Microbial Metabolites Research Articles

The Oral Microbiota, Microbial Metabolites, and Immuno-Inflammatory Mechanisms in Cardiovascular Disease

Cardiovascular diseases (CVDs) remain a leading cause of global morbidity and mortality. Recent advancements in high-throughput omics techniques have enhanced our understanding of the human microbiome’s role in the development of CVDs. Although the relationship between the gut microbiome and CVDs has attracted considerable research attention and has been rapidly evolving in recent years, the role of the oral microbiome remains less understood, with most prior studies focusing on periodontitis-related pathogens. In this review, we summarized previously reported associations between the oral microbiome and CVD, highlighting known CVD-associated taxa such as Porphyromonas gingivalis, Fusobacterium nucleatum, and Aggregatibacter actinomycetemcomitans. We also discussed the interactions between the oral and gut microbes. The potential mechanisms by which the oral microbiota can influence CVD development include oral and systemic inflammation, immune responses, cytokine release, translocation of oral bacteria into the bloodstream, and the impact of microbial-related products such as microbial metabolites (e.g., short-chain fatty acids [SCFAs], trimethylamine oxide [TMAO], hydrogen sulfide [H2S], nitric oxide [NO]) and specific toxins (e.g., lipopolysaccharide [LPS], leukotoxin [LtxA]). The processes driven by these mechanisms may contribute to atherosclerosis, endothelial dysfunction, and other cardiovascular pathologies. Integrated multi-omics methodologies, along with large-scale longitudinal population studies and intervention studies, will facilitate a deeper understanding of the metabolic and functional roles of the oral microbiome in cardiovascular health. This fundamental knowledge will support the development of targeted interventions and effective therapies to prevent or reduce the progression from cardiovascular risk to clinical CVD events.

Synergistic Interplay of Diet, Gut Microbiota, and Insulin Resistance: Unraveling the Molecular Nexus.

This comprehensive review explores the intricate relationship between gut microbiota, diet, and insulin resistance, emphasizing the novel roles of diet-induced microbial changes in influencing metabolic health. It highlights how diet significantly influences gut microbiota composition, with different dietary patterns fostering diverse microbial communities. These diet-induced changes in the microbiome impact human metabolism by affecting inflammation, energy balance, and insulin sensitivity, particularly through microbial metabolites like short-chain fatty acids (SCFAs). Focusing the key mediators like endotoxemia and systemic inflammation, and introduces personalized microbiome-based therapeutic strategies, it also investigates the effects of dietary components-fiber, polyphenols, and lipids-on microbiota and insulin sensitivity, along with the roles of protein intake and amino acid metabolism. The study compares the effects of Western and Mediterranean diets on the microbiota-insulin resistance axis. Therapeutic implications, including probiotics, fecal microbiota transplantation (FMT), and personalized diets, are discussed. Key findings reveal that high-fat diets, especially those rich in saturated fats, contribute to dysbiosis and increased intestinal permeability, while high-fiber diets promote beneficial bacteria and SCFAs. The review underscores the future potential of food and microbiota interventions for preventing or managing insulin resistance.

Soil Microbial and Metabolomic Shifts Induced by Phosphate-Solubilizing Bacterial Inoculation in Torreya grandis Seedlings

Phosphorus is crucial for plant growth and development, but excess fertilizer not absorbed by plants often binds with metal ions like iron and manganese, forming insoluble compounds that contribute to soil environmental pollution. This study investigates the impact of Burkholderia sp., a phosphate-solubilizing bacterium utilized as a biofertilizer, on the fertility of T. grandis soil, alongside the associated shifts in soil metabolites and their relationship with microbial communities after inoculation. The soil microbial community structures and metabolite profiles were analyzed via amplicon sequencing and high-resolution untargeted metabolomics. The inoculation of phosphate-solubilizing bacteria led to a significant (p < 0.05) enhancement in total phosphorus, potassium, and nitrogen concentrations in the soil, with a marked increase in available phosphorus in bulk soil (p < 0.05). Moreover, the microbial community structure exhibited significant shifts, particularly in the abundance of bacterial phyla such as Acidobacteria, Chloroflexi, Proteobacteria, and the fungal phylum Ascomycota. Metabolomic analysis revealed distinct metabolites, including fatty acids, hormones, amino acids, and drug-related compounds. Key microbial taxa such as Chloroflexi, Proteobacteria, Acidobacteria, Verrucomicrobia, Mucoromycota, and Ascomycota indirectly contributed to soil phosphorus metabolism by influencing these differential metabolites. In conclusion, the application of phosphate-solubilizing bacteria offers an innovative approach to improving soil quality in T. grandis, promoting phosphorus utilization efficiency, and enhancing soil ecosystem health by optimizing microbial communities and metabolite compositions.

The roles of the gut microbiota, metabolites, and epigenetics in the effects of maternal exercise on offspring metabolism.

Metabolic diseases, including obesity, dyslipidemia, and type 2 diabetes, have become severe challenges worldwide. The developmental origins of health and disease (DOHaD) hypothesis suggests that an adverse intrauterine environment can increase the risk of metabolic disorders in offspring. Studies have demonstrated that maternal exercise is an effective intervention for improving the offspring metabolic health. However, the pathways through which exercise works are unclear. It has been reported that the gut microbiota mediates the effect of maternal exercise on offspring metabolism, and epigenetic modifications have also been proposed to be important molecular mechanisms. Microbial metabolites can influence epigenetics by providing substrates for DNA or histone modifications, binding to G-protein coupled receptors to affect downstream pathways, or regulating the activity of epigenetic modifying enzymes. This review aims to summarize the intergenerational effect of maternal exercise and proposes that gut microbiota-metabolites-epigenetic regulation is an important mechanism by which maternal exercise improves offspring metabolism, which may yield novel targets for the early prevention and intervention of metabolic diseases.

Inflammation-targeted delivery of Urolithin A mitigates chemical- and immune checkpoint inhibitor-induced colitis.

Inflammatory bowel disease (IBD) treatment often involves systemic administration of anti-inflammatory drugs or biologics such as anti-TNF-α antibodies. However, current drug therapies suffer from limited efficacy due to unresponsiveness and adverse side effects. To address these challenges, we developed inflammation-targeting nanoparticles (ITNPs) using biopolymers derived from the gum kondagogu (Cochlospermum gossypium) plant. These ITNPs enable selective drug delivery to inflamed regions, offering improved therapeutic outcomes. We designed ITNPs that specifically bind to inflamed regions in both human and mouse intestines, facilitating more effective, uniform, and prolonged drug delivery within the inflamed tissues. Furthermore, we demonstrated that oral administration of ITNPs loaded with urolithin A (UroA), a microbial metabolite or its synthetic analogue UAS03 significantly attenuated chemical- and immune checkpoint inhibitor- induced colitis in pre-clinical models. In conclusion, ITNPs show great promise for delivering UroA or its analogues while enhancing therapeutic efficacy at lower doses and reduced frequency compared to free drug administration. This targeted approach offers a potential solution to enhance IBD treatment while minimizing systemic side effects.

Regulation of Milk Fat Synthesis: Key Genes and Microbial Functions

Milk is rich in a variety of essential nutrients, including fats, proteins, and trace elements that are important for human health. In particular, milk fat has an alleviating effect on diseases such as heart disease and diabetes. Fatty acids, the basic units of milk fat, play an important role in many biological reactions in the body, including the involvement of glycerophospholipids and sphingolipids in the formation of cell membranes. However, milk fat synthesis is a complex biological process involving multiple organs and tissues, and how to improve milk fat of dairy cows has been a hot research issue in the industry. There exists a close relationship between milk fat synthesis, genes, and microbial functions, as a result of the organic integration between the different tissues of the cow’s organism and the external environment. This review paper aims (1) to highlight the synthesis and regulation of milk fat by the first and second genomes (gastrointestinal microbial genome) and (2) to discuss the effects of ruminal microorganisms and host metabolites on milk fat synthesis. Through exploring the interactions between the first and second genomes, and discovering the relationship between microbial and host metabolite in the milk fat synthesis pathway, it may become a new direction for future research on the mechanism of milk fat synthesis in dairy cows.

Gut Microbial Metabolites and Future Risk of Parkinson's Disease: A Metabolome-Wide Association Study.

Alterations in gut microbiota are observed in Parkinson's disease (PD). Previous studies on microbiota-derived metabolites in PD were small-scale and post-diagnosis, raising concerns about reverse causality. Our goal was to prospectively investigate the association between plasma microbial metabolites and PD risk within a metabolomics framework. A nested case-control study within the prospective EPIC4PD cohort, measured pre-diagnostic plasma microbial metabolites using untargeted metabolomics. Thirteen microbial metabolites were identified nominally associated with PD risk (P-value < 0.05), including amino acids, bile acid, indoles, and hydroxy acid, although none remained significant after multiple testing correction. Three pathways were implicated in PD risk: valine, leucine, and isoleucine degradation, butanoate metabolism, and propanoate metabolism. PD-associated microbial pathways were more pronounced in men, smokers, and overweight/obese individuals. Changes in microbial metabolites may represent a pre-diagnostic feature of PD. We observed biologically plausible associations between microbial pathways and PD, potentially influenced by individual characteristics. © 2024 The Author(s). Movement Disorders published by Wiley Periodicals LLC on behalf of International Parkinson and Movement Disorder Society.

An integrated microbiome- and metabolome-genome-wide association study reveals the role of heritable ruminal microbial carbohydrate metabolism in lactation performance in Holstein dairy cows.

Despite the growing number of studies investigating the connection between host genetics and the rumen microbiota, there remains a dearth of systematic research exploring the composition, function, and metabolic traits of highly heritable rumen microbiota influenced by host genetics. Furthermore, the impact of these highly heritable subsets on lactation performance in cows remains unknown. To address this gap, we collected and analyzed whole-genome resequencing data, rumen metagenomes, rumen metabolomes and short-chain fatty acids (SCFAs) content, and lactation performance phenotypes from a cohort of 304 dairy cows. The results indicated that the proportions of highly heritable subsets (h2 ≥ 0.2) of the rumen microbial composition (55%), function (39% KEGG and 28% CAZy), and metabolites (18%) decreased sequentially. Moreover, the highly heritable microbes can increase energy-corrected milk (ECM) production by reducing the rumen acetate/propionate ratio, according to the structural equation model (SEM) analysis (CFI = 0.898). Furthermore, the highly heritable enzymes involved in the SCFA synthesis metabolic pathway can promote the synthesis of propionate and inhibit the acetate synthesis. Next, the same significant SNP variants were used to integrate information from genome-wide association studies (GWASs), microbiome-GWASs, metabolome-GWASs, and microbiome-wide association studies (mWASs). The identified single nucleotide polymorphisms (SNPs) of rs43470227 and rs43472732 on SLC30A9 (Zn2+ transport) (P < 0.05/nSNPs) can affect the abundance of rumen microbes such as Prevotella_sp., Prevotella_sp._E15-22, Prevotella_sp._E13-27, which have the oligosaccharide-degradation enzymes genes, including the GH10, GH13, GH43, GH95, and GH115 families. The identified SNPs of chr25:11,177 on 5s_rRNA (small ribosomal RNA) (P < 0.05/nSNPs) were linked to ECM, the abundance alteration of Pseudobutyrivibrio_sp. (a genus that was also showed to be linked to the ECM production via the mWASs analysis), GH24 (lysozyme), and 9,10,13-TriHOME (linoleic acid metabolism). Moreover, ECM, and the abundances of Pseudobutyrivibrio sp., GH24, and 9,10,13-TRIHOME were significantly greater in the GG genotype than in the AG genotype at chr25:11,177 (P < 0.05). By further the SEM analysis, GH24 was positively correlated with Pseudobutyrivibrio sp., which was positively correlated with 9,10,13-triHOME and subsequently positively correlated with ECM (CFI = 0.942). Our comprehensive study revealed the distinct heritability patterns of rumen microbial composition, function, and metabolism. Additionally, we shed light on the influence of host SNP variants on the rumen microbes with carbohydrate metabolism and their subsequent effects on lactation performance. Collectively, these findings offer compelling evidence for the host-microbe interactions, wherein cows actively modulate their rumen microbiota through SNP variants to regulate their own lactation performance. Video Abstract.

CNSC-38. INFLUENCE OF AGE, IMMUNOREGULATORY IDO, AND IMMUNOTHERAPY ON THE MICROBIOME IN MICE WITH AN EXPERIMENTAL BRAIN TUMOR

Abstract OBJECTIVE This study aimed to determine how IDO and subject age impact the gut microbiome and microbial metabolites during immunotherapy for glioblastoma (GBM). METHODS Serum and colon contents were collected from young 16-20- or older adult 92-118-week-old wild-type (WT; C57BL/6), IDO knockout (IDOKO), and IDO enzyme null (H350A) mice analyzed for 16S rRNA gut microbiome composition and microbial-derived aromatic amino acid metabolites via LC/MS/MS. Fecal samples from young 7-8 or older adult 81-85 week-old WT mice with intracranial GL261 brain tumors treated with or without brain radiation (RT) and PD-1 mAb were also analyzed. RESULTS Young and old IDOKO and H350A mice demonstrated a unique gut microbiome signature with an elevated abundance of Bifidobacterium and Helicobacter (p&amp;lt;0.05) and a reduced abundance of Ventriosum and Sireaum compared to WT mice (p&amp;lt;0.001). Prevotellaceae, Muribaculum, Alistipes, Enterohabdus, Clostridia, and Akkermansia were different in IDOKO and H350A mice compared to WT - but only in old mice. Serum aryl-lactates including phenyllactate, indolelacatate, and 4-hydroxyphenyllactate were increased in IDOKO mice compared to WT and H350A mice (p&amp;lt;0.001) – again, only in old mice. Older adult WT mice with GL261 showed lower fecal aryl-lactates compared to younger counterparts. Treatment with RT + PD-1 mAb decreased phenyllactate levels in old but not young mice with GL261 (p&amp;lt;0.05). CONCLUSIONS There are IDO enzyme- and non-enzyme-dependent effects on gut microbiota composition and bioactive microbial aromatic amino acid metabolites. These data warrant further investigation into how microbial metabolism affects immunotherapy efficacy and brain tumor survival across the lifespan.

Effects of Key Rumen Bacteria and Microbial Metabolites on Fatty Acid Deposition in Goat Muscle

In this study, the fatty acid composition in the muscles of Hechuan white goats was correlated with the metabolome and metagenome of their rumen contents, and potential effects of the metabolites and microorganisms in the rumen on host muscle fatty acid deposition were analyzed. The results of the correlation analysis between the rumen content’s metabolome and muscle fatty acid content showed that vitamin-B-related metabolites were significantly correlated with fatty acid content (p &lt; 0.05). Most of these metabolites were positively correlated with stearic acid and negatively correlated with palmitic acid. In accordance with the level of fatty acid content, significant differences were found in the microbial species and abundance among groups at the species level. An abundance of Bacteroides, Ruminococcaceae P7, Eubacterium ruminant, and Prevotella in the rumen was significantly correlated with fatty acid content. These results provide data support for the development of targeted feeding management strategies to improve the quality of goat meat.

Microbial community succession patterns and metabolite profiles in cigar tobacco during different mildew stages

Mildew in cigar tobacco leaves (CTLs) degrades both quality and market value. This research systematically examines dynamic changes in key metabolic compounds and microbial community succession throughout the mildew process, categorized into three stages: un-mildew (d0), early-mildew (d4 and d8), and late-mildew (d12 and d16). As mildew progresses, carbohydrates decrease, nitrogen metabolism is hindered, the carbon-nitrogen ratio (C/N) declines, and pH rises, making the tobacco weakly alkaline. The total amount of volatile flavor compounds (VFCs) increases, with the proportion of nitrogen-containing compounds such as nicotine rising, while neophytadiene, ketones, and alcohols decrease, leading to a disruption in the coordination of various aroma substances. Microbial diversity declines, with shifts in populations of Staphylococcus, Pseudomonas, Aspergillus, and Sampaiozyma. Six fungal and five bacterial genera are the characteristic dominate microorganisms at different stages. Co-occurrence network analysis shows that complexity decreases and stability declines, while microbial diversity peaks at the early-mold stage and is severely compromised at the late-mold stage in terms of stability and functional diversity. Two-way Orthogonal Partial Least Squares (O2PLS) identified 12 fungal and 3 bacterial genera as key drivers of metabolic changes. Partial Least Squares Structural Equation Modeling (PLS-SEM) emphasized the role of fungi in CTL degradation and the impact of C/N ratio on fungal metabolism. This study, for the first time, elucidates the complex relationship between microbial succession and metabolite compounds during mildew process, providing a reference for dynamic monitoring of fermented tobacco quality.

The gut microbial metabolite indole-3-aldehyde alleviates impaired intestinal development by promoting intestinal stem cell expansion in weaned piglets

BackgroundWeaning stress-induced diarrhea is widely recognized as being associated with gut microbiota dysbiosis. However, it has been challenging to clarify which specific intestinal microbiota and their metabolites play a crucial role in the antidiarrhea process of weaned piglets.ResultsIn this study, we first observed that piglets with diarrhea exhibited a lower average daily gain and higher diarrhea score, and elevated levels of lipopolysaccharide (LPS) and D-lactate (D-LA) compared to healthy piglets. Subsequently, we analyzed the differences in intestinal microbial composition and metabolite levels between healthy and diarrheal weaned piglets. Diarrheal piglets demonstrated intestinal microbiota dysbiosis, characterized primarily by a higher Firmicutes to Bacteroidota ratio, a deficiency of Lactobacillus amylovorus and Lactobacillus reuteri, and an increased abundance of Bacteroides sp.HF-5287 and Bacteroides thetaiotaomicron. Functional profiling of the gut microbiota based on Kyoto Encyclopedia of Genes and Genomes (KEGG) data was performed, and the results showed that tryptophan metabolism was the most significantly inhibited pathway in piglets with diarrhea. Most tryptophan metabolites were detected at lower concentrations in diarrheal piglets than in healthy piglets. Furthermore, we explored the effects of dietary indole-3-aldehyde (IAld), a key tryptophan metabolite, on intestinal development and gut barrier function in weaned piglets. Supplementation with 100 mg/kg IAld in the diet increased the small intestine index and improved intestinal barrier function by promoting intestinal stem cell (ISC) expansion in piglets. The promotion of ISC expansion by IAld was also confirmed in porcine intestinal organoids.ConclusionsThese findings revealed that intestinal microbial tryptophan metabolite IAld alleviates impaired intestinal development by promoting ISC expansion in weaned piglets.

Tetrandrine Alleviates Pulmonary Fibrosis by Modulating Lung Microbiota-Derived Metabolism and Ameliorating Alveolar Epithelial Cell Senescence.

Tetrandrine (TET) is a minimally toxic drug extracted from the root of Stephania tetrandra. We previously demonstrated that TET could ameliorate pulmonary fibrosis (PF) by modulating autophagy. However, the mechanism behind TET's protective effects on PF remains unclear. In this study, we utilized 16S rRNA gene sequencing, nontargeted metabolomic analysis, and network pharmacology to identify changes in lung microbiota and metabolites that mediate alveolar epithelial cell senescence in bleomycin (BLM)-induced PF in mice. Additionally, we employed Western blot analysis, RT-PCR, and immunofluorescence staining to investigate the invitro and invivo effects of TET and its influential bacterial metabolites on PF. The TET intervention alleviated PF by regulating the compositions of lung microbial communities (Streptococcus, Micrococcus, Acinetobacter, Altererythrobacter, Atopostipes, Candidatus Cloacimonas, Clostridium sensu stricto 1, Sphingomonas, Listeria, Blautia, and Pseudomonas) and metabolites (3,4-dihydroxyphenylpropionic acid (3,4-DHPPA), 6-Aminonicotinamide, N-acetyl-5-methoxykynuramine, and resiniferatoxin). Through network pharmacological analysis, it was determined that 3,4-DHPPA played a crucial role in alleviating PF by further inhibiting the senescence of alveolar epithelial cells, a finding further validated in exvivo experiments. TET mitigated BLM-induced PF in murine models through the modulation of lung microbiota composition and metabolism. Specifically, TET augmented the level of the microbiota-derived metabolite, 3,4-DHPPA, which in turn attenuated alveolar epithelial cell senescence.

MetOrigin 2.0: Advancing the discovery of microbial metabolites and their origins

MetOrigin 2.0: Advancing the discovery of microbial metabolites and their origins

Gut Microbiota Disorders and Metabolic Syndrome: Tales of a Crosstalk Process

Abstract The microbiota in humans consists of trillions of microorganisms that are involved in the regulation of the gastrointestinal tract and immune and metabolic homeostasis. The gut microbiota (GM) has a prominent impact on the pathogenesis of metabolic syndrome (MetS). This process is reciprocal, constituting a crosstalk process between the GM and MetS. In this review, GM directly or indirectly inducing MetS via the host–microbial metabolic axis has been systematically reviewed. Additionally, the specifically altered GM in MetS are detailed in this review. Moreover, short-chain fatty acids (SCFAs), as unique gut microbial metabolites, have a remarkable effect on MetS, and the role of SCFAs in MetS-related diseases is highlighted to supplement the gaps in this area. Finally, the existing therapeutics are outlined, and the superiority and shortcomings of different therapeutic approaches are discussed, in hopes that this review can contribute to the development of potential treatment strategies.

Fecal tryptophan metabolite profiling in newborns in relation to microbiota and antibiotic treatment

In the first days of life, the newborns’ intestinal microbiota develops simultaneously with the intestinal gut barrier and follows intestinal immunity. The mode of delivery shows significant impact on microbial development and, thus, the initiation of the tryptophan catabolism pathway. Further antibiotics (ATB) treatment of mothers before or during delivery affects the microbial and tryptophan metabolite composition of stool of the caesarean- and vaginal-delivered newborns. The determination of microbiome and levels of tryptophan microbial metabolites in meconium and stool can characterize intestinal colonization of a newborn. From 134 samples from the Central European Longitudinal Studies of Parents and Children: The Next Generation (CELSPAC: TNG) cohort study, 16S rRNA gene sequencing was performed, and microbial tryptophan metabolites were quantified using ultra-high-performance liquid chromatography with triple-quadrupole mass spectrometry. Microbial diversity and concentrations of tryptophan metabolites were significantly higher in stool compared to meconium. Treatment of mothers with ATB before or during delivery affects metabolite composition and microbial diversity in stool of vaginal- and caesarean-delivered newborns. Correlation of microbial and metabolite composition shows significant positive correlations of indol-3-lactic acid, N-acetyl-tryptophan and indol-3-acetic acid with Bifidobacterium, Bacteroides and Peptoclostridium. The positive effect of vaginal delivery on newborns’ microbiome development is degraded when mother is treated with ATB before or during delivery.Key points• Antibiotic treatment diminishes the positive effects of vaginal delivery.• Antibiotic treatment affects metabolite and microbial composition in newborns.• Bifidobacterium and Peptoclostridium could be the producer of indole-lactic acid.

Novel application of cyclo(-Phe-Pro) in mitigating aluminum toxicity through oxidative stress alleviation in wheat roots

Microbial secondary metabolites are crucial in plant-microorganism interactions, regulating plant growth and stress responses. In this study, we found that cyclo(-Phe-Pro), a proline-based cyclic dipeptide secreted by many microorganisms, alleviated aluminum toxicity in wheat roots by increasing root growth, decreasing callose deposition, and decreasing Al accumulation. Cyclo(-Phe-Pro) also significantly reduced Al-induced reactive oxygen species (ROS) with H2O2, O2•-, and •OH levels decreasing by 19.1%, 42.8%, and 17.9% in root tips, thus protecting the plasma membrane from oxidative damage. Although Al stress increased the activities of superoxide dismutase (SOD), catalase (CAT), peroxidase (POD), and ascorbate peroxidase (APX) in wheat roots, cyclo(-Phe-Pro) application reduced these enzyme activities. However, compared to the Al treatment, cyclo(-Phe-Pro) application increased DPPH and FRAP activities by 16.8% and 14.9%, indicating increased non-enzymatic antioxidant capacity in wheat roots. We observed that Al caused the oxidation of ascorbate (AsA) and glutathione (GSH) to dehydroascorbate (DHA) and glutathione disulfide (GSSG), respectively. Under Al stress, cyclo(-Phe-Pro) treatment maintained reduced AsA and GSH levels, as well as high AsA/DHA and GSH/GSSG redox pair ratios in wheat roots. High AsA/DHA and GSH/GSSG ratios can reduce Al toxicity by neutralizing free radicals and restoring redox homeostasis via antioxidant properties. These results suggest that cyclo(-Phe-Pro) maintains ASA- and GSH-dependent redox homeostasis to alleviate oxidative and Al stress in wheat roots. Findings of this study establishes a theoretical foundation for using microbial metabolites to mitigate Al toxicity in acidic soils, highlighting their potential in sustainable agriculture.

Trends in dietary choline and betaine intake among Chinese adults: the China Health and Nutrition Survey 1991-2011.

Choline and its derivative betaine are important methyl donors, components of cell membrane phospholipids, or precursors of the neurotransmitter acetylcholine and the gut microbial metabolite trimethylamine-N-oxide. We aimed to investigate trends in dietary intake and food sources of total choline, individual choline forms, and betaine in Chinese adults using data from the China Health and Nutrition Survey (CHNS) 1991-2011. The sample was drawn from urban and rural communities in 12 provinces or autonomous regions with a multistage, random cluster design. Dietary intake was estimated using three consecutive 24-hour dietary recalls in combination with a household food inventory. Linear mixed-effect models were constructed to calculate adjusted mean intake values and 95% confidence intervals (CIs) using R version 4.2.2. A total of 11,188 men and 12,279 women aged 18 years or older were included. Between 1991 and 2011, total choline intake increased from 219.3 (95% CI: 215.1-223.4) mg/d to 269.0 (95% CI: 265.6-272.5) mg/d in men and from 195.6 (95% CI: 191.8-199.4) mg/d to 240.4 (95% CI: 237.4-243.5) mg/d in women (both P-trends <0.001). Phosphatidylcholine was the major form of dietary choline and its contribution to total choline increased from 46.9% in 1991 to 58.8% in 2011. Cereals were the primary food source of total choline before 2000 while eggs had ranked at the top since 2004. Dietary betaine intake was relatively steady over time with a range of 134.0-151.5 mg/d in men (P-trend <0.001) and 111.7-125.3 mg/d in women (P-trend >0.05). In conclusion, Chinese adults experienced a significant increase in dietary intake of choline, particularly phosphatidylcholine during 1991-2011 and animal-derived foods have replaced plant-based foods as the main food sources of choline. Betaine intake remained relatively stable over time. Future efforts should address the health effects of these changes.

Long-Term Implicit Epigenetic Stress Information in the Enteric Nervous System and its Contribution to Developing and Perpetuating IBS.

Psychiatric and mood disorders may play an important role in the development and persistence of irritable bowel syndrome (IBS). Previously, we hypothesized that stress-induced implicit memories may persist throughout life via epigenetic processes in the enteric nervous system (ENS), independent of the central nervous system (CNS). These epigenetic memories in the ENS may contribute to developing and perpetuating IBS. Here, we further elaborate on our earlier hypothesis. That is, during pregnancy, maternal prenatal stresses perturb the HPA axis and increase circulating cortisol levels, which can affect the maternal gut microbiota. Maternal cortisol can cross the placental barrier and increase cortisol-circulating levels in the fetus. This leads to dysregulation of the HPA axis, affecting the gut microbiota, microbial metabolites, and intestinal permeability in the fetus. Microbial metabolites, such as short-chain fatty acids (which also regulate the development of fetal ENS), can modulate a range of diseases by inducing epigenetic changes. These mentioned processes suggest that stress-related, implicit, long-term epigenetic memories may be programmed into the fetal ENS during pregnancy. Subsequently, this implicit epigenetic stress information from the fetal ENS could be conveyed to the CNS through the bidirectional microbiota-gut-brain axis (MGBA), leading to perturbed functional connectivity among various brain networks and the dysregulation of affective and pain processes.

Ex vivo and miniaturized in vitro models to study microbiota-gut-brain axis.

The microbiota-gut-brain axis involves complex bidirectional communication through neural, immune, and endocrine pathways. Microbial metabolites, such as short-chain fatty acids, influence gut motility and brain function by interacting with gut receptors and modulating hormone release. Additionally, microbial components such as lipopolysaccharides and cytokines can cross the gut epithelium and the blood-brain barrier, impacting immune responses and cognitive function. Ex vivo models, which preserve gut tissue and neural segments, offer insight into localized gut-brain communication by allowing for detailed study of nerve excitability in response to microbial signals, but they are limited in systemic complexity. Miniaturized in vitro models, including organ-on-chip platforms, enable precise control of the cellular environment and simulate complex microbiota-host interactions. These systems allow for the study of microbial metabolites, immune responses, and neuronal activity, providing valuable insights into gut-brain communication. Despite challenges such as replicating long-term biological processes and integrating immune and hormonal systems, advancements in bioengineered platforms are enhancing the physiological relevance of these models, offering new opportunities for understanding the mechanisms of the microbiota-gut-brain axis. This review aims to describe the ex vivo and miniaturized in vitro models which are used to mimic the in vivo conditions and facilitate more precise studies of gut brain communication.