1016/j.phymed.2023.155320 -
Nutrients May 2024Ulcerative colitis (UC) is an inflammatory bowel disease with an increasing prevalence year over year, and the medications used to treat patients with UC clinically have...
Ulcerative colitis (UC) is an inflammatory bowel disease with an increasing prevalence year over year, and the medications used to treat patients with UC clinically have severe side effects. Oyster peptides (OPs) have anti-inflammatory and antioxidant properties as functional foods that can alleviate a wide range of inflammatory conditions. However, the application of oyster peptides in ulcerative colitis is not well studied. In this work, an animal model of acute colitis was established using 3% dextran sulfate sodium (DSS), and the impact of OP therapy on colitis in mice was examined. Supplementing with OPs prevented DSS-induced colitis from worsening, reduced the expression of oxidative stress and inflammatory markers, and restored the intestinal barrier damage caused by DSS-induced colitis in mice. The 16S rDNA results showed that the OP treatment improved the gut microbiota structure of the UC mice, including increasing microbial diversity, increasing beneficial bacteria, and decreasing harmful bacteria. In the UC mice, the OP therapy decreased the relative abundance of Family_XIII_AD3011_group and Prevotella_9 and increased the relative abundance of Alistipes. In conclusion, OP treatment can inhibit the TLR4/NF-κB pathway and improve the intestinal microbiota in UC mice, which in turn alleviates DSS-induced colitis, providing a reference for the treatment of clinical UC patients.
Topics: Animals; Colitis, Ulcerative; Gastrointestinal Microbiome; Toll-Like Receptor 4; Dextran Sulfate; NF-kappa B; Mice; Peptides; Signal Transduction; Disease Models, Animal; Ostreidae; Male; Mice, Inbred C57BL; Oxidative Stress; Anti-Inflammatory Agents
PubMed: 38892524
DOI: 10.3390/nu16111591 -
International Journal of Molecular... May 2024The role of the gut microbiota and its interplay with host metabolic health, particularly in the context of type 2 diabetes mellitus (T2DM) management, is garnering... (Comparative Study)
Comparative Study
The role of the gut microbiota and its interplay with host metabolic health, particularly in the context of type 2 diabetes mellitus (T2DM) management, is garnering increasing attention. Dipeptidyl peptidase 4 (DPP4) inhibitors, commonly known as gliptins, constitute a class of drugs extensively used in T2DM treatment. However, their potential interactions with gut microbiota remain poorly understood. In this study, we employed computational methodologies to investigate the binding affinities of various gliptins to DPP4-like homologs produced by intestinal bacteria. The 3D structures of DPP4 homologs from gut microbiota species, including , , , , and sp., were predicted using computational modeling techniques. Subsequently, molecular dynamics simulations were conducted for 200 ns to ensure the stability of the predicted structures. Stable structures were then utilized to predict the binding interactions with known gliptins through molecular docking algorithms. Our results revealed binding similarities of gliptins toward bacterial DPP4 homologs compared to human DPP4. Specifically, certain gliptins exhibited similar binding scores to bacterial DPP4 homologs as they did with human DPP4, suggesting a potential interaction of these drugs with gut microbiota. These findings could help in understanding the interplay between gliptins and gut microbiota DPP4 homologs, considering the intricate relationship between the host metabolism and microbial communities in the gut.
Topics: Dipeptidyl Peptidase 4; Diabetes Mellitus, Type 2; Humans; Dipeptidyl-Peptidase IV Inhibitors; Molecular Dynamics Simulation; Gastrointestinal Microbiome; Molecular Docking Simulation; Protein Binding; Bacteria; Bacterial Proteins; Binding Sites
PubMed: 38891933
DOI: 10.3390/ijms25115744 -
Animals : An Open Access Journal From... May 2024A total of 320 1-day-old broilers were randomly divided into five groups. The control group (CON) received a basal diet, while the FAP4, FAP2, and FAP1 groups were...
A total of 320 1-day-old broilers were randomly divided into five groups. The control group (CON) received a basal diet, while the FAP4, FAP2, and FAP1 groups were provided with the basal diet supplemented with 4%, 2%, and 1% fermented powder, respectively. The unfermented powder (UAP2) group was fed the basal diet supplemented with 2% UAP. Each group contained eight replicates of eight chicks each. The results revealed that the final BW and ADG in the FAP 1 and FAP2 were higher than those in the UAP2 and CON groups, while reducing F/G from day 14 to day 42. On day 42, the thymus index in the UAP and FAP groups as well as the bursa index in the FAP4 group showed significant increases compared to those in the CON group. Supplementation with 2% FAP elevated serum IgA levels in broilers on day 28 and day 42, and it also increased serum IgG levels on day 42. Furthermore, supplementation with 2% FAP elevated serum albumin (ALB) levels in broilers, while supplementation with 4% FAP increased serum (glucose) GLU levels in broilers on day 28. The serum biochemical parameters and pathological observation of the liver and kidney in the groups did not show any adverse effects on broilers' health. In addition, the serum total antioxidant capacity (T-AOC) level significantly increased in the FAP4 and FAP2 groups on day 28, and the malondialdehyde (MDA) level in both serum and liver tissue decreased in the FAP2 group on day 28 and day 42. Compared to the CON group, 2% FAP and 2% UAP supplementation reduced the relative abundance of and supplementation with 2% FAP increased the relative abundance of on day 42. In conclusion, the dietary supplementation of FAP can enhance the growth performance, immune function, and antioxidant capacity and regulate microflora in broilers, of which 2% FAP is more effective. It indicates FAP exhibits significant application potential as a promising feed additive for broilers.
PubMed: 38891675
DOI: 10.3390/ani14111628 -
Mammalian Genome : Official Journal of... Jun 2024Esophageal adenocarcinoma (EAC) is one of the most malignant tumors in the digestive system. To make thing worse, the scarcity of treatment options is disheartening....
Esophageal adenocarcinoma (EAC) is one of the most malignant tumors in the digestive system. To make thing worse, the scarcity of treatment options is disheartening. However, if detected early, there is a possibility of reversing the condition. Unfortunately, there is still a lack of relevant early screening methods. Considering that Barrett's esophagus (BE), a precursor lesion of EAC, has been confirmed as the only known precursor of EAC. Analyzing which BE cases will progress to EAC and understanding the processes and mechanisms involved is of great significance for early screening of such patients. Considering the significant alterations in the gut microbiota of patients with BE and its potential role in the progression to EAC, this study aims to analyze the relationship between BE, EAC, and GM to identify potential diagnostic biomarkers and therapeutic targets. This study utilized comprehensive statistical data on gut microbiota from a large-scale genome-wide association meta-analysis conducted by the MiBioGen consortium (n = 18,340). Subsequently, we selected a set of single nucleotide polymorphisms (SNPs) that fell below the genome-wide significance threshold (1 × 10-5) as instrumental variables. To investigate the causal relationship between gut microbiota and BE and EAC, we employed various MR analysis methods, including Inverse Variance Weighting (IVW), MR-Egger regression, weighted median (WM), and weighted mean. Additionally, we assessed the level of pleiotropy, heterogeneity, and stability of genetic variations through MR-Egger intercept test, MR-PRESSO, Cochran's Q test, and "leave-one-out" sensitivity analysis. Furthermore, we conducted reverse MR analysis to identify the causal relationships between gut microbiota and BE and EAC. The results from the Inverse Variance-Weighted (IVW) analysis indicate that Alistipes (P = 4.86 × 10), Lactobacillus (P = 2.11 × 10), Prevotella 7 (P = 4.28 × 10), and RuminococcaceaeUCG004 (P = 4.34 × 10) are risk factors for Barrett's esophagus (BE), while Flavonifractor (P = 8.81 × 10) and RuminococcaceaeUCG004 (P = 4.99 × 10) are risk factors for esophageal adenocarcinoma (EAC). On the other hand, certain gut microbiota genera appear to have a protective effect against both BE and EAC. These include Eubacterium (nodatum group) (P = 4.51 × 10), Holdemania (P = 1.22 × 10), and Lactococcus (P = 3.39 × 10) in the BE cohort, as well as Eubacterium (hallii group) (P = 4.07 × 10) and Actinomyces (P = 3.62 × 10) in the EAC cohort. According to the results of reverse MR analysis, no significant causal effects of BE and EAC on gut microbiota were observed. Furthermore, no significant heterogeneity or pleiotropy was detected in the instrumental variables. We have established a causal relationship between the gut microbiota and BE and EAC. This study holds profound significance for screening BE patients who may be at risk of deterioration, as it can provide them with timely medical interventions to reverse the condition.
PubMed: 38886201
DOI: 10.1007/s00335-024-10042-7 -
PloS One 2024The dysbiosis of microbiota has been reported to be associated with numerous human pathophysiological processes, including inflammatory bowel disease (IBD). With...
The dysbiosis of microbiota has been reported to be associated with numerous human pathophysiological processes, including inflammatory bowel disease (IBD). With advancements in high-throughput sequencing, various methods have been developed to study the alteration of microbiota in the development and progression of diseases. However, a suitable approach to assess the global stability of the microbiota in disease states through time-series microbiome data is yet to be established. In this study, we have introduced a novel Energy Landscape construction method, which incorporates the Latent Dirichlet Allocation (LDA) model and the pairwise Maximum Entropy (MaxEnt) model for their complementary advantages, and demonstrate its utility by applying it to an IBD time-series dataset. Through this approach, we obtained the microbial assemblages' energy profile of the whole microbiota under the IBD condition and uncovered the hidden stable stages of microbiota structure during the disease development with time-series microbiome data. The Bacteroides-dominated assemblages presenting in multiple stable states suggest the potential contribution of Bacteroides and interactions with other microbial genera, like Alistipes, and Faecalibacterium, to the development of IBD. Our proposed method provides a novel and insightful tool for understanding the alteration and stability of the microbiota under disease states and offers a more holistic view of the complex dynamics at play in microbiota-mediated diseases.
Topics: Inflammatory Bowel Diseases; Humans; Gastrointestinal Microbiome; Bacteria; Entropy; Dysbiosis; Bacteroides
PubMed: 38885178
DOI: 10.1371/journal.pone.0302151 -
IMeta Apr 2024Inflammatory bowel disease (IBD) is a significant global health concern. The gut microbiota plays an essential role in the onset and development of IBD. (SH), a...
Inflammatory bowel disease (IBD) is a significant global health concern. The gut microbiota plays an essential role in the onset and development of IBD. (SH), a traditional Chinese medicinal mushroom, has excellent anti-inflammatory effects and is effective at modulating the gut microbiota. Despite these attributes, the specific anticolitic effects of SH and the mechanisms through which the gut microbiota mediates its benefits remain unclear. Herein, we demonstrated that polyphenol-rich extract from SH effectively alleviated the pathological symptoms of dextran sodium sulfate (DSS)-induced colitis in mice by modulating the gut microbiota. Treatment with SH distinctly enriched , especially , and its metabolite 5-hydroxyindole-3-acetic acid (5HIAA). Oral gavage of live or 5HIAA potently mitigated DSS-induced colitis in mice. Moreover, both 5HIAA and SH significantly activated the aromatic hydrocarbon receptor (AhR), and the administration of an AhR antagonist abrogated their protective effects against colitis. These results underscore the potent efficacy of SH in diminishing DSS-induced colitis through the promotion of and 5HIAA, ultimately activating AhR signaling. This study unveils potential avenues for developing therapeutic strategies for colitis based on the interplay between SH and the gut microbiota.
PubMed: 38882491
DOI: 10.1002/imt2.180