Intestinal Metabolism Research Articles

Recent Advances in the Gastrointestinal Complex in Vitro Model for ADME Studies.

Intestinal absorption is a complex process involving the permeability of the epithelial barrier, efflux transporter activity, and intestinal metabolism. Identifying the key factors that govern intestinal absorption for each investigational drug is crucial. To assess and predict intestinal absorption in humans, it is necessary to leverage appropriate in vitro systems. Traditionally, Caco-2 monolayer systems and intestinal Ussing chamber studies have been considered the 'gold standard' for studying intestinal absorption. However, these methods have limitations that hinder their universal use in drug discovery and development. Recently, there has been an increasing number of reports on complex in vitro models (CIVMs) using human intestinal organoids derived from intestinal tissue specimens or iPSC-derived enterocytes plated on 2D or 3D in microphysiological systems. These CIVMs provide a more physiologically relevant representation of key ADME-related proteins compared to conventional in vitro methods. They hold great promise for use in drug discovery and development due to their ability to replicate the expressions and functions of these proteins. This review highlights recent advances in gut CIVMs employing intestinal organoid model systems compared to conventional methods. It is important to note that each CIVM should be tailored to the investigational drug properties and research questions at hand.

Metabolism in the large intestine wall after injury of the thoracic spinal cord (experimental study)

Ailm: to assess metabolic processes in the serous layer of the large intestine in the acute period of spinal injury.Materials and Methods: the experiment was carried out on laboratory animals — Wistar rats (n = 20). Spinal injury was simulated by complete transection of the spinal cord at the level of Th5-Th6 vertebrae. Metabolic changes in the intestinal wall were assessed before injury, 3 and 24 hours after spinal cord transection. Metabolism was assessed in vivo using fluorescence time-resolved macroimaging technology (macroFLIM) by autofluorescence in the spectral channel of the metabolic cofactor NAD(P)H.Results: a significant (p = 0.041) increase in the mean fluorescence lifetime (τm) by 12% and the lifetime of the long component (τ2) of the NAD(P)H cofactor by 13% (p = 0.008) was detected 24 hours after injury. MacroFLIM showed an increase in the intensity of metabolism in the large intestine wall.Conclusion: for the first time in an in vivo experiment, it has been shown that the acute period of spinal injury is accompanied by an increase in metabolic activity in the tissues of the large intestine. The revealed phenomenon confirms the role of the large intestine in compensatory reactions to spinal injury and open up new possibilities for therapy in the acute period of spinal cord injury.

Characterization of the chemical composition of different parts of Dolichos lablab L. and revelation of its anti-ulcerative colitis effects by modulating the gut microbiota and host metabolism

Ethnopharmacological relevanceUlcerative colitis (UC) is a non-specific inflammatory disease characterized by long duration and easy relapse. Dolichos lablab L. (DLL) belongs to the family Fabaceae, was listed in a famous Chinese medical classic, Compendium of Materia Medic, and described as possessing features that invigorate the spleen, alleviate dampness, provide diarrhea relief, and other effects. The DLL-dried white mature seeds (DS) and dried flower (DF), which hold significant medicinal value in China, were used in clinical prescriptions to prevent and treat UC. DS and DF have appeared in different editions of the Pharmacopoeia of the People's Republic of China from 1977 to 2020. However, their chemical composition, pharmacological effects, and mechanism of treating UC are unclear. Aim of the studyThis study aimed to characterize the chemical composition of different parts of DLL (seeds and flowers), further explore their pharmacological effects, and elaborate its underlying mechanism of treating UC. MethodsThe chemical composition of DS and DF crude polysaccharides (DSP and DFP) and ethanolic extracts (DSE and DFE) were characterized by high-performance anion-exchange chromatography (HPAEC), ultra-high performance liquid chromatography-mass spectrometry (UHPLC-MS), and gas chromatography-mass spectrometry (GC-MS). Then, based on the acute UC mice model, the pharmacodynamic effects were investigated by Western blotting, ELISA, and other methods. Finally, the 16S rRNA gene sequencing and metabonomic analysis were used to explore the regulatory effects of DS and DF on intestinal microbiota and host metabolism. ResultsDSE and DFE inhibited the oxidative stress response, reducing proinflammatory factor production and maintaining intestinal barrier integrity in UC mice. The 16S rRNA gene sequencing and metabonomic analysis revealed that DS and DF treated UC by regulating the intestinal microbiota structure and reversing the abnormal metabolism of the host. ConclusionThis study suggested that different parts of DLL (flowers and seeds) may be potential medicines for treating UC, which exert their therapeutic effects through various active ingredients and might contribute significantly to reducing the economic pressures and challenges of UC treatment worldwide.

HOST-MICROBE METABOLIC INTERACTIONS IN DISEASE AND AGING

Abstract As a key mediator of environmental influences on cellular functions, metabolism is crucial for cellular adaptation to the environment. Perturbations of metabolic homeostasis by various environmental factors, including diet and lifestyle, are associated with numerous metabolic diseases and contribute to acceleration of aging. To understand how metabolism mediates environmental regulation of cellular functions and how disruption of metabolic homeostasis contributes to pathogenesis of diseases and aging, we have been focused on a nutrient-sensing pathway consisting of NAD+, SIRT1, the most conserved mammalian NAD+-dependent protein deacetylase/deacylase, and protein acylations. Employing genetically modified mice and cultured cells as model systems, we have recently shown that NAD+ and SIRT1 are key mediators of host-microbe metabolic interactions. On one hand, host NAD metabolism is regulated by gut microbiota. On the other hand, SIRT1 age-dependently modulates gut microbiota through regulation of intestinal bile acid metabolism and Paneth cell activation. Furthermore, we identified SIRT1 as a key regulator of methionine metabolism in embryonic stem cells and developing embryos, thereby modulating their sensitivity to methionine restriction, a dietary regimen that protects against metabolic diseases and aging. Intriguingly, we recently demonstrated that dietary methionine restriction impairs anti-tumor immunity through interaction with gut-microbiota. Together, our findings uncover an important role of the NAD+-SIRT1 axis in mediating host-microbe metabolic interactions that influence disease and aging.

Resveratrol ameliorates intestinal lipid metabolism through the PPAR signaling pathway in high-fat diet-fed red tilapia (Oreochromis niloticus)

Feeding high-fat (HF) diets has been shown to cause hepatic and intestinal impairment in fish species, but the mode of action, especially the pathways involved in the intestine, has not been determined yet. In this study, the effects of resveratrol (RES) supplementation on the intestinal structure, microbial flora, and fat metabolism in red tilapia (Oreochromis niloticus) were determined. The results showed RES maintained the structural integrity of the intestine and significantly increased the number of goblet cells in the midgut. RES significantly induced interferon (IL)-1β, IL-6, IL-10, and tumor necrosis factor (TNF)-α, serumal and fecal trimetlylamine oxide (TMAO) and lipopolysaccharides (LPS), intestinal acetic acid levels. However, the concentrations of bound bile acids increased in HF-fed red tilapia. Atp5fa1 and Pafah1b3 significantly increased, Pmt and Acss2 significantly decreased, respectively, with RES supplementation, which was alleviated and retained at the same level in the selisistat (EX527) group. While for transcriptome and proteomics results, RES was found to promote fatty acid β-oxidation and arachidonic acid metabolism associated with the peroxisome proliferator-activated receptor (PPAR) signaling pathway. The next validation experiment showed some genes related to apoptosis and fatty acid metabolism pathways were altered by RES supplementation. Namely, sn6, loc100702698, new_14481, and prkaa1 were upregulated, while ffrs1, ap3s1, and loc100705861 were downregulated. RES significantly increased Planctomycetes and Verrucomicrobia while decreased Moonvirus, Citrobacter, and Pseudomonas. Akkermansia and Fusobacterium significantly increased and Aeromonas significantly decreased. Thus, unsaturated fatty acid biosynthesis significantly increased and carbohydrate/energy metabolism decreased. To conclude, RES enabled the body to complete fatty acid β-oxidation and arachidonic acid metabolism, whereas the addition of inhibitors increased the expression of the phagosome transcriptome and reduced fatty acid β-oxidative metabolism.

Latin-American consensus on the transition into adult life of patients with X-linked hypophosphatemia

IntroductionX-linked hypophosphatemia is an orphan disease of genetic origin and multisystem involvement. It is characterized by a mutation of the PHEX gene which results in excess FGF23 production, with abnormal renal and intestinal phosphorus metabolism, hypophosphatemia and osteomalacia secondary to chronic renal excretion of phosphate. Clinical manifestations include hypophosphatemic rickets leading to growth abnormalities and osteomalacia, myopathy, bone pain and dental abscesses. The transition of these patients to adult life continues to pose challenges to health systems, medical practitioners, patients and families. For this reason, the aim of this consensus is to provide a set of recommendations to facilitate this process and ensure adequate management and follow-up, as well as the quality of life for patients with X-linked hypophosphatemia as they transition to adult life.Materials and MethodsEight Latin American experts on the subject participated in the consensus and two of them were appointed as coordinators. The consensus work was done in accordance with the nominal group technique in 6 phases: (1) question standardization, (2) definition of the maximum number of choices, (3) production of individual solutions or answers, (4) individual question review, (5) analysis and synthesis of the information and (6) synchronic meetings for clarification and voting. An agreement was determined to exist with 80% votes in favor in three voting cycles.Results and DiscussionTransition to adult life in patients with hypophosphatemia is a complex process that requires a comprehensive approach, taking into consideration medical interventions and associated care, but also the psychosocial components of adult life and the participation of multiple stakeholders to ensure a successful process. The consensus proposes a total of 33 recommendations based on the evidence and the knowledge and experience of the experts. The goal of the recommendations is to optimize the management of these patients during their transition to adulthood, bearing in mind the need for multidisciplinary management, as well as the most relevant medical and psychosocial factors in the region.

Genomic and biochemical analysis reveals fermented product of a putative novel Romboutsia species involves the glycometabolism of tilapia

Fish have a restricted capacity to utilize carbohydrates. Gut microbiota contribute to carbohydrate degradation in the host. The connection between the intestinal microbiota and carbohydrate metabolism is not well known in fish. We found that when feed was transformed from zooplankton-based to plant-based diet, the population of genus Romboutsia in tilapia gut increased. We inferred that the abundance of the genus Romboutsia was positively correlated with dietary sugar levels. Then, a strain of genus Romboutsia was obtained and designated MY01. Strain MY01 was a novel species of Romboutsia based on its genomic analysis. Many genes involved in carbohydrate metabolism were found in its genome, including Carbohydrate Active enZymes (CAZymes) genes associated with dietary fiber fermentation. An increased quantity of short-chain fatty acids (SCFAs) and decreased quantity of carbohydrates in feed fermented with MY01 were revealed by GC–MS and HPLC analysis. Fermented feed with MY01 increased the insulin content and decreased the glucose content of tilapia serum. Our in vivo and in vitro results are the first to suggest that fermented feed with Romboutsia regulates the tilapia glycometabolism by producing SCFAs to stimulate insulin secretion, and by reducing carbohydrates content of feed simultaneously to decrease blood glucose eventually. In further, the study provides a potential source of SCFAs production.

Transcriptome analysis reveal the effect of freshwater sediments containing 2,3,7,8-tetrachlorodibenzo-p-dioxin on the Macrobrachium rosenbergii hepatopancreas, intestine, and muscle

This research evaluated the hepatopancreas, intestine, and muscle transcriptome alternation of Macrobrachium rosenbergii, and to confirm the relative glycerophospholipid, cytochrome P450 system, and fatty acid metabolism gene expression in sediments containing 2,3,7,8-tetrachlorodibenzo-p-dioxin (TCDD) of 60 ng/sediment (g) and 700 ng/sediment (g) for 90 days of culture.Transcriptome analysis revealed that the TCDD sediment affected the hepatopancreatic metabolism of xenobiotics in M. rosenbergii via the cytochrome P450 system, drug metabolism-other enzymes, drug metabolism-cytochrome P450, chemical carcinogenesis, and lysosome function. Intestinal analysis also showed a similar phenomenon, but this finding was not observed in the muscle tissue.qPCR analysis indicated that the expression levels of APTG4, LPGAT1, ACHE, GPX4, ECHS1, ATP5B, FABP, and ACC in the hepatopancreatic and intestinal tissues decreased, but those in the muscle tissues did not.In summary, TCDD sediment induced tissue metabolism, especially in the hepatopancreas and intestine. TCDD sediment mainly affected the digestive enzyme gene expression with concentration. These results indicated that the presence of TCDD in the sediment played a major role in the hepatopancreatic and intestinal metabolism system of M. rosenbergii.

Walnut peptide alleviates obesity, inflammation and dyslipidemia in mice fed a high-fat diet by modulating the intestinal flora and metabolites.

Obesity is a chronic disease in which the body stores excess energy in the form of fat, and intestinal bacterial metabolism and inflammatory host phenotypes influence the development of obesity. Walnut peptide (WP) is a small molecule biopeptide, and the mechanism of action of WP against metabolic disorders has not been fully elucidated. In this study, we explored the potential intervention mechanism of WP on high-fat diet (HFD)-induced obesity through bioinformatics combined with animal experiments. PPI networks of Amino acids and their metabolites in WP (AMWP) and "obesity" and "inflammation" diseases were searched and constructed by using the database, and their core targets were enriched and analyzed. Subsequently, Cytoscape software was used to construct the network diagram of the AMWP-core target-KEGG pathway and analyze the topological parameters. MOE2019.0102 was used to verify the molecular docking of core AMWP and core target. Subsequently, an obese Mice model induced by an HFD was established, and the effects of WP on obesity were verified by observing weight changes, glucose, and lipid metabolism levels, liver pathological changes, the size of adipocytes in groin adipose tissue, inflammatory infiltration of colon tissue, and intestinal microorganisms and their metabolites. The network pharmacology and molecular docking showed that glutathione oxide may be the main active component of AMWP, and its main targets may be EGFR, NOS3, MMP2, PLG, PTGS2, AR. Animal experiments showed that WP could reduce weight gain and improve glucose-lipid metabolism in HFD-induced obesity model mice, attenuate hepatic lesions reduce the size of adipocytes in inguinal adipose tissue, and reduce the inflammatory infiltration in colonic tissue. In addition, the abundance and diversity of intestinal flora were remodeled, reducing the phylum Firmicutes/Bacteroidetes (F/B) ratio, while the intestinal mucosal barrier was repaired, altering the content of short-chain fatty acids (SCFAs), and alleviating intestinal inflammation in HFD-fed mice. These results suggest that WP intervenes in HFD-induced obesity and dyslipidemia by repairing the intestinal microenvironment, regulating flora metabolism and anti-inflammation. Our findings suggest that WP intervenes in HFD-induced obesity and dyslipidemia by repairing the intestinal microenvironment, regulating flora metabolism, and exerting anti-inflammatory effects. Thus, WP may be a potential therapeutic strategy for preventing and treating metabolic diseases, and for alleviating the intestinal flora disorders induced by these diseases. This provides valuable insights for the development of WP therapies.

Differential effects of dietary polyphenols on oral pharmacokinetics of cyclin-dependent kinase inhibitors in rats: a mechanistic framework for in vitro-in vivo extrapolation.

Cyclin-dependent kinase inhibitors are subject to rapid first-pass metabolism, and their oral absorption is hindered by intestinal CYP3A4 and P-gp. The present study investigates the impact of dietary polyphenols on the oral pharmacokinetics of palbociclib and ribociclib, considering their potential as modulators of CYP3A4 and P-gp. Therefore, potential inhibitory effects of dietary polyphenols on drug metabolism and efflux of these drugs were investigated using molecular docking; in vitro preclinical assay using rat liver microsomes and Caco-2 cell monolayers; in vivo, pharmacokinetic parameters were determined in rats pretreated with dietary polyphenols. Curcumin and quercetin have the highest binding affinities to the PXR's AF-2 region cluster. Curcumin and quercetin significantly inhibited both intestinal efflux and CYP3A4-mediated metabolism of palbociclib and ribociclib (P < .05). In rats pretreated with curcumin, Cmax of palbociclib exhibited a 5.13% increase, while the AUC0-24h of ribociclib showed a significant increase of 18.83% (P < .05). Quercetin administration, notably, impedes the pharmacokinetics of palbociclib. However, the pharmacokinetics of ribociclib remains unaffected by quercetin. In conclusion, the utilization of curcumin as a bioenhancer can enhance the bioavailability of dual substrates of P-gp and CYP3A4.

Ginkgo biloba Extract Drives Gut Flora and Microbial Metabolism Variation in a Mouse Model of Alzheimer's Disease.

Alzheimer's disease (AD) is a complex neurodegenerative disease. Numerous investigations have demonstrated that medications that regulate the "brain-gut" axis can ameliorate disease symptoms of AD. Studies have shown that Ginkgo biloba extract (EGb) is involved in intestinal metabolism to meet the goal of illness treatment. EGb is currently utilized extensively in the clinical prevention and treatment of cardiovascular and cerebrovascular diseases. However, the regulatory effect of EGb on intestinal flora and its metabolites in AD pathology remains largely speculative. In this study, the Morris water maze test showed a significant improvement of spatial memory in the AD mouse model (APP/PS1 mice) after EGb treatment. We next confirmed the positive effects of EGb on the gut flora and metabolites of APP/PS1 mice and further showed that EGb treatment reshaped the disturbed gut microbiome, in particular by reducing the Firmicutes/Bacteroides ratio and increasing the abundance of Bacteroidetes, Uroviricota, Streptophyta, and Spirochaetes. Meanwhile, a non-targeted metabolomics analysis showed that EGb treatment significantly reversed the dysfunction of the microbial metabolic phenotype by altering Limosilactobacillus and Parvibacte, with 300 differential metabolites modulated (131 up-regulated, 169 down-regulated). Our findings highlight the significant regulatory impact of EGb on intestinal microflora and microbial metabolism in AD mice models and provide a potential therapeutic strategy for AD.

Simultaneous Prediction Method for Intestinal Absorption and Metabolism Using the Mini-Ussing Chamber System.

Many evaluation tools for predicting human absorption are well-known for using cultured cell lines such as Caco-2, MDCK, and so on. Since the combinatorial chemistry and high throughput screening system, pharmacological assay, and pharmaceutical profiling assay are mainstays of drug development, PAMPA has been used to evaluate human drug absorption. In addition, cultured cell lines from iPS cells have been attracting attention because they morphologically resemble human intestinal tissues. In this review, we used human intestinal tissues to estimate human intestinal absorption and metabolism. The Ussing chamber uses human intestinal tissues to directly assay a drug candidate's permeability and determine the electrophysiological parameters such as potential differences (PD), short circuit current (Isc), and resistance (R). Thus, it is an attractive tool for elucidating human intestinal permeability and metabolism. We have presented a novel prediction method for intestinal absorption and metabolism by utilizing a mini-Ussing chamber using human intestinal tissues and animal intestinal tissues, based on the transport index (TI). The TI value was calculated by taking the change in drug concentrations on the apical side due to precipitation and the total amounts accumulated in the tissue (Tcorr) and transported to the basal side (Xcorr). The drug absorbability in rank order, as well as the fraction of dose absorbed (Fa) in humans, was predicted, and the intestinal metabolism of dogs and rats was also predicted, although it was not quantitative. However, the metabolites formation index (MFI) values, which are included in the TI values, can predict the evaluation of intestinal metabolism and absorption by using ketoconazole. Therefore, the mini-Ussing chamber, equipped with human and animal intestinal tissues, would be an ultimate method to predict intestinal absorption and metabolism simultaneously.

Regulation of Inorganic Zinc Supplementation on Intestinal Absorption, Metabolism, and Muscle Development in Broilers Fed Low-Protein Diets

The issue of nitrogen fertilizer contamination resulting from high-protein diets can be effectively solved by adopting low-protein diets. The objective of this study was to investigate the effects of inorganic zinc supplementation in low-protein diets on 42-day-old broilers across a multitude of parameters. To determine the optimal dose of inorganic zinc in broiler diets with a 1.5% reduction in crude protein, 1-day-old Arbor Acres broilers (n = 270) were randomly assigned to five groups, each containing 54 broilers. Our results revealed that inorganic zinc supplementation at levels of 130 mg/kg elevated growth performance and carcass traits (p &lt; 0.05). It also significantly increased the ratio of intestinal villi heights to crypt depths (p &lt; 0.001), changed intestinal morphology, and significantly increased albumin content in serum (p &lt; 0.05). Furthermore, analysis of mRNA expression showed that 130 mg/kg and 150 mg/kg of inorganic zinc improved the myogenic differentiation involved in muscle development, as well as intestinal tight junction and liver metallothionein capacity (p &lt; 0.001). Additionally, these groups exhibited lower zinc excretion compared with other treatments (p &lt; 0.001). In summary, our findings suggest that inorganic zinc supplementation in low-protein diets holds the potential to support muscle and intestinal development in broilers, presenting a viable nutritional strategy.

Genitourinary syndrome of menopause and intestinal microbiota.

Genitourinary syndrome of menopause (GSM) is one of the pathological symptoms of menopause, which causes significant physical, psycho-emotional, and sexual discomfort to a woman. The study describes an examination of 65 middle-aged women, who were divided into 2 groups. Group I included 39 patients with GSM, who, depending on the duration of symptoms (3-5 years, more than 7 years), were divided into subgroups Ia and Ib. Group II included 26 patients who did not have clinical manifestations of GSM. All patients underwent general clinical studies. Bacteriological examination of faeces was used to assess the state of the intestinal microbiota. It was found that menopause occurred in women with GSM earlier, compared with patients without manifestations of urogenital disorders. Also, the women with GSM were more likely to be diagnosed with type 2 diabetes mellitus, metabolic syndrome, overweight, and iron deficiency anaemia. When analysing the results of a bacteriological study in this group of patients, a statistically significant decrease in the colonization of Bifidobacterium and Lactobacillus, as well as excessive bacterial growth of such conditionally pathogenic bacteria as Escherichia coli with reduced enzymatic activity, and Klebsiella and Streptococcus was revealed. Conclusions: Conducting a fundamental study on the characteristics of the intestinal microbiota in menopausal disorders will be an important step towards understanding the pathogenetic mechanisms of their formation, and correction of intestinal metabolism can become an important condition for effective prevention and treatment.

Parishin treatment alleviates cardiac aging in naturally aged mice

BackgroundCardiac aging progressively decreases physiological function and drives chronic/degenerative aging-related heart diseases. Therefore, it is crucial to postpone the aging process of heart and create products that combat aging. Aims & methodsThe objective of this study is to examine the effects of parishin, a phenolic glucoside isolated from traditional Chinese medicine Gastrodia elata, on anti-aging and its underlying mechanism. To assess the senescent biomarkers, cardiac function, cardiac weight/body weight ratio, cardiac transcriptomic changes, and cardiac histopathological features, heart tissue samples were obtained from young mice (12 weeks), aged mice (19 months) treated with parishin, and aged mice that were not treated. ResultsParishin treatment improved cardiac function, ameliorated aging-induced cardiac injury, hypertrophy, and fibrosis, decreased cardiac senescence biomarkers p16Ink4a, p21Cip1, and IL-6, and increased the “longevity factor” SIRT1 expression in heart tissue. Furthermore, the transcriptomic analysis demonstrated that parishin treatment alleviated the cardiac aging-related Gja1 downregulation and Cyp2e1, Ccna2, Cdca3, and Fgf12 upregulation in the heart tissues. The correlation analysis suggested a strong connection between the anti-aging effect of parishin and its regulation of gut microbiota and metabolism in the aged intestine. ConclusionThe present study demonstrates the protective role and underlying mechanism of parishin against cardiac aging in naturally aged mice.

Fatty acid translocase (FAT/CD36) in silver pomfret (Pampus argenteus): Molecular cloning and functional characterization

Understanding the mechanisms of lipid transport and metabolism in fish is crucial to enhance dietary lipid utilization. Here, fatty acid translocase (CD36) gene was characterized in silver pomfret (Pampus argenteus). The open reading frame of silver pomfret cd36 gene was 1395 bp, encoding 464 amino acids. The silver pomfret CD36 protein contained typical transmembrane regions and N-glycosylation modification sites, and was localized to the cytomembrane. The cd36 gene was ubiquitously expressed in all tested tissues, with the highest expression observed in brain tissue. In vivo, both fasting and short-term high-fat feeding could increase cd36 expression in intestinal tissue. In vitro, cd36 expression was induced by palmitic acid, oleic acid, linolenic acid, eicosapentaenoic acid (EPA), and docosahexaenoic acid treatment in intestinal tissue. Furthermore, dual-luciferase reporter assay results indicated that peroxisome proliferator-activated receptor gamma (PPARγ) could enhance cd36 promoter activity, and the co-expression of cd36 and pparγ was observed in EPA-incubated intestine, suggesting that EPA may regulate the expression of cd36 via PPARγ to maintain the homeostasis of intestinal lipid metabolism in silver pomfret. These results highlighted the crucial role of CD36 in silver pomfret, and suggested that the cd36 expression may be regulated by PPARγ. This study could contribute to a greater understanding of lipid metabolism and the development of effective strategies for nutrient requirements in fish.

Urolithin A conjugation with NSAIDs inhibits its glucuronidation and maintains improvement of Caco-2 monolayers' barrier function

Urolithin A (UA) is an ellagitannin-derived postbiotic metabolite which emerged as a promising health-boosting agent, promoting mitophagy, improving skeletal muscle function, and suppressing the inflammatory response. However, phase II intestinal metabolism severely limits its biopotency, leading to the formation of nonactive glucuronides. To address this constraint, a set of new UA derivatives (UADs), conjugated with nonsteroidal anti-inflammatory drugs (NSAIDs), was synthesized. The bioavailability and inhibitory activity of UADs against UA-glucuronidation were evaluated using differentiated Caco-2 cell monolayers. Parallelly, after the administration of tested substances, the transepithelial electrical resistance (TEER) of the cell monolayers was continuously monitored using the CellZscope device. Though investigated UADs did not penetrate Caco-2 monolayers, all of them significantly suppressed the glucuronidation rate of UA, while conjugates with diclofenac increased the concentration of free molecule on the basolateral side. Moreover, esters of UA with diclofenac (DicloUA) and aspirin (AspUA) positively influenced cell membrane integrity. Western blot analysis revealed that some UADs, including DicloUA, increased the expression of pore-sealing tight junction proteins and decreased the level of pore-forming claudin-2, which may contribute to their beneficial activity towards the barrier function. To provide comprehensive insight into the mechanism of action of DicloUA, Caco-2 cells were subjected to transcriptomic analysis. Next-generation sequencing (NGS) uncovered substantial changes in the expression of genes involved, for instance, in multivesicular body organization and zinc ion homeostasis. The results presented in this study offer new perspectives on the beneficial effects of modifying UA's structure on its intestinal metabolism and bioactivity in vitro.

Agaricus blazei Polysaccharide Alleviates DSS-Induced Colitis in Mice by Modulating Intestinal Barrier and Remodeling Metabolism

Ulcerative colitis (UC) is a chronic noninfectious intestinal disease that severely affects patients’ quality of life. Agaricus blazei Murrill polysaccharide (ABP) is an effective active ingredient extracted from Agaricus blazei Murrill (ABM). It has good efficacy in inhibiting tumor cell growth, lowering blood pressure, and improving atherosclerosis. However, its effect on colitis is unclear. The aim of this study was to analyze the protective effects and potential mechanisms of ABP against dextran sulfate sodium (DSS)-induced acute colitis in mice. The results showed that dietary supplementation with ABP significantly alleviated DSS-induced colitis symptoms, inflammatory responses, and oxidative stress. Meanwhile, ABP intervention was able to maintain the integrity of the intestinal mechanical barrier by promoting the expression of ZO-1 and Occludin tight junction proteins and facilitating mucus secretion. Moreover, 16S rRNA sequencing results suggested that ABP intervention was able to alleviate DSS-induced gut microbiota disruption, and nontargeted metabolomics results indicated that ABP was able to remodel metabolism. In conclusion, these results demonstrate that dietary supplementation with ABP alleviated DSS-induced acute colitis by maintaining intestinal barrier integrity and remodeling metabolism. These results improve our understanding of ABP function and provide a theoretical basis for the use of dietary supplementation with ABP for the prevention of ulcerative colitis.

Efficacy and underlying mechanisms of berberine against lipid metabolic diseases: a review.

Lipid-lowering therapy is an important tool for the treatment of lipid metabolic diseases, which are increasing in prevalence. However, the failure of conventional lipid-lowering drugs to achieve the desired efficacy in some patients, and the side-effects of these drug regimens, highlight the urgent need for novel lipid-lowering drugs. The liver and intestine are important in the production and removal of endogenous and exogenous lipids, respectively, and have an important impact on circulating lipid levels. Elevated circulating lipids predisposes an individual to lipid deposition in the vascular wall, affecting vascular function. Berberine (BBR) modulates liver lipid production and clearance by regulating cellular targets such as cluster of differentiation 36 (CD36), acetyl-CoA carboxylase (ACC), microsomal triglyceride transfer protein (MTTP), scavenger receptor class B type 1 (SR-BI), low-density lipoprotein receptor (LDLR), and ATP-binding cassette transporter A1 (ABCA1). It influences intestinal lipid synthesis and metabolism by modulating gut microbiota composition and metabolism. Finally, BBR maintains vascular function by targeting proteins such as endothelial nitric oxide synthase (eNOS) and lectin-like oxidized low-density lipoprotein receptor-1 (LOX-1). This paper elucidates and summarizes the pharmacological mechanisms of berberine in lipid metabolic diseases from a multi-organ (liver, intestine, and vascular system) and multi-target perspective.

Fiber-deficient diet inhibits colitis through the regulation of the niche and metabolism of a gut pathobiont

Exclusive enteral nutrition (EEN) with fiber-free diets is an effective steroid-sparing treatment to induce clinical remission in children with Crohn's disease (CD). However, the mechanism underlying the beneficial effects of EEN remains obscure. Using a model of microbiota-dependent colitis with the hallmarks of CD, we find that the administration of a fiber-free diet prevents the development of colitis and inhibits intestinal inflammation in colitic animals. Remarkably, fiber-free dietalters the intestinal localization of Mucispirillum schaedleri, a mucus-dwelling pathobiont, which is required for triggering disease. Mechanistically, the absence of dietary fiber reduces nutrient availability and impairs the dissimilatory nitrate reduction to ammonia (DNRA) metabolic pathway of Mucispirillum, leading to its exclusion from the mucus layer and disease remission. Thus, appropriate localization of the specific pathobiont in the mucus layer is critical for disease development, which is disrupted by fiber exclusion. These results suggest strategies to treat CD by targeting the intestinal niche and metabolism of disease-causing microbes.