Short-chain Fatty Acid Receptor Research Articles

Short-chain fatty acids stimulate dendrite elongation in dendritic cells by inhibiting histone deacetylase.

Dendritic cells activate immune responses by presenting pathogen-derived molecules. The dendrites of dendritic cells contribute to the incorporation of foreign antigens or presenting antigens to T cells. Short-chain fatty acids (SCFAs), such as acetic, propionic, butyric and valeric acids, have many effects on immune responses by activating specific receptors or inhibiting a histone deacetylase (HDAC), although their effect on dendrite formation in dendritic cells is unknown. In the present study, we aimed to investigate the effect of SCFAs on dendrite elongation using a dendritic cell line (DC2.4 cells) and mouse bone marrow-derived dendritic cells. We found that SCFAs induced dendrite elongation. The elongation was reduced by inhibitors of Src family kinase (SFK), phosphatidylinositol-3 kinase (PI3K), Rho family GTPases (Cdc42, Rac1) or actin polymerization, indicating that SCFAs promote dendrite elongation by activating actin polymerization via the SFK/PI3K/Rho family GTPase signaling pathway. We showed that agonists for SCFA receptors GPR43 and GPR109a did not promote dendrite elongation. By contrast, HDAC inhibitors, including trichostatin A, promoted dendrite elongation in DC2.4 cells, and the promoting activity of trichostatin A was decreased by inhibiting the SFK/PI3K/Rho family GTPase signaling pathway or actin polymerization. Furthermore, DC2.4 cells treated with valeric acid showed enhanced uptake of soluble proteins, insoluble beads and Staphylococcus aureus. We also found that treatment with valeric acid enhanced major histocompatibility complex class II-mediated antigen presentation in bone marrow-derived dendritic cells. These results suggest that SCFAs promote dendrite elongation by inhibiting HDAC, stimulating the SFK/PI3K/Rho family pathway and activating actin polymerization, resulting in increased antigen uptake and presentation in dendritic cells.

Short-chain fatty acids inhibit the activation of T lymphocytes and myeloid cells and induce innate immune tolerance.

The intestinal microbiota contributes to gut immune homeostasis, where short-chain fatty acids (SCFAs) function as the major mediators. We aimed to elucidate the immunomodulatory effects of acetate, propionate, and butyrate. With that in mind, we sought to characterise the expression of SCFA receptors and transporters as well as SCFAs' impact on the activation of different immune cells. Whereas all three SCFAs decreased tumour necrosis factor (TNF)-α production in activated T cells, only butyrate and propionate inhibited interferon (IFN)-γ, interleukin (IL)-17, IL-13, and IL-10 production. Butyrate and propionate inhibited the expression of the chemokine receptors CCR9 and CCR10 in activated T- and B-cells, respectively. Similarly, butyrate and propionate were effective inhibitors of IL-1β, IL-6, TNF-α, and IL-10 production in myeloid cells upon lipopolysaccharide and R848 stimulation. Acetate was less efficient at inhibiting cytokine production except for IFN-α. Moreover, SCFAs inhibited the production of IL-6 and TNF-α in monocytes, myeloid dendritic cells (mDC), and plasmacytoid dendritic cells (pDC), whereas acetate effects were relatively more prominent in pDCs. In monocytes and mDCs, acetate was a less efficient inhibitor, but it was equally effective in inhibiting pDCs activation. We also studied the ability of SCFAs to induce trained immunity or tolerance. Butyrate and propionate- but not acetate- prevented Toll-like receptor-mediated activation in SCFA-trained cells, as demonstrated by a reduced production of IL-6 and TNF-α. Our findings indicate that butyrate and propionate are equally efficient in inhibiting the adaptive and innate immune response and did not induce trained immunity. The findings may be explained by differential SCFA receptor and transporter expression profiles of the immune cells.

Maternal sodium acetate supplementation promotes lactation performance of sows and their offspring growth performance.

Milk yield and composition are critical determining factors for the early growth and development of neonates. The objective of this experiment was to comprehensively evaluate the effects of dietary sodium acetate (SA) supplementation on the milk yield and composition of sows and the growth performance of their offspring. A total of 80 sows (Landrace×Yorkshire, 3 to 6 parity) were randomly assigned to 2 groups (with or without 0.1% SA) from d 85 of gestation to d 21 of lactation. The result shows that maternal 0.1% SA supplementation significantly increased sows milk yield, milk fat, immunoglobulin A (IgA) and IgG content in milk (P<0.05), with the up-regulation of short-chain fatty acids receptors (GPR41 and GPR43) expression and the activation of mammalian target of rapamycin complex C1 (mTORC1) signaling pathway. Consistently, in our invitro experiment, SA also activated mTORC1 signaling in porcine mammary epithelial cells (P<0.05). Furthermore, the improvement of milk quality and quantity caused by maternal SA supplementation led to the increase in body weight (BW) and average daily weight gain (ADG) of weaning piglets, with the improvement of gut health and colonization of the beneficial bacteria (P<0.05). In conclusion, maternal supplementation of 0.1% SA improved the lactation performance (milk yield and milk fat) of sows, possibly with the activation of GPR41/GPR43-mTORC1 signaling. Furthermore, enhanced milk quality improved growth performance, gut health and the colonization of beneficial microbial flora of their piglets.

Oral administration of Bifidobacterium longum WHH2270 ameliorates type 2 diabetes in rats.

Accumulating evidence suggests that specific probiotic strains exert hypoglycemic effects on type 2 diabetes mellitus (T2DM), and probiotic strains within Bifidobacterium exhibit potential beneficial effects on T2DM. In this study, α-glucosidase inhibitory activities of 14 Bifidobacterium strains were assessed in vitro. The hypoglycemic effects of Bifidobacterium longum WHH2270 with high α-glucosidase inhibitory activity (42.03%) were then investigated in a high-fat diet/streptozotocin-induced T2DM rat model. Oral administration of WHH2270 (4 × 109 CFU/kg/day) for 8weeks significantly reversed the reduced body weight and ameliorated the levels of fasting blood glucose, serum triglyceride, serum total cholesterol, glucose tolerance, and insulin resistance in T2DM rats. Using 16S rRNA high-throughput sequencing of feces, WHH2270 was revealed to reshape the gut microbiome composition by increasing the abundances of Lactobacillus and Bifidobacterium and decreasing the abundances of UCG_005, Clostridium, and Faecalibacterium in T2DM rats. Besides, the fecal levels of short-chain fatty acids (SCFAs) including acetate, propionate, and butyrate were also elevated after WHH2270 administration. Moreover, the gene expressions of SCFA receptors FFAR2 and FFAR3 in the colon and pancreas of T2DM rats were restored by WHH2270 administration, accompanied by increased levels of serum acetate. In summary, these results provide evidence that WHH2270 has the potential to improve T2DM symptoms by alleviating hyperglycemia, which was associated with changes in the gut microbiome composition and SCFA production. PRACTICAL APPLICATION: Bifidobacterium longum WHH2270 with high α-glucosidase inhibitory activity may serve as a promising hypoglycemic agent for the treatment of T2DM.

Dendrobium officinale Polysaccharide Prevents Diabetes via the Regulation of Gut Microbiota in Prediabetic Mice.

Dendrobium officinale polysaccharide (DOP), which serves as a prebiotic, exhibits a variety of biological activities, including hypoglycemic activities. However, the effects of DOP on diabetes prevention and its hypoglycemic mechanisms are still unclear. In this study, the effects of DOP treatment on the prediabetic mice model were studied and the mechanism was investigated. The results showed that 200 mg/kg/d of DOP reduced the relative risk of type 2 diabetes mellitus (T2DM) from prediabetes by 63.7%. Meanwhile, DOP decreased the level of LPS and inhibited the expression of TLR4 by regulating the composition of the gut microbiota, consequently relieving the inflammation and alleviating insulin resistance. In addition, DOP increased the abundance of SCFA (short chain fatty acid)-producing bacteria in the intestine, increased the levels of intestinal SCFAs, promoted the expression of short-chain fatty acid receptors FFAR2/FFAR3, and increased the secretion of the intestinal hormones GLP-1 and PYY, which helped to repair islet damage, suppress appetite, and improve insulin resistance. Our results suggested that DOP is a promising functional food supplement for the prevention of T2DM.

GPR43 stimulation on TCRαβ+ intraepithelial colonic lymphocytes inhibits the recruitment of encephalitogenic T-cells into the central nervous system and attenuates the development of autoimmunity

IntroductionGut microbiota plays a critical role in the regulation of immune homeostasis. Accordingly, several autoimmune disorders have been associated with dysbiosis in the gut microbiota. Notably, the dysbiosis associated with central nervous system (CNS) autoimmunity involves a substantial reduction of bacteria belonging to Clostridia clusters IV and XIVa, which constitute major producers of short-chain fatty acids (SCFAs). Here we addressed the role of the surface receptor-mediated effects of SCFAs on mucosal T-cells in the development of CNS autoimmunity.MethodsTo induce CNS autoimmunity, we used the mouse model of experimental autoimmune encephalomyelitis (EAE) induced by immunization with the myelin oligodendrocyte glycoprotein (MOG)-derived peptide (MOG35-55 peptide). To address the effects of GPR43 stimulation on colonic TCRαβ+ T-cells upon CNS autoimmunity, mucosal lymphocytes were isolated and stimulated with a selective GPR43 agonist ex vivo and then transferred into congenic mice undergoing EAE. Several subsets of lymphocytes infiltrating the CNS or those present in the gut epithelium and gut lamina propria were analysed by flow cytometry. In vitro migration assays were conducted with mucosal T-cells using transwells.ResultsOur results show a sharp and selective reduction of intestinal propionate at the peak of EAE development, accompanied by increased IFN-γ and decreased IL-22 in the colonic mucosa. Further analyses indicated that GPR43 was the primary SCFAs receptor expressed on T-cells, which was downregulated on colonic TCRαβ+ T-cells upon CNS autoimmunity. The pharmacologic stimulation of GPR43 increased the anti-inflammatory function and reduced the pro-inflammatory features in several TCRαβ+ T-cell subsets in the colonic mucosa upon EAE development. Furthermore, GPR43 stimulation induced the arrest of CNS-autoreactive T-cells in the colonic lamina propria, thus avoiding their infiltration into the CNS and dampening the disease development. Mechanistic analyses revealed that GPR43-stimulation on mucosal TCRαβ+ T-cells inhibits their CXCR3-mediated migration towards CXCL11, which is released from the CNS upon neuroinflammation.ConclusionsThese findings provide a novel mechanism involved in the gut-brain axis by which bacterial-derived products secreted in the gut mucosa might control the CNS tropism of autoreactive T-cells. Moreover, this study shows GPR43 expressed on T-cells as a promising therapeutic target for CNS autoimmunity.

Intracellular Polysaccharides of Aspergillus cristatus from Fuzhuan Brick Tea Leverage the Gut Microbiota and Repair the Intestinal Barrier to Ameliorate DSS-Induced Colitis in Mice.

The intracellular polysaccharides of Aspergillus cristatus (IPSs) from Fuzhuan brick tea have been demonstrated to improve immune function linked to modulating the gut microbiota. Herein, to further investigate the efficacy of IPSs to maintain gut homeostasis, the protection of the purified fraction of IPSs (IPSs-2) on the mice with colitis induced by dextran sulfate sodium (DSS) and the underlying mechanisms were explored in this study. The results revealed that IPSs-2 alleviated the typical symptoms of colitis and suppressed the excessive inflammatory mediators, regulating the genes related to inflammatory responses in the colon at the mRNA level. Meanwhile, IPSs-2 treatment reinforced the intestinal barrier function by ameliorating the DSS-induced histological injury, facilitating the differentiation of goblet cells to enhance Mucin-2 generation, and enhancing the expression of tight junction proteins to alleviate colitis. In addition, IPSs protected against colitis by promoting the production of short-chain fatty acids (SCFAs), the activation of SCFAs receptors, and the leverage of the gut microbiota via the enrichment of Bacteroides, Parabacteroides, Faecalibacterium, Flavonifractor_plautii, and Butyricicoccus, linking with reducing inflammation and repairing intestinal barrier function. Overall, our research revealed the therapeutic potential of IPSs-2 as a prebiotic for attenuating inflammatory bowel disease and provided a rationale for future investigation.

Pulsatilla chinensis saponins improve SCFAs regulating GPR43-NLRP3 signaling pathway in the treatment of ulcerative colitis.

Pulsatilla decoction has been extensively used to treat ulcerative colitis (UC) in recent years. Pulsatilla chinensis saponin (PRS), the active ingredient of its monarch medicine Pulsatilla chinensis (Bunge) Regel, plays a crucial role in the treatment of UC, but its specific mechanism of action has not been fully elucidated. This study aims to investigate the protective effect and possible mechanism of PRS on DSS-induced ulcerative colitis in rats. In this study, the DSS-induced colitis model was used to explore the metabolism and absorption of PRS under UC, detect the content of short-chain fatty acids (SCFAs) in colon tissue, the expression of receptor G Protein-Coupled Receptor 43 (GPR43) protein and inflammasome NLRP3, and observe the expression level of IL-1β, IL-6 and TNF-α in colon tissue. The protective effect of the PRS was also observed. It was found that in the UC group, the absorption rate and extent of drugs increased, and the elimination was accelerated. Compared with the control group, PRS increased the content of short-chain fatty acids (SCFAs) in colon tissue, promoted the expression of SCFAs receptor GPR43 protein, inhibited the activation of the NLRP3 inflammasome, and decreased the content of IL-1β, IL-6 and TNF-α. PRS protects the colon in DSS-induced inflammatory bowel disease by increasing the content of SCFAs, promoting the expression of GPR43 protein, inhibiting the activation of the NLRP3 inflammasome, and reversing the increase in IL-1β, IL-6 and TNF-α levels. PRS can increase the content of colonic SCFAs, activate the GPR43-NLRP3 signaling pathway, and reduce the levels of pro-inflammatory cytokines, thereby improving the symptoms of DSS-induced colitis.

The role of short-chain fatty acid receptors in the hypothalamic paraventricular nucleus of adult offspring in hypertension programmed by maternal high fructose diet exposure

The role of short-chain fatty acids (SCFAs) in the brain on developmental programming of hypertension is poorly understood. The present study aimed to explore the dysregulated tissue levels of SCFAs and expression of SCFA-sensing receptors in the hypothalamic paraventricular nucleus (PVN), a key forebrain region engaged in neural regulation of blood pressure, of offspring to maternal high fructose diet (HFD) exposure. We further investigated the engagement of SCFA-sensing receptors in the PVN on the beneficial effects of -biotics (prebiotic, probiotic, synbiotic and postbiotic) on programmed hypertension primed by maternal HFD. Maternal HFD during gestation and lactation significantly reduced circulating butyrate, along with decreased tissue level of butyrate and increased expression of the SCFA-sensing receptors, GPR41 and olfr78, in the PVN of HFD offspring that could be rectified by oral supplement with prebiotic, probiotic, or synbiotic. The maternal HFD-primed programmed hypertension in adult offspring was accompanied by tissue oxidative stress and neuroinflammation in the PVN, both of which were reversed by oral supplement with the -biotics. Gene silencing of GPR41 or olfr78 mRNA in the PVN also protected adult HFD offspring from programmed hypertension and alleviated the induced oxidative stress and inflammation in the PVN. In addition, oral supplement with the postbiotic butyrate notably restored tissue butyrate level and rectified the expressions of GPR41 and olfr78 in the PVN of HFD offspring. The same treatment also protected against programmed hypertension in adult HFD offspring. These data together suggest that alterations in tissue butyrate level and expression of the SCFA-sensing receptors of GPR41 and olfr78, as well as activation of the SCFA-sensing receptor-dependent tissue oxidative stress and neuroinflammation in the PVN could be novel mechanisms that underlie hypertension programmed by maternal HFD exposure in adult offspring. Furthermore, oral -biotics supplementation may exert beneficial effects on hypertension of developmental origin by targeting the dysfunctional SCFA-sensing receptors in the PVN to exert antioxidant and anti-inflammatory actions in the brain. This research was funded in part by the Chang Gung Medical Foundation, Taiwan (grant number: OMRPG8G0011), and the Ministry of Science and Technology, Taiwan (grant number: MOST111-2320-B-182A-015). This is the full abstract presented at the American Physiology Summit 2023 meeting and is only available in HTML format. There are no additional versions or additional content available for this abstract. Physiology was not involved in the peer review process.

Melatonin improves skin barrier damage caused by sleep restriction through gut microbiota.

It is widely known that lack of sleep damages the skin. Therefore, it is necessary to explore the relationship between sleep deprivation and skin damage and to find effective treatments. We established a 28-day sleep restriction (SR) mice model simulating continuous long-term sleep loss. We found that SR would damage the barrier function of mice's skin, cause oxidative stress damage to the skin, weaken the oscillations of the skin's biological clock, and make the circadian rhythm of Bacteroides disappear. The circadian rhythm of short-chain fatty acids (SCFA) receptors in the skin was disordered. After melatonin supplementation, the skin damage caused by SR was improved, the oscillations of the biological clock were enhanced, the circadian rhythm of Bacteroides was restored, and the rhythm of the receptor GPR43 of propionic acid was restored. We speculated that the improving effect of melatonin may be mediated by propionic acid produced by the gut microbiota. We verified in vitro that propionic acid could improve the keratinocytes barrier function of oxidative damage. We then consumed the gut microbiota of mice through antibiotics and found that oral melatonin could not improve skin damage. Moreover, supplementing mice with propionic acid could improve skin damage. Our research showed that lack of sleep impaired skin barrier function. Oral melatonin could improve skin damage by restoring the circadian rhythm of Bacteroides and its propionic acid metabolite.

Inulin alleviates offspring asthma by altering maternal intestinal microbiome composition to increase short-chain fatty acids.

Technically, symptom of offspring asthma is also closely reliant on its maternal high-fiber diet as well as the intestinal microbiome. Fruits and vegetables are abundant in inulin, and this naturally soluble dietary fiber is endowed with a potential value on offspring asthma control through the maternal intake, but the mechanism now remains less studied. In this study, rats were given with inulin-included drinking water, whereas in normal group rats were allowed with normal water. Afterwards, we analyzed both the formations of the offspring intestinal microbiome ahead of asthma model establishment and of the maternal intestinal microbiome through high throughput sequence and the short-chain fatty acids (SCFAs) by metabolomic analysis. Subsequently, lung inflammation indexes were detected by Elisa, and the expression of short-chain fatty acid receptors (GPR41, GPR43) in the offspring of asthma models were evaluated through qPCR assay. Inulin intake resulted in altered maternal intestinal microbiome composition, with a significant increase in SCFAs-producing bacteria (mainly Bifidobacterium), attenuating the asthmatic inflammatory response in the offspring. Meanwhile, inulin intake during pregnancy modulates the composition of the intestinal microbiome of the offspring, and this alteration appears before the onset of asthma, hence, there should be further studies onto the impacts of offspring's intestinal microbiome on asthma procession.

Gut-Microbiota-Derived Metabolites Maintain Gut and Systemic Immune Homeostasis.

The gut microbiota, including bacteria, archaea, fungi, viruses and phages, inhabits the gastrointestinal tract. This commensal microbiota can contribute to the regulation of host immune response and homeostasis. Alterations of the gut microbiota have been found in many immune-related diseases. The metabolites generated by specific microorganisms in the gut microbiota, such as short-chain fatty acids (SCFAs), tryptophan (Trp) and bile acid (BA) metabolites, not only affect genetic and epigenetic regulation but also impact metabolism in the immune cells, including immunosuppressive and inflammatory cells. The immunosuppressive cells (such as tolerogenic macrophages (tMacs), tolerogenic dendritic cells (tDCs), myeloid-derived suppressive cells (MDSCs), regulatory T cells (Tregs), regulatory B cells (Breg) and innate lymphocytes (ILCs)) and inflammatory cells (such as inflammatory Macs (iMacs), DCs, CD4 T helper (Th)1, CD4Th2, Th17, natural killer (NK) T cells, NK cells and neutrophils) can express different receptors for SCFAs, Trp and BA metabolites from different microorganisms. Activation of these receptors not only promotes the differentiation and function of immunosuppressive cells but also inhibits inflammatory cells, causing the reprogramming of the local and systemic immune system to maintain the homeostasis of the individuals. We here will summarize the recent advances in understanding the metabolism of SCFAs, Trp and BA in the gut microbiota and the effects of SCFAs, Trp and BA metabolites on gut and systemic immune homeostasis, especially on the differentiation and functions of the immune cells.

GPR41 Regulates the Proliferation of BRECs via the PIK3-AKT-mTOR Pathway

Short-chain fatty acids (SCFAs) play a pivotal role in regulating the proliferation and development of bovine rumen epithelial cells (BRECs). G protein-coupled receptor 41 (GPR41) is involved in the signal transduction in BRECs as a receptor for SCFAs. Nevertheless, the impact of GPR41 on the proliferation of BRECs has not been reported. The results of this research showed that the knockdown of GPR41 (GRP41KD) decreased BRECs proliferation compared with the wild-type BRECs (WT) (p < 0.001). The RNA sequencing (RNA-seq) analysis showed that the gene expression profiles differed between WT and GPR41KD BRECs, with the major differential genes enriched in phosphatidylinositol 3-kinase (PIK3) signaling, cell cycle, and amino acid transport pathways (p < 0.05). The transcriptome data were further validated by Western blot and qRT-PCR. It was evident that the GPR41KD BRECs downregulated the level of the PIK3-Protein kinase B (AKT)-mammalian target of the rapamycin (mTOR) signaling pathway core genes, such as PIK3, AKT, eukaryotic translation initiation factor 4E binding protein 1 (4EBP1) and mTOR contrasted with the WT cells (p < 0.01). Furthermore, the GPR41KD BRECs downregulated the level of Cyclin D2 p < 0.001) and Cyclin E2 (p < 0.05) compared with the WT cells. Therefore, it was proposed that GPR41 may affect the proliferation of BRECs by mediating the PIK3-AKT-mTOR signaling pathway.

Inhibition of inflammatory microglia by dietary fiber and short-chain fatty acids

Microglia play a vital role maintaining brain homeostasis but can also cause persistent neuroinflammation. Short-chain fatty acids (SCFAs) produced by the intestinal microbiota have been suggested to regulate microglia inflammation indirectly by signaling through the gut-brain axis or directly by reaching the brain. The present work evaluated the anti-inflammatory effects of SCFAs on lipopolysaccharide (LPS)-stimulated microglia from mice fed inulin, a soluble fiber that is fermented by intestinal microbiota to produce SCFAs in vivo, and SCFAs applied to primary microglia in vitro. Feeding mice inulin increased SCFAs in the cecum and in plasma collected from the hepatic portal vein. Microglia isolated from mice fed inulin and stimulated with LPS in vitro secreted less tumor necrosis factor α (TNF-α) compared to microglia from mice not given inulin. Additionally, when mice were fed inulin and injected i.p with LPS, the ex vivo secretion of TNF-α by isolated microglia was lower than that secreted by microglia from mice not fed inulin and injected with LPS. Similarly, in vitro treatment of primary microglia with acetate and butyrate either alone or in combination downregulated microglia cytokine production with the effects being additive. SCFAs reduced histone deacetylase activity and nuclear factor-κB nuclear translocation after LPS treatment in vitro. Whereas microglia expression of SCFA receptors Ffar2 or Ffar3 was not detected by single-cell RNA sequencing analysis, the SCFA transporters Mct1 and Mct4 were. Nevertheless, inhibiting monocarboxylate transporters on primary microglia did not interfere with the anti-inflammatory effects of SCFAs, suggesting that if SCFAs produced in the gut regulate microglia directly it is likely through an epigenetic mechanism following diffusion.

Maternal helminth infection protects offspring from high-fat-diet-induced obesity through altered microbiota and SCFAs.

Helminth-induced Th2 immunity and gut microbiota have been recently shown to be highly effective in modulating metabolic syndromes in animal models. This study aimed to determine whether maternal immunity and microbial factors affect the induction and development of obesity in offspring. Here, Heligomosomoides polygyrus (Hp)-infected or control female C57BL/6J mice mated with normal males and their offspring were fed a high-fat diet (HFD) for 9 weeks after weaning. Our results showed that Hp-induced maternal outcomes during gestation and lactation significantly impacted offspring metabolic phenotypes. This was evidenced by results showing that offspring from helminth-infected mothers on an HFD (Hp-offspring + HFD) gained significantly less body weight than those from uninfected mothers (Cont-offspring + HFD). Hp-offspring + HFD exhibited no Th2 phenotype but displayed a pattern of gut microbiota composition similar to that of Hp-infected mothers. Cross-fostering experiments confirmed that the helminth-induced maternal attenuation of offspring obesity was mediated through both prenatal and postnatal effects. Our results further showed that helminth-infected dams and their offspring had a markedly altered gut microbiome composition, with increased production of short-chain fatty acids (SCFAs). Intriguingly, Hp-infected mothers and Hp-offspring + HFD showed increased SCFA receptor (GPR) expression in adipose and colonic tissues compared to noninfected mothers and Cont-offspring + HFD, respectively. Moreover, SCFA supplementation to the pups of uninfected control mothers during lactation protected against HFD-induced weight gain, which corresponded with changes in gut bacterial colonization. Collectively, our findings provide new insights into the complex interaction of maternal immune status and gut microbiome, Hp infection, and the immunity and gut microbiome in obese-prone offspring in infant life.

Eucommia Bark/Leaf Extract Improves Lipid Metabolism Disorders by Affecting Intestinal Microbiota and Microbiome-Host Interaction in HFD Mice.

Eucommia bark contains many bioactive compounds and has anti-hyperlipidemic effects. However, due to the slow growth rate of the plant, there is a limited supply of this resource. Studies have demonstrated that Eucommia leaves contain active ingredients similar to those of Eucommia bark and also have anti-hyperlipidemic effects. It is not currently clear whether Eucommia leaf can be used as a substitute for Eucommia bark. Furthermore, their mechanism of action for anti-hyperlipidemia by improving the structure of the gut microbiota is also unclear. We aimed to determine the composition of the active ingredients in EBE and ELE by HPLC, establish an HFD-induced hyperlipidemia model, and combine fecal microbiota transplantation (FMT) experiments to investigate the mechanism of EBE/ELE anti-hyperlipidemia by modifying the structure of intestinal microbiota, as well as to compare the effects of EBE and ELE. Our results showed that EBE and ELE contained similar active ingredients and significantly alleviated lipid metabolism disorders and blood glucose levels in the HFD-induced hyperlipidemia model. In this study, EBE and ELE significantly reduced the relative abundance of Desulfovibrionaceae and Erysipelotrichaceae and significantly increased the relative abundance of Ruminococcaceae. They also promoted the production of short-chain fatty acids (SCFAs) and activated the gene expression of the SCFA receptors G protein-coupled receptor 41 (GPR41) and GPR43. In addition, EBE and ELE can significantly increase the expression of the fasting-induced adipose factor (Fiaf) gene in the colon and inhibit the secretion of lipoprotein lipase (LPL) in the liver, thereby inhibiting triglyceride (TG) synthesis. They also significantly activate the expression of GPR41 and GPR43 genes in the epididymal fat tissue, leading to reduced lipid accumulation in adipocytes. These effects on the target genes were associated with changes in the abundance of Desulfovibrionaceae, Erysipelotrichaceae, and Ruminococcaceae bacteria in the intestinal microbiota. Thus, regulating the relative abundance of these microbes may serve as prospective targets for EBE/ELE to influence the Fiaf-LPL gut-liver axis and the SCFAs-GPR41/GPR43 gut-fat axis. In addition, there was no significant difference in the anti-hyperlipidemic effects of ELE and EBE, suggesting that Eucommia leaf may be a suitable alternative to Eucommia bark for managing hyperlipidemia by regulating the structure of the intestinal microbiota. These findings suggest that Eucommia leaves have great potential for development as a functional food with lipid-lowering properties.

The short-chain fatty acid butyrate exerts a specific effect on VE-cadherin phosphorylation and alters the integrity of aortic endothelial cells.

Short-chain fatty acids (SCFAs) like butyrate (BUT) largely influence vascular integrity and are closely associated with the onset and progression of cardiovascular diseases. However, their impact on vascular endothelial cadherin (VEC), a major vascular adhesion and signaling molecule, is largely unknown. Here, we explored the effect of the SCFA BUT on the phosphorylation of specific tyrosine residues of VEC (Y731, Y685, and Y658), which are reported to be critical for VEC regulation and vascular integrity. Moreover, we shed light on the signaling pathway engaged by BUT to affect the phosphorylation of VEC. Thereby, we used phospho-specific antibodies to evaluate the phosphorylation of VEC in response to the SCFA sodium butyrate in human aortic endothelial cells (HAOECs) and performed dextran assays to analyze the permeability of the EC monolayer. The role of c-Src and SCFA receptors FFAR2 and FFAR3 in the induction of VEC phosphorylation was analyzed using inhibitors and antagonists for c-Src family kinases and FFAR2/3, respectively, as well as by RNAi-mediated knockdown. Localization of VEC in response to BUT was assessed by fluorescence microscopy. BUT treatment of HAOEC resulted in the specific phosphorylation of Y731 at VEC with minor effects on Y685 and Y658. Thereby, BUT engages FFAR3, FFAR2, and c-Src kinase to induce phosphorylation of VEC. VEC phosphorylation correlated with enhanced endothelial permeability and c-Src-dependent remodeling of junctional VEC. Our data suggest that BUT, an SCFA and gut microbiota-derived metabolite, impacts vascular integrity by targeting VEC phosphorylation with potential impact on the pathophysiology and therapy of vascular diseases.

Disturbance of lipid metabolism in germ-free mice transplanted with gut microbiota of DSS-induced colitis mice.

Hepatobiliary abnormality and metabolic disorders are frequently observed complications in patients with inflammatory bowel diseases (IBD). Given that microbiota dysbiosis is a common pathophysiological feature of both IBD and metabolic diseases, we examined how the IBD-induced dysbiosis affects the host metabolism and contributes to the development of associated metabolic diseases using germ-free (GF) mice transplanted with fecal microbiota of DSS-induced colitis mice. There was no significant change in inflammation or barrier integrity in the gut of GF mice that received microbiota from colitis mice compared to their counterparts that were transplanted with microbiota from non-colitis healthy mice. Interestingly, it was observed that the GF recipients of colitis-induced altered microbiota showed a significant decrease in the weight of adipose tissues including mesenteric, epididymal, subcutaneous, and brown fat without any change in body weight, which was accompanied by abnormalities in adipose tissue functions such as fat storage and adiponectin production. Transplantation of colitis-induced altered microbiota also disrupted hepatic lipid metabolism in the GF recipient mice, which was observed by increases in synthesis and accumulation of cholesterol and bile acids in hepatocytes and a decrease in plasma HDL-cholesterol. Additional observations including elevated plasma levels of insulin, decreased hepatic production of FGF21, and decreased levels of fecal short chain fatty acids (SCFAs) and hepatic expression of SCFA receptors led to a conclusion that the transplantation of the colitis-associated dysbiotic microbiota was causally associated with impairments of insulin action and FGF21-adiponectin axis, possibly due to the low SCFA-producing capacity of the colonized microbiota, leading to metabolic abnormalities including adipose tissue dysfunction and dysregulated hepatic lipid metabolism. Our findings suggest potential mechanisms that explain how colitis-associated gut dysbiosis may contribute to the development of metabolic dysfunctions, which could be applied to clinical practice to improve the efficacy of treatment of IBD patients with comorbid metabolic disorders or vice versa.

Resveratrol Butyrate Ester Supplementation Blunts the Development of Offspring Hypertension in a Maternal Di-2-ethylhexyl Phthalate Exposure Rat Model.

Resveratrol (REV) is a plant polyphenol with a plethora of beneficial properties. We previously enhanced the efficacy of REV via esterification of REV with butyrate to form resveratrol butyrate ester (RBE). Compared with REV, RBE exhibits higher bioavailability and better antioxidant effects. Hypertension can originate in early life because of maternal toxic chemical exposure. This study aims to examine the effectiveness of RBE in the protection of offspring hypertension induced by maternal di-2-ethylhexylphthalate (DEHP) exposure and to explore the underlying mechanisms. DEHP (10 mg/kg/day) was used as oral gavage to pregnant rats during gestation and lactation. The control group received the vehicle. Three groups of DEHP-exposed dams received REV (6.67 mg/kg/day), or low-dose (3.33 mg/kg/day) or high-dose (6.67 mg/kg/day) RBE in drinking water during gestation and lactation. Perinatal DEHP exposure resulted in hypertension and bodyweight gain in adult male offspring, which was prevented by high-dose RBE. REV supplementation attenuated DEHP exposure-induced increases in blood pressure but not bodyweight. High-dose RBE decreased renal oxidative damage, increased plasma butyrate concentrations, and altered short chain fatty acid receptor (SCFA) expression. Low-dose RBE treatment reduced downstream mediators of the acryl hydrocarbon receptor (AHR) signaling pathway. Moreover, DEHP exposure, REV and RBE treatment differentially shaped the offspring's gut microbiota. In particular, high-dose RBE increased the abundance of the genus Duncaniella. The beneficial effects of RBE treatment were related to reducing oxidative damage, increasing plasma butyrate concentrations, downregulating SCFA receptor expression, antagonizing AHR signaling, and altering the gut microbiota. This study provides the first evidence of RBE as a novel plant polyphenol bioproduct targeting the oxidative stress and gut microbiota to protect against maternal DEHP exposure-primed offspring hypertension.

Virus induced dysbiosis promotes type 1 diabetes onset.

Autoimmune disorders are complex diseases of unclear etiology, although evidence suggests that the convergence of genetic susceptibility and environmental factors are critical. In type 1 diabetes (T1D), enterovirus infection and disruption of the intestinal microbiota are two environmental factors that have been independently associated with T1D onset in both humans and animal models. However, the possible interaction between viral infection and the intestinal microbiota remains unknown. Here, we demonstrate that Coxsackievirus B4 (CVB4), an enterovirus that accelerates T1D onset in non-obese diabetic (NOD) mice, induced restructuring of the intestinal microbiome prior to T1D onset. Microbiome restructuring was associated with an eroded mucosal barrier, bacterial translocation to the pancreatic lymph node, and increased circulating and intestinal commensal-reactive antibodies. The CVB4-induced change in community composition was strikingly similar to that of uninfected NOD mice that spontaneously developed diabetes, implying a mutual "diabetogenic" microbiome. Notably, members of the Bifidobacteria and Akkermansia genera emerged as conspicuous members of this diabetogenic microbiome, implicating these taxa, among others, in diabetes onset. Further, fecal microbiome transfer (FMT) of the diabetogenic microbiota from CVB4-infected mice enhanced T1D susceptibility and led to diminished expression of the short chain fatty acid receptor GPR43 and fewer IL-10-expressing regulatory CD4+ T cells in the intestine of naïve NOD recipients. These findings support an overlap in known environmental risk factors of T1D, and suggest that microbiome disruption and impaired intestinal homeostasis contribute to CVB-enhanced autoreactivity and T1D.