Metabolites Short-chain Fatty Acids Research Articles

Dietary Dihydroquercetin Alleviated Colitis via the Short-Chain Fatty Acids/miR-10a-5p/PI3K-Akt Signaling Pathway.

Gut microbiota provides an important insight into clarifying the mechanism of active substances with low bioavailability, but its specific action mechanism varied case by case and remained unclear. Dihydroquercetin (DHQ) is a bioactive flavonoid with low bioavailability, which showed beneficial effects on colitis alleviation and gut microbiota modulation. Herein, we aimed to explore the microbiota-dependent anticolitis mechanism of DHQ in sight of gut microbiota metabolites and their interactions with microRNAs (miRNAs). Dietary supplementation of DHQ alleviated dextran sulfate sodium-induced colitis phenotypes and improved gut microbiota dysbiosis. Fecal microbiota transplantation further revealed that the anticolitis activity of DHQ was mediated by gut microbiota. To clarify how the modulated gut microbiota alleviated colitis in mice, the tandem analyses of the microbiome and targeted metabolome were performed, and altered profiles of metabolite short-chain fatty acids (SCFAs) and bile acids and their producers were observed in DHQ-treated mice. In addition, SCFA treatment showed anticolitis activity compared to that of bile acids, along with the specific inhibition on the phosphoinositide-3-kinase (PI3K)-protein kinase B (Akt) pathway. Subsequently, the colonic miRNA profile of mice receiving SCFA treatment was sequenced, and a differentially expressed miR-10a-5p was identified. Both prediction analysis and dual-luciferase reporter assay indicated that miR-10a-5p directly bind to the 3'-untranslated regions of gene pik3ca, inhibit the PI3K-Akt pathway activation, and lead to colitis alleviation. Together, we proposed that gut microbiota mediated the anticolitis activity of DHQ through the SCFAs/miR-10a-5p/PI3K-Akt axis, and it provided a novel insight into clarifying the microbiota-dependent mechanism via the interaction between metabolites and miRNAs.

Deficiency of SLC26A3 promotes jejunal barrier damage in metabolic disease-susceptible transgenic pigs

Intestinal disorders are common in metabolic syndrome. However, their pathogenesis is still not fully understood. Pig and human intestines are highly similar in terms of associated metabolic processes. Here, we successfully constructed a metabolic disease-susceptible transgenic (TG) Bama pig model by knocking in three humanized disease risk genes with the CRISPR/Cas9 technique to assess its potential as a model for human intestinal diseases and explore the possible pathological mechanisms involved. We found that jejunal barrier integrity was disrupted and that the infiltration of inflammatory cells increased in TG pigs after high-fat and high-sucrose diet (HFHSD) treatment. We revealed significant differences in the transcriptome, associated microbiome profiles and microbial metabolite short-chain fatty acid (SCFA) content of the jejunum of TG pigs. Notably, we found that SLC26A3 was significantly downregulated in TG pigs. Knockdown or overexpression of the SLC26A3 gene in IPEC-J2 cells significantly affected the expression of MUC2, MUC13 and occludin. Furthermore, in vitro experiments further verified that CDX2 directly regulated the expression of SLC26A3. Mechanistically, CDX2 mediated intestinal barrier function by enhancing the expression of SLC26A3 by binding to its promoter region between −1120 and − 1070 bp. TG pigs represent a promising model that provides new insights into preclinical research on human intestinal metabolic diseases associated with metabolic disorders and revealed that SLC26A3 may be a potential therapeutic target for intestinal metabolic diseases.

A review of gut microbial metabolites and therapeutic approaches in hypertension

Abstract Background Hypertension is a prevalent and complex disease that is increasingly recognized to be influenced by the gut microbiome and its metabolites. Understanding the relationship between gut microbial metabolites and blood pressure regulation could provide new therapeutic avenues. Main body This review examines the role of key microbial metabolites—short-chain fatty acids, trimethylamine N-oxide, tryptophan derivatives, polyamines, bile acids, and phenylacetylglutamine—in blood pressure regulation. Short-chain fatty acids, produced through dietary fiber fermentation, can lower blood pressure by modulating immune responses and reducing inflammation. Elevated trimethylamine N-oxide levels are associated with increased cardiovascular risk and hypertension, influencing cholesterol metabolism and promoting atherosclerosis. Tryptophan derivatives interact with vascular and renal functions to modulate blood pressure. Polyamines affect blood pressure regulation through their impact on nitric oxide synthesis and vascular tone. Bile acids influence blood pressure via gut microbiota modulation and activation of metabolic receptors. Phenylacetylglutamine has been linked to hypertension through its effects on platelet hyperactivity and thrombosis. Therapeutic approaches targeting these metabolites, including probiotics, prebiotics, fecal microbiota transplantation, dietary interventions, and polyphenols, have shown varying degrees of success. Probiotics and prebiotics promote the growth of beneficial gut bacteria and may lower blood pressure. Dietary interventions, such as the Mediterranean diet, positively affect blood pressure and cardiovascular health by modulating the gut microbiota. Polyphenols, known for their antioxidant properties, are associated with blood pressure reductions and improved vascular function. Fecal microbiota transplantation shows promise in restoring gut microbial balance and improving metabolic health, potentially influencing blood pressure regulation. Conclusion The review highlights the significant role of gut microbial metabolites in regulating blood pressure, offering new avenues for hypertension management. Key metabolites, including short-chain fatty acids, trimethylamine N-oxide, and bile acids, play critical roles in blood pressure modulation. Therapeutic strategies targeting these metabolites, such as probiotics, prebiotics, and dietary interventions, hold promise, though further research is needed to fully understand their mechanisms and optimize their use. Advancing microbiota-based interventions through large-scale studies and exploring personalized therapies will be essential for developing effective treatments in hypertension management.

Shenling Baizhu powder attenuates lard diet in a fatigued state-induced diarrhea via targeting microbial metabolites short chain fatty acids-mediated lipid metabolism.

Shenling Baizhu Powder (SLBZP), a traditional Chinese medicine (TCM) prescription renowned for its efficacy, is specifically recognized for its therapeutic effects in managing diarrhea associated with spleen qi deficiency. Our previous research has demonstrated that a lard diet in a fatigued state induced diarrhea belonging to spleen qi deficiency in TCM. Through a comprehensive investigation, we aimed to provide insights into the intricate relationship between SLBZP and the modulation of gut microbiota in alleviating symptoms associated with spleen qi deficiency-induced diarrhea. We induced diarrhea in mice by subjecting them to continuous standing on a multiple-platform apparatus while administering lard through intragastric administration for 14days. Subsequently, we conducted gavage administration of SLBZP at a concentration of 0.637g/ml for seven days. We observed a therapeutic effect of SLBZP on diarrhea induced by a lard diet in a fatigued state. SLBZP mitigated disorders in lipid metabolism and diminished hepatic oxidative responses. Additionally, SLBZP reversed gut microbiota dysbiosis of diarrheic mice and notably increased the production of short-chain fatty acids (SCFAs), primarily acetic acid, butyric acid, and valeric acid. Through correlation analysis, we additionally identified Lactobacillus reuteri and Lactobacillus intestinalisas potentially pivotal species associated with the therapeutic effects of SLBZP. We demonstrated that SLBZP exerts therapeutic effects on diarrhea caused by a lard diet in a fatigued state by repairing the intestinal mucosal barrier, improving lipid metabolism disorders, and regulating gut microbiota and metabolites SCFAs.

Recent advancements in targeting the immune system to treat hypertension

Hypertension is the key leading risk factor for death globally, affecting ∼1.3 billion adults, particularly in low- and middle-income countries. Most people living with hypertension have uncontrolled high blood pressure, increasing their likelihood of cardiovascular events. Significant issues preventing blood pressure control include lack of diagnosis, treatment, and response to existing therapy. For example, monotherapy and combination therapy are often unable to lower blood pressure to target levels. New therapies are urgently required to tackle this issue, particularly those that target the mechanisms behind hypertension instead of treating its symptoms. Acting via an increase in systemic and tissue-specific inflammation, the immune system is a critical contributor to blood pressure regulation and is considered an early mechanism leading to hypertension development. Here, we review the immune system's role in hypertension, evaluate clinical trials that target inflammation, and discuss knowledge gaps in pre-clinical and clinical data. We examine the effects of anti-inflammatory drugs colchicine and methotrexate on hypertension and evaluate the blockade of pro-inflammatory cytokines IL-1β and TNF-α on blood pressure in clinical trials. Lastly, we highlight how we can move forward to target specific components of the immune system to lower blood pressure. This includes targeting isolevuglandins, which accumulate in dendritic cells to promote T cell activation and cytokine production in salt-induced hypertension. We discuss the potential of the dietary fibre-derived metabolites short-chain fatty acids, which have anti-inflammatory and blood pressure-lowering effects via the gut microbiome. This would limit adverse events, leading to improved medication adherence and better blood pressure control.

Different Short-Chain Fatty Acids Unequally Modulate Intestinal Homeostasis and Reverse Obesity-Related Symptoms in Lead-Exposed High-Fat Diet Mice.

Our previous study showed that heavy metal lead (Pb) exposure exacerbates high-fat-diet (HFD)-induced metabolic damage and significantly depletes the gut microbiota-derived metabolite short-chain fatty acid (SCFA) levels. However, it remains unclear whether SCFA is a key metabolite involved in accelerating adverse consequences after Pb exposure. In this study, we explored the effects of exogenous supplementation of acetate, propionate, and butyrate on a metabolic disorder model in Pb-exposed HFD mice. We found that three SCFA interventions attenuated glycolipid metabolism disorders and liver damage, with butyrate performing the best effects in improving obesity-related symptoms. All three SCFA promoted the abundance of Muribaculaceae and Muribaculum, acetate specifically enriched Christensenellaceae, Blautia, and Ruminococcus, and butyrate specifically enriched Parasutterella, Rikenella, Prevotellaceae_UCG-001, and Bacteroides, which contributed to the positive promotion of SCFA production forming a virtuous cycle. Besides, butyrate inhibited Gram-negative bacteria Escherichia-Shigella. All of these events alleviated the intestinal Th17/Treg imbalance and inflammatory response through crosstalk between the G protein-coupled receptor (GPR)/histone deacetylase 3 (HDAC3) and lipopolysaccharide (LPS)/toll-like receptors 4 (TLR4)/nuclear factor κ-B (NF-κB) pathways and ultimately improved the intestinal barrier function. SCFA further upregulated the monocarboxylate transporter 1 (MCT1) and GPR43/adenosine 5'-monophosphate-activated protein kinase (AMPK) pathways to inhibit hepatic lipid accumulation. Overall, SCFA, especially butyrate, is an effective modulator to improve metabolic disorders in obese individuals exposed to heavy metals by targeting gut microecology.

Analysis of the microecological mechanism of diabetic kidney disease based on the theory of "gut-kidney axis": A systematic review.

Diabetic kidney disease (DKD) is one of the main microvascular complications of diabetes mellitus, as well as the leading cause of end-stage renal disease. Intestinal microbiota has emerged as a crucial regulator of its occurrence and development. Dysbiosis of the intestinal microbiota can disrupt the intestinal mucosal barrier, abnormal immunological response, reduction in short-chain fatty acid metabolites, and elevation of uremic toxins, all closely related to the occurrence and development of DKD. However, the underlying mechanisms of how intestinal microbiota and its metabolites influence the onset and progression of DKD has not been fully elucidated. In the current review, we will try to summarize the microecological mechanism of DKD by focusing on three aspects: the intestinal microbiota and its associated metabolites, and the "gut-kidney axis," and try to summarize therapies targeted at managing the intestinal microbiota, expecting to provide theoretical basis for the subsequent study of the relationship between intestinal homeostasis and DKD, and will open an emerging perspective and orientation for DKD treatment.

Short-chain fatty acids suppresses astrocyte activation by amplifying Trp-AhR-AQP4 signaling in experimental autoimmune encephalomyelitis mice.

The function of astrocytes in response to gut microbiota-derived signals has an important role in the pathophysiological processes of central nervous system (CNS) diseases. However, the specific effects of microbiota-derived metabolites on astrocyte activation have not been elucidated yet. Experimental autoimmune encephalomyelitis (EAE) was induced in female C57BL/6 mice as a classical MS model. The alterations of gut microbiota and the levels of short-chain fatty acids (SCFAs) were assessed after EAE induction. We observed that EAE mice exhibit low levels of Allobaculum, Clostridium_IV, Clostridium_XlVb, Lactobacillus genera, and microbial-derived SCFAs metabolites. SCFAs supplementation suppressed astrocyte activation by increasing the level of tryptophan (Trp)-derived AhR ligands that activating the AhR. The beneficial effects of SCFAs supplementation on the clinical scores, histopathological alterations, and the blood brain barrier (BBB)-glymphatic function were abolished by intracisterna magna injection of AAV-GFAP-shAhR. Moreover, SCFAs supplementation suppressed the loss of AQP4 polarity within astrocytes in an AhR-dependent manner. Together, SCFAs potentially suppresses astrocyte activation by amplifying Trp-AhR-AQP4 signaling in EAE mice. Our study demonstrates that SCFAs supplementation may serve as a viable therapy for inflammatory disorders of the CNS.

Effects of environmentally relevant concentrations of florfenicol on the glucose metabolism system, intestinal microbiome, and liver metabolome of zebrafish

Florfenicol, a widely used veterinary antibiotic, has now been frequently detected in various water environments and human urines, with high concentrations. Accordingly, the ecological risks and health hazards of florfenicol are attracting increasing attention. In recent years, antibiotic exposure has been implicated in the disruption of animal glucose metabolism. However, the specific effects of florfenicol on the glucose metabolism system and the underlying mechanisms are largely unknown. Herein, zebrafish as an animal model were exposed to environmentally relevant concentrations of florfenicol for 28 days. Using biochemical and molecular analyses, we found that exposure to florfenicol disturbed glucose homeostasis, as evidenced by the abnormal levels of blood glucose and hepatic/muscular glycogen, and the altered expression of genes involved in glycogenolysis, gluconeogenesis, glycogenesis, and glycolysis. Considering the efficient antibacterial activity of florfenicol and the crucial role of intestinal flora in host glucose metabolism, we then analyzed changes in the gut microbiome and its key metabolite short-chain fatty acids (SCFAs). Results indicated that exposure to florfenicol caused gut microbiota dysbiosis, inhibited the production of intestinal SCFAs, and ultimately affected the downstream signaling pathways of SCFA involved in glucose metabolism. Moreover, non-targeted metabolomics revealed that arachidonic acid and linoleic acid metabolic pathways may be associated with insulin sensitivity changes in florfenicol-exposed livers. Overall, this study highlighted a crucial aspect of the environmental risks of florfenicol to both non-target organisms and humans, and presented novel insights into the mechanistic elucidation of metabolic toxicity of antibiotics.

Effects of alimentary-derived bacterial metabolites on energy metabolism in colonic epithelial cells and inflammatory bowel diseases

In this review, we present the main luminal fuels that are responsible for energy production in colonocytes, namely the bacterial metabolites short-chain fatty acids and lactate, which are produced from undigestible polysaccharides and proteins, and hydrogen sulfide that is mainly produced from undigested proteins. In addition to these luminal fuels, colonocytes can use glutamine, and to a lower extent glucose, as energy substrates provided by arterial capillaries. The effects of excessive concentrations of bacterial metabolites within the colonic luminal fluid (including butyrate, hydrogen sulfide, p-cresol, indole derivatives, ammonia, 4-hydroxyphenylacetic acid, and acetaldehyde) on the mitochondrial energy metabolism in colonic epithelial cells and the consequences of altered ATP production on the colonic epithelium renewal and barrier function are detailed, as well as consequences for water and electrolyte absorption. The relationships between modifications of these latter processes and development of colitis are then discussed. Finally, several mechanisms that are considered as adaptive against deleterious effects of bacterial metabolites on colonic epithelial cell energy metabolism are presented.

Co-exposure to lead and high-fat diet aggravates systemic inflammation in mice by altering gut microbiota and the LPS/TLR4 pathway.

This study reports the toxicity of Pb exposure on systemic inflammation in high-fat-diet (HFD) mice and the potential mechanisms. Results indicated that Pb exacerbated intestinal barrier damage and increased serum levels of lipopolysaccharide (LPS) and diamine oxidase in HFD mice. Elevated LPS activates the colonic and ileal LPS-TLR4 inflammatory signaling pathway and further induces hepatic and adipose inflammatory expression. The 16S rRNA gene sequencing results showed that Pb promoted the abundance of potentially harmful and LPS-producing bacteria such as Coriobacteriaceae_UCG-002, Alloprevotella, and Oscillibacter in the intestines of HFD mice, and their abundance was positively correlated with LPS levels. Additionally, Pb inhibited the abundance of the beneficial bacteria Akkermansia, resulting in lower levels of the metabolite short-chain fatty acids (SCFAs). Meanwhile, Pb inhibited adenosine 5'-monophosphate-activated protein kinase signaling-mediated lipid metabolism pathways, promoting hepatic lipid accumulation. The above results suggest that Pb exacerbates systemic inflammation and lipid disorders in HFD mice by altering the gut microbiota, intestinal barrier, and the mediation of metabolites LPS and SCFAs. Our study provides potential novel mechanisms of human health related to Pb-induced metabolic damage and offers new evidence for a comprehensive assessment of Pb risk.

Microbiota-derived acetate attenuates neuroinflammation in rostral ventrolateral medulla of spontaneously hypertensive rats.

Increased neuroinflammation in brain regions regulating sympathetic nerves is associated with hypertension. Emerging evidence from both human and animal studies suggests a link between hypertension and gut microbiota, as well as microbiota-derived metabolites short-chain fatty acids (SCFAs). However, the precise mechanisms underlying this gut-brain axis remain unclear. The levels of microbiota-derived SCFAs in spontaneously hypertensive rats (SHRs) were determined by gas chromatography-mass spectrometry. To observe the effect of acetate on arterial blood pressure (ABP) in rats, sodium acetate was supplemented via drinking water for continuous 7 days. ABP was recorded by radio telemetry. The inflammatory factors, morphology of microglia and astrocytes in rostral ventrolateral medulla (RVLM) were detected. In addition, blood-brain barrier (BBB) permeability, composition and metabolomics of the gut microbiome, and intestinal pathological manifestations were also measured. The serum acetate levels in SHRs are lower than in normotensive control rats. Supplementation with acetate reduces ABP, inhibits sympathetic nerve activity in SHRs. Furthermore, acetate suppresses RVLM neuroinflammation in SHRs, increases microglia and astrocyte morphologic complexity, decreases BBB permeability, modulates intestinal flora, increases fecal flora metabolites, and inhibits intestinal fibrosis. Microbiota-derived acetate exerts antihypertensive effects by modulating microglia and astrocytes and inhibiting neuroinflammation and sympathetic output.

Exploring the possible relationship between skin microbiome and brain cognitive functions: a pilot EEG study

Human microbiota mainly resides on the skin and in the gut. Human gut microbiota can produce a variety of short chain fatty acids (SCFAs) that affect many physiological functions and most importantly modulate brain functions through the bidirectional gut-brain axis. Similarly, skin microorganisms also have identical metabolites of SCFAs reported to be involved in maintaining skin homeostasis. However, it remains unclear whether these SCFAs produced by skin bacteria can affect brain cognitive functions. In this study, we hypothesize that the brain’s functional activities are associated with the skin bacterial population and examine the influence of local skin-bacterial growth on event-related potentials (ERPs) during an oddball task using EEG. Additionally, five machine learning (ML) methods were employed to discern the relationship between skin microbiota and cognitive functions. Twenty healthy subjects underwent three rounds of tests under different conditions—alcohol, glycerol, and water. Statistical tests confirmed a significant increase in bacterial population under water and glycerol conditions when compared to the alcohol condition. The metabolites of bacteria can turn phenol red from red–orange to yellow, confirming an increase in acidity. P3 amplitudes were significantly enhanced in response to only oddball stimulus at four channels (Fz, FCz, and Cz) and were observed after the removal of bacteria when compared with that under the water and glycerol manipulations. By using machine learning methods, we demonstrated that EEG features could be separated with a good accuracy (> 88%) after experimental manipulations. Our results suggest a relationship between skin microbiota and brain functions. We hope our findings motivate further study into the underlying mechanism. Ultimately, an understanding of the relationship between skin microbiota and brain functions can contribute to the treatment and intervention of diseases that link with this pathway.

Microbial influence on blood pressure: unraveling the complex relationship for health insights.

Hypertension, a critical global health concern, is characterized by persistent high blood pressure and is a major cause of cardiovascular events. This perspective explores the multifaceted implications of hypertension, its association with cardiovascular diseases, and the emerging role of the gut microbiota. The gut microbiota, a dynamic community in the gastrointestinal tract, plays a pivotal role in hypertension by influencing blood pressure through the generation of antioxidant, anti-inflammatory, and short-chain fatty acids metabolites, and the conversion of nitrates into nitric oxide. Antihypertensive medications interact with the gut microbiota, impacting drug pharmacokinetics and efficacy. Prebiotics and probiotics present promising avenues for hypertension management, with prebiotics modulating blood pressure through lipid and cholesterol modulation, and probiotics exhibiting a general beneficial effect. Personalized choices based on individual factors are crucial for optimizing prebiotic and probiotic interventions. In conclusion, the gut microbiota's intricate influence on blood pressure regulation offers innovative perspectives in hypertension therapeutics, with targeted strategies proving valuable for holistic blood pressure management and health promotion.

Gracilaria extract reduce hyperglycemia by modulating gut microbial and short chain fatty acids

High blood sugar is the main feature of diabetes. In order to effectively regulate blood glucose levels, in this study, we used Gracilaria as raw material and found that 70% ethanol extract of Gracilaria (GE) and complex protease hydrolysate of Gracilaria (GH) were beneficial for decreasing fasting blood glucose, improving insulin resistance, enhancing the function of islet β-cells, and regulating the abnormal increase of TC, TG, LDL-c caused by hyperglycemia in diabetic mice. Moreover, 70% ethanol extract of Gracilaria (GE) and complex protease hydrolysate of Gracilaria (GH) affected the gut microbiota structure of diabetic mice, decreased the Firmicutes/Bacteroidetes ratio, increased the abundance of Lactobacillus and Collinsella etc. and reduced the abundance of Helicobacter and Oscillibacter etc. In addition, the content of acetic acid and butyric acid in metabolites of short-chain fatty acids had increased, which had the effect of regulating blood glucose level. The results have showed that 70% ethanol extract of Gracilaria (GE) and complex protease hydrolysate of Gracilaria (GH) are potential marine foods for maintaining blood sugar health.

Role of gut microbiota derived short chain fatty acid metabolites in modulating female reproductive health

Short chain fatty acids (SCFA) have been linked to women's reproductive health, though to a lesser extent, alteration in the production of SCFA and SCFA-producing bacteria has been associated significantly with pregnancy-related complications, unfavourable pregnancy outcomes, menstrual anomalies, and gynaecological cancer.The female reproductive system is a delicate, intricate, hormone-dependent group of tissues required for the continuity of life and the species' survival. Reproductive health impacts the ovarian function to implantation and foetal development. Several environmental and physiological factors contribute to mammalian infertility concerns caused by a change in reproductive health status. Several lifestyle factors have been demonstrated to affect reproductive health, including age, body weight, smoking, alcohol consumption, work stress, exercise, diet, and nutrition. Nutrition influences puberty, the menstrual cycle, ovulation, conception, implantation and early foetal development. This review provides an overview of how intestinal derived SCFAs maintains female reproductive health summarizing the current knowledge and future perspectives. Microbial SCFAs improve human metabolism by interfering with, glucose homeostasis, appetite regulation and lipid metabolism. Also affect host immunity and intestinal barrier integrity via primary by inhibition of Histone deacetylases (HDAC) mechanism. Therefore, SCFAs exhibit anti-inflammatory, anti-obesity, immunoregulatory, anti-diabetes, anti-cancer, hepatoprotective, cardiovascular protective and neuroprotective properties.This review highlights recent findings on SCFA and gynaecological pathologies such as preeclampsia, gestational diabetes, pregnancy complications, polycystic ovary syndrome, bacterial vaginosis, and endometriosis to describe current knowledge of the relationship between SCFA and reproductive health and disease in women.

Selenium Yeast Alleviates Dextran Sulfate Sodium-Induced Chronic Colitis in Mice by Reducing Proinflammatory Cytokines and Regulating the Gut Microbiota and Their Metabolites.

Inflammatory bowel disease (IBD) is a chronic recurrent gastrointestinal inflammatory disease. Selenium has been reported to have therapeutic potential in IBD. Selenium yeast is a common selenium supplement that is convenient to access. This study explored the effect of selenium yeast on dextran sulfate sodium- (DSS-)induced chronic colitis in mice. Mice were randomly divided into four groups: the control group, selenium yeast group, chronic colitis group, and chronic colitis+selenium yeast group (n=6). Mice were killed on the 26th day. The disease activity index (DAI) score and histological damage score were calculated. Cytokines, serum selenium, colonic tissue selenium, gut microbiota and their metabolites short-chain fatty acids (SCFAs) were evaluated. Selenium yeast lowered IL-1β, IL-6, TNF-α, IL-17A, IL-22 and IFN-γ (P<0.05). In addition, selenium yeast significantly elevated Turicibacter, Bifidobacterium, Allobaculum, Prevotella, Halomonas, Adlercreutzia (P<0.05), and butyric acid (P<0.05). Selenium yeast could improve DSS-induced chronic colitis in mice by regulating cytokines, gut microbiota and their metabolites.

P036 Microbiota Metabolite Butyrate Attenuates Intestinal Inflammation Through Autophagy Activation

Abstract Background Alteration of the microbiota metabolite short chain fatty acids (SCFAs) may contribute to the development of inflammatory bowel disease (IBD). Butyrate, one of the SCFAs produced by bacteria, is known to be beneficial in attenuating intestinal inflammation. However, the mechanisms underlying anti-inflammatory effects of butyrate have not yet been entirely investigated. Methods In vivo, wild-type C57BL/6J mice were given a gavage of sodium butyrate (SB) (0.12g/ml) for 5 days. The mice were then administered 2% dextran sodium sulfate to induce experimental colitis models. Fecal microbiota was analysed by 16S rDNA sequencing. In vitro, HCT116 cell line was used to investigate the protective roles of SB on lipopolysaccharide (LPS)-induced inflammatory response. The levels of inflammatory cytokines, intestinal tight junction and autophagy were detected by western blotting and quantitative polymerase chain reaction. Results We observed that SB treatment significantly attenuated colitis in rodent models with reduced tumor necrosis factor α (TNF-α), interleukin-6 (IL-6) and interleukin-1β expression, and tended to restore intestinal barrier dysfunction. Mechanically, we identified that the inclusion of SB enhanced protein level of Atg16l1, which indicated enhanced autophagy function. In vitro cell experiments also proved that mRNA levels of IL-6 and TNF-α were decreased, while autophagy-related Beclin was enhanced. Furthermore, our results revealed a distinct alteration mediated by butyrate in the gut microbiota by restored ratio of Firmicutes/Bacteroides, increasing Erysipelotrichaceae and reduced Desulfovibrio abundance. Conclusion This study provides the first data demonstrating that butyrate supplementation attenuates intestinal inflammation probably via promoting autophagy and regulating intestinal microbiota. Our findings provide new insights into butyrate-mediated remission of IBD and butyrate as a potential modulator for autophagy to prevent and treat IBD.

P175 HucMSC-Exo ameliorate experimental colitis via modulating gut microbiota and metabolites

Abstract Background Gut microbiota and metabolites have been shown to influence the development of inflammatory bowel disease (IBD). Exosomes derived from human umbilical cord mesenchymal stem cells (HucMSC-Exo) have been identified as a promising biological therapy for the treatment of IBD. Previous studies have described that HucMSC-Exo could modulate gut microbiota. However, the mechanism remains unclear. Here, we explored the role of gut microbiota and metabolites in HucMSC-Exo-mediated amelioration of experimental colitis. Methods Dextran sulfate sodium (DSS) was used to induce colitis. The role of HucMSC-Exo were assessed in colitis mice. Fecal microbiota transplantation (FMT) and sterile fecal filtrate gavage were employed to evaluate the effect of gut microbiota and metabolites. Gut microbiota and metabolites were analyzed through 16S rRNA sequencing and metabolomic profiling. The proportion of CD4+ T cells were phenotyped by multicolour flow cytometry. Results HucMSC-Exo treatment alleviated colon inflammation by regulating flora composition, significantly up-regulated the levels of bacteria such as Bacteroides, Parabacteroides distasonis, and Tannerellaceae. Meanwhile, HucMSC-Exo transformed metabolite short-chain fatty acid (SCFA) profiles, particularly increased butyrate level. Additionally, HucMSC-Exo selectively up-regulated the frequencies of regulatory T (Treg) cells as well as down-regulated the ratio of T helper type 17 (Th17) cells in colonic lamina propria to maintain intestinal immune homeostasis and repaired the colonic mucus barrier. FMT and sterile fecal filtrate gavage were conducted to confirm the above mechanism. Microbiota from HucMSC-Exo-treated mice alleviated the colitis over microbiota from DSS-treated mice. Sterile fecal filtrate from HucMSC-Exo-treated mice and butyrate induced similar beneficial outcomes, such as improved the Th17/Treg balance and repaired the colonic mucus barrier. Collectively, HucMSC-Exo ameliorate colitis by directly modulating gut microbiota and metabolites. Conclusion HucMSC-Exo ameliorated experimental colitis via directly modulating gut microbiota and metabolite butyrate, which could regulate CD4+T cells homeostasis and repair colonic mucus barrier. The findings demonstrated the HucMSC-Exo as a potential gut microbiota and metabolites modulator to treat IBD.

Microfluidics-Derived Microparticles with Prebiotics and Probiotics for Enhanced In Situ Colonization and Immunoregulation of Colitis.

Oral administration of probiotics orchestrates the balance between intestinal microbes and the immune response. However, effective delivery and in situ colonization are limited by the harsh environment of the gastrointestinal tract. Herein, we provide a microfluidics-derived encapsulation strategy to address this problem. A novel synergistic delivery system composed of EcN Nissle 1917 and prebiotics, including alginate sodium and inulin gel, for treating inflammatory bowel disease and colitis-associated colorectal cancer is proposed. We demonstrated that EcN@AN microparticles yielded promising gastrointestinal resistance for on-demand probiotic delivery and colon-retentive capability. EcN@AN microparticles efficiently ameliorated intestinal inflammation and modulated the gut microbiome in experimental colitis. Moreover, the prebiotic composition of EcN@AN enhanced the fermentation of relative short-chain fatty acid metabolites, a kind of postbiotics, to exert anti-inflammatory and tumor-suppressive effects in murine models. This microfluidcis-based approach for the coordinated delivery of probiotics and prebiotics may have broad implications for gastrointestinal bacteriotherapy applications.