Short-chain Fatty Acid Receptor Research Articles

Conservation of members of the free fatty acid receptor gene family in common carp

Accumulating evidence supports the crucial role intestinal microbiota and their metabolites play in the homeostasis of organisms. An important class of metabolites that have been shown to affect the immune system are short chain fatty acids (SCFAs). These SCFAs can affect the host cells via passive diffusion or via ligation to receptors, among others G-protein coupled receptor (GPR) 41 and 43. GPR41 and GPR43 are both part of a family of GPR40-related receptors. Mammalian studies have shown an important role for GPR41 and GPR43 in the modulation of immune responses by SCFAs. However, up till date, no validated coding sequences for orthologues of these SCFA receptors have been published for teleost fish. We used genomic resources and cDNA cloning, to identify and validate ten coding sequences for gpr40L genes in common carp. Phylogenetic analysis showed a division into three subclasses, putatively named class a, b and c, and showed the common carp genes had a closer phylogenetic relationship to mammalian GPR43 than to mammalian GPR41. Synteny analysis revealed a clear conservation of syntenic relationships between gpr40L in the genomes of spotted gar and common carp with the relevant region in the human genome. This conservation of synteny validates the genes identified, as gpr40L. Finally, presence of gpr40L genes was investigated in silico for genomes of 25 different, mostly teleost, fish species largely confirming the observations for gpr40L of common carp with regards to both, subdivision in three subclasses a-c and conservation of synteny. Our data provide an important first step towards an understanding of the role and function of receptors for SCFAs and immunomodulation in fish.

Short-chain fatty acid receptors involved in epithelial acetylcholine release in rat caecum

Short-chain fatty acids (SCFAs) produced by the microbial fermentation of carbohydrates are important energy substrates for mammals. Intestinal epithelia respond to these metabolites by stimulation of anion secretion via the release of epithelial acetylcholine. The present experiments were performed to discover which of the known receptors for SCFAs are expressed in rat caecum, the most important site of fermentation within the intestine of non-ruminant mammals.Using the increase in short-circuit current (Isc) induced by anion secretion as the readout, the order of efficiency of the tested SCFAs in rat caecum was propionate > butyrate > acetate. Both synthetic high-affinity selective free fatty acid (FFA) receptor agonists 4-CMTB (FFA2 receptor) and AR420626 (FFA3 receptor) partially mimicked the effect of propionate on Isc (IProp). IProp was concentration-dependently inhibited by the FFA3 receptor antagonist β-OH-butyrate. Although no antagonist of rat FFA2 receptor is available, coadministration of the allosteric FFA2 receptor agonist 4-CMTB together with a low concentration of propionate potentiated IProp, suggesting that FFA2 receptor is involved in sensing of short-chain fatty acids as well. The expression of both receptor types was confirmed by qPCR (with FFA2 > FFA3 receptor). Immunohistochemical staining revealed the localization of FFA2 receptor in the surface epithelium and the FFA3 receptor expression predominantly in enteroendocrine cells and subepithelial nerve-like fibers.Taken together, the present results demonstrate that the anion secretion induced by the microbial metabolite propionate in rat caecum is enhanced by activation of FFA2 and FFA3 receptor expressed in different cell types within the caecal epithelium.

The Taste of Fermentation: Propionic Acid Is Judged More Pleasant Than Other Short Chain Fatty Acids

Abstract Objectives Short chain fatty acids (SCFAs), such as acetic, propionic and butyric acids have many health benefits, but they have been almost exclusively studied in the context of the gut, where they are produced as by-products of the gut microbiome. SCFAs, however, are also found in fermented foods as metabolites of beneficial microbes, and may signal to taste centers of the brain that these healthful bacteria are present and, if consumed, can colonize the gut and promote health. Two free fatty acid receptors (FFARs), FFAR2 and FFAR3, have been identified in taste tissue and have different binding affinities for SCFAs based on their carbon chain length, though both bind propionic acid. Our objective was to assess whether propionic acid is preferred over the other SCFAs. Methods With nose clips on, 10 participants tasted five samples of a mildly sweet solution (200 mM glucose) mixed with (1) 20 mM acetic acid, (2) 20 mM propionic acid, (3) 20 mM butyric acid, (4) citric acid matched for sourness, or (5) the glucose solution neat. Participants ranked the five samples by preference, and then repeated the ranking without nose clips. All tests were done in duplicate. Results Participants ranked the glucose + propionic acid as highly as the glucose + citric acid and the glucose neat solutions both with and without nose clips unlike the other SCFAs. Conclusions These results suggest that humans show preference for the taste of propionic acid, a metabolic by-product of fermentation. The observation indicates that the ingestion of health-promoting fermented foods may have been a positive evolutionary pressure resulting in short-chain fatty acid receptors in taste tissue. Future research will focus on identifying the receptors and signaling pathways involved in the taste detection of and preference for SCFAs in foods. Funding Sources This research was supported by NIH DC014286 and USDA HATCHNJ14120 to PASB.

FC 083PROBIOTIC L.CASEI ZHANG SLOWS THE PROGRESSION OF ACUTE AND CHRONIC KIDNEY DISEASE

Abstract Background and Aims The relationship between gut microbial dysbiosis and acute or chronic kidney disease is currently acknowledged to be a health concern which is characterized by immune dysregulation and metabolic disorder. However, the therapeutic strategies remain to be developed. In the present study, we examined the protective effects and mechanisms of action of probiotic Lactobacillus casei Zhang (L. casei Zhang) on bilateral renal ischemia-reperfusion (I/R)-induced injury in mice. Method We orally gavaged male C57BL/6 mice with or without L. casei Zhang and probiotic Lactobacillus acidophilus (L. acidophilus) for 4 weeks (1 × 109 CFU per day) prior to being subjected to ischemia-reperfusion (I/R)-induced injury. Serum, colons and renal samples were collected after 5 days and 28 days. The composition and abundance of gut microbiota was investigated by using 16S rRNA. LC-MS metabolomic analysis technology and GC-MS analysis technology were used to investigate the metabolic alterations. To define the intra-renal cell subsets that are involved in L. casei Zhang-induced renoprotection, we performed single-cell RNA-sequencing (scRNA-seq) of kidney samples dissected from L. casei Zhang pretreated mice at day 5 after I/R along with samples from non-treated controls. Results Compared to L.acidophilus, L. casei Zhang demonstrated superior capacity in restoring intestinal flora homeostasis, protecting intestinal mucosal barrier function and improving the disrupted metabolomic profile. L. casei Zhang not only elevated the short chain fatty acids (SCFAs) in serum and kidney, but also significantly increased nicotinamide, by which L. casei Zhang inhibited renal inflammatory response and alleviated the damage of renal tubular epithelial cells (TECs) via interacting with SCFAs receptors on macrophages and TECs, and activating NAD+ metabolism in injured kidneys. Conclusion These results show that oral administration of L. casei Zhang, by altering SCFAs and nicotinamide metabolism, is a potential therapy to mitigate kidney injury and slow the progression of renal decline.

Effects induced by polyethylene microplastics oral exposure on colon mucin release, inflammation, gut microflora composition and metabolism in mice

Microplastics are plastic fragments widely distributed in the environment and accumulate in the organisms. However, the research on microplastics effects in mammals is limited. Polyethylene is the main kind of microplastics in the environment. We hypothesized that polyethylene exposure disrupts host intestine metabolism by modifying intestine microflora composition and then lipopolysaccharide (LPS) pathway. Female mice were orally exposed to 0, 0.002 and 0.2 μg/g/d polyethylene microplastics (PE MPs) for 30 days. Colon mucin density was quantized after AB-PAS staining. Mucin 2 (MUC2), inflammatory factors (IL-1β, IL-6, IL-8 and IL-10), short-chain fatty acid receptors (GPR41 and GPR43), LPS receptors (TLR4 and MyD88) and LPS pathway downstream genes (ERK1 and NF-κB) mRNA levels in colon were measured. Feces were collected on the 15th day of exposure for gut microflora analysis. Blood biochemical analysis was performed. Results showed that 0.2 μg/g/d PE MPs exposure significantly decreased colon mucin expression (p < 0.05), decreased IL-1β (p < 0.05) and increased IL-8 and IL-10 levels (p < 0.01 and p < 0.001 respectively). Microflora data showed that in 0.2 μg/g/d PE MPs group the number of Firmicutes decreased and the number of Bacteroides increased (both p < 0.01). Predicted KEGG metabolic pathways by piecrust method indicated that PE MPs enhanced amino acids metabolism in microflora. ERK1 and NF-κB mRNA were significantly lower in 0.2 μg/g/d PE MPs group (both p < 0.001). Blood total protein, albumin and globulin levels significantly increased after 0.2 μg/g/d PE MPs exposure (p < 0.01, p < 0.01 and p < 0.05 respectively). These results indicate that PE MPs exposure induced decreased mucin production, a slight immune response and increased the microflora amino acid metabolism in the mice colon by modifying colon microflora composition. SummaryPolyethylene microplastics exposure decreased colon mucin release and increased amino acid metabolism by modifying colon microflora composition.

FFAR from the Gut Microbiome Crowd: SCFA Receptors in T1D Pathology.

The gut microbiome has emerged as a novel determinant of type 1 diabetes (T1D), but the underlying mechanisms are unknown. In this context, major gut microbial metabolites, short-chain fatty acids (SCFAs), are considered to be an important link between the host and gut microbiome. We, along with other laboratories, have explored how SCFAs and their cognate receptors affect various metabolic conditions, including obesity, type 2 diabetes, and metabolic syndrome. Though gut microbiome and SCFA-level changes have been reported in T1D and in mouse models of the disease, the role of SCFA receptors in T1D remains under explored. In this review article, we will highlight the existing and possible roles of these receptors in T1D pathology. We conclude with a discussion of SCFA receptors as therapeutic targets for T1D, exploring an exciting new potential for novel treatments of glucometabolic disorders.

Investigation of the vascular effects of short chain fatty acids in rat mesenteric resistance arteries

Fiber rich diets have been shown to prevent the onset and reduce severity of hypertension1, a condition affecting 20-30% of adults in North America. High fiber diets facilitate the production of short chain fatty acids (SCFAs) by gut bacteria of which, in humans, acetate is the most abundant, followed by propionate and butyrate. It has been proposed that these three SCFAs may have direct effects on blood vessels and so may contribute to regulation of blood pressure2. Further research is needed to determine the mechanisms underlying the vascular actions of SCFAs. We tested the hypothesis that SCFAs can induce vasodilation and limit nerve-evoked vasoconstriction in rat mesenteric vasculature. Direct effects on vascular tone were assessed by constructing cumulative concentration-response curves to SCFAs in isolated third order rat mesenteric arteries mounted in a wire myograph and pre-stimulated with phenylephrine (PE) to increase tone. The effects of SCFAs on nerve-evoked vasoconstriction were assessed by constructing frequency-responses curves to perivascular nerve stimulation in a perfused rat mesenteric bed in the presence and absence of SCFAs added to the perfusate. In both experimental approaches, pharmacological tools were used to investigate the mechanism of action of SCFAs. Propionate (3 μM - 1 mM) and acetate (0.3 μM - 1 mM) caused reductions in PE-evoked tone with maximum relaxation of 32.7 ± 7% and 31.6 ± 8.2%, respectively, and attenuated nerve-evoked vasoconstriction in mesenteric arteries at 10 mM - 60 mM propionate and 30 mM - 50 mM acetate. These effects were inhibited by blockers of nitric oxide (NO) synthase (L-NG-nitroarginine methyl ester, L-NAME, 100 μM) and endothelial Ca2+-activated K+ (KCa) channels (apamin, 50 nM; TRAM-34, 1 μM). L-NAME alone significantly inhibited relaxations elicited by acetate indicating a predominant role for NO, whereas the actions of propionate were significantly inhibited by apamin and TRAM-34, indicating a predominant role for endothelial KCa channels in this response. These data indicate that SCFAs may cause vasodilation in mesenteric resistance arteries via activation of endothelial pathways and that there may be a differential contribution of NO and KCa channels to responses of individual SCFAs. 1. Appel LJ, Moore TJ, Obarzanek E, et al. A clinical trial of the effects of dietary patterns on blood pressure. DASH Collaborative Research Group. N Engl J Med. 1997;336(16):1117-1124. doi:10.1056/NEJM199704173361601 2. Pluznick J. A novel SCFA receptor, the microbiota, and blood pressure regulation. Gut Microbes. 2014;5(2):202-207. doi:10.4161/gmic.27492

Gut Dysbiosis and Barrier Disruption Are Associated with Diastolic Dysfunction in a Novel Mouse Model of Heart Failure with Preserved Ejection Fraction

Gut dysbiosis has recently been associated with the severity of the complex syndrome of heart failure (HF) in patients. The mechanisms of action involving gut microbes and immune responses are starting to be characterized in experimental models of HF. More than 50% of HF patients present with HF with preserved ejection fraction (HFpEF), characterized by impaired relaxation (diastolic function) and preserved contractility (systolic function), which do not respond to any of the available treatments for HF. Obesity and hypertension are major risk factors for HFpEF, and have been independently associated with gut dysbiosis, and modulation of the microbiota in experimental models of these risk factors has revealed mechanistic insights. However, whether and how the microbiota contributes to HFpEF is unknown. Recently, a novel mouse model of HFpEF induced by a combination of high-fat diet (HFD) and L-NAME, to mimic obesity and hypertension, respectively. We hypothesize that specific microbiota and derived metabolites, are altered in HFpEF and contribute to systemic inflammation and diastolic dysfunction. C57/BL6 WT mice were fed HFD and L-NAME (H/L) to induce HFpEF. We used invasive hemodynamics to determine diastolic and systolic function, and 16S rRNA sequencing in fecal samples to characterize gut bacteria and perform metabolic pathway analysis. The heart, the intestine and plasma were collected and evaluated for indicators of cardiac remodeling and gut permeability using flow cytometry and qPCR. As expected, H/L triggered diastolic dysfunction at 5 weeks. At this time, H/L intestinal epithelial cells (iECs) showed downregulation in gene expression of the junctional markers cadherin-1, ZO-1 and occludin, suggesting the induction of leaky gut. We also found increased concentration of proinflammatory molecules in serum (e.g. IL-6, IL-17 and CXCL1). Strikingly, H/L treatment resulted in gut dysbiosis in H/L mice compared to those that received standard diet (STD). The main phyla analysis showed a higher Firmicutes/Bacteroidetes ratio in H/L, which has been associated with obesity, compared to STD. At the family level, Ruminococcaceae, also linked to obesity in humans, showed elevated relative abundance in H/L group compared to STD, and Rikenellaceae and Christensenellaceae significantly decreased their numbers. Interestingly, gut bacteria from H/L-treated mice revealed an enrichment of metabolic pathways related to synthesis and degradation of fatty acids. We studied the gene expression of the main short-chain fatty acid (SCFA) receptors, associated with improvement in cardiovascular health. FFAR2 (GPR43) expression did not change in the heart neither the gut, but strikingly, FFAR3 (GPR41) expression was significantly upregulated in the heart in the H/L group compared to STD, but not in iECs. In conclusion, we demonstrated that a novel mouse model of HFpEF induced gut dysbiosis and alterations in gut permeability, and identified a dysregulation of fatty acid synthesis and degradation metabolic pathways. Mechanistic studies are needed to see the role of fatty acids and its receptors in cardiac inflammation during diastolic dysfunction.

Metabolic regulation via ketone body receptors under ketogenic conditions

Ketone bodies, including β-hydroxybutyrate and acetoacetate, are important alternative energy sources during energy shortage. β-Hydroxybutyrate also acts as a signaling molecule via specific G protein-coupled receptors (GPCRs) GPR41 and GPR109A (1, 2); however, the specific associated GPCRs and physiological functions of acetoacetate remain unknown. Here we identified acetoacetate as an endogenous agonist for short-chain fatty acid (SCFA) receptor GPR43 by ligand screening in a heterologous expression system (3). Under ketogenic conditions, such as starvation and low-carbohydrate diets, plasma ketone body levels increased markedly, whereas plasma and cecal SCFA levels decreased dramatically, along with an altered gut microbiota composition. In addition, ketone body receptors-deficient mice showed reduced weight loss and suppressed plasma lipoprotein lipase activity during fasting and eucaloric ketogenic diet feeding. Moreover, these mice exhibited minimal weight decrease after intermittent fasting. These observations provide insight into the role of ketone bodies in energy metabolism under shifts in nutrition and may contribute to the development of preventive medicine via diet and foods. (1); Kimura et al., Proc Natl Acad Sci U S A. 2011 (2); Kimura et al., Physiol Rev. 2020 (3); Miyamoto et al., Proc Natl Acad Sci U S A. 2019

Lung immune tone via gut-lung axis: gut-derived LPS and short-chain fatty acids' immunometabolic regulation of lung IL-1β, FFAR2, and FFAR3 expression.

Microbial metabolites produced by the gut microbiome, e.g. short-chain fatty acids (SCFA), have been found to influence lung physiology and injury responses. However, how lung immune activity is regulated by SCFA is unknown. We examined fresh human lung tissue and observed the presence of SCFA with interindividual variability. In vitro, SCFA were capable of modifying the metabolic programming in LPS-exposed alveolar macrophages (AM). We hypothesized that lung immune tone could be defined by baseline detection of lung intracellular IL-1β. Therefore, we interrogated naïve mouse lungs with intact gut microbiota for IL-1β mRNA expression and localized its presence within alveolar spaces, specifically within AM subsets. We established that metabolically active gut microbiota, which produce SCFA, can transmit LPS and SCFA to the lung and thereby could create primed lung immunometabolic tone. To understand how murine lung cells sensed and upregulated IL-1β in response to gut microbiome-derived factors, we determined that, in vitro, AM and alveolar type II (AT2) cells expressed SCFA receptors, free fatty acid receptor 2 (FFAR2), free fatty acid receptor 3 (FFAR3), and IL-1β but with distinct expression patterns and different responses to LPS. Finally, we observed that IL-1β, FFAR2, and FFAR3 were expressed in isolated human AM and AT2 cells ex vivo, but in fresh human lung sections in situ, only AM expressed IL-1β at rest and after LPS challenge. Together, this translational study using mouse and human lung tissue and cells point to an important role for the gut microbiome and their SCFA in establishing and regulating lung immune tone.

Gut microbial short-chain fatty acids-mediated olfactory receptor 78 stimulation promotes anorexigenic gut hormone peptide YY secretion in mice

Olfactory receptor 78 (Olfr78), which is also known as a receptor for short-chain fatty acids (SCFAs) produced via gut microbial fermentation from indigestible polysaccharides such as dietary fibers, is expressed in the enteroendocrine cells of the colon. However, the role of Olfr78 in gut hormone secretion remains unknown. Here, we aimed to investigate the function and mechanism of action of Olfr78 in vivo and in vitro. Toward this, we assessed the expression of Olfr78 in several tissues, affinity of Olfr78 to various monocarboxylates, and the secretion of anorexigenic gut hormone peptide YY (PYY) via Olfr78 using various molecular and biochemical techniques. Olfr78 was abundantly expressed in the colon and mouse enteroendocrine cell line STC-1 and showed specific affinity to SCFAs such as acetate and propionate, but not butyrate, in a monocarboxylate ligand screening assay using a heterologous expression system. Acetate promoted PYY secretion in STC-1 cells via Olfr78-protein kinase A signaling, whereas the effects were abolished by Olfr78 RNA interference. Colonic SCFAs production via oral administration of fructo-oligosaccharide significantly increased plasma PYY levels, whereas this effect was abolished in Olfr78-deficient and germ-free mice. These results suggested that the SCFA receptor Olfr78 is important for anti-obesity and anorexigenic effects of the gut microbiota and dietary fibers.

Host genetics exerts lifelong effects upon hindgut microbiota and its association with bovine growth and immunity

The gut microbiota is a complex ecological community that plays multiple critical roles within a host. Known intrinsic and extrinsic factors affect gut microbiota structure, but the influence of host genetics is understudied. To investigate the role of host genetics upon the gut microbiota structure, we performed a longitudinal study in which we evaluated the hindgut microbiota and its association with animal growth and immunity across life. We evaluated three different growth stages in an Angus-Brahman multibreed population with a graduated spectrum of genetic variation, raised under variable environmental conditions and diets. We found the gut microbiota structure was changed significantly during growth when preweaning, and fattening calves experienced large variations in diet and environmental changes. However, regardless of the growth stage, we found gut microbiota is significantly influenced by breed composition throughout life. Host genetics explained the relative abundances of 52.2%, 40.0%, and 37.3% of core bacterial taxa at the genus level in preweaning, postweaning, and fattening calves, respectively. Sutterella, Oscillospira, and Roseburia were consistently associated with breed composition at these three growth stages. Especially, butyrate-producing bacteria, Roseburia and Oscillospira, were associated with nine single-nucleotide polymorphisms (SNPs) located in genes involved in the regulation of host immunity and metabolism in the hindgut. Furthermore, minor allele frequency analysis found breed-associated SNPs in the short-chain fatty acids (SCFAs) receptor genes that promote anti-inflammation and enhance intestinal epithelial barrier functions. Our findings provide evidence of dynamic and lifelong host genetic effects upon gut microbiota, regardless of growth stages. We propose that diet, environmental changes, and genetic components may explain observed variation in critical hindgut microbiota throughout life.

The Combination of Scutellaria baicalensis Georgi and Sophora japonica L. ameliorate Renal Function by Regulating Gut Microbiota in Spontaneously Hypertensive Rats.

Chronic kidney disease (CKD) is becoming a notable health concern globally. The combination of Scutellaria baicalensis Georgi (SB) and Sophora japonica L. (SJ) has been demonstrated to have anti-hypertensive effects and improve kidney injury clinically. This study aimed to explore the renal protective effect of the combination of SB and SJ against CKD and clarify the potential mechanisms. Male spontaneously hypertensive rats (SHR) were used to induce hypertensive nephropathy and were treated with SB or SJ separately or in combination for 15 weeks, and an antibiotic group was used for a rescue experiment. Blood pressure, serum or urine biochemical markers, serum inflammation factors, short-chain fatty acids (SCFAs), indoxyl sulfate (IS), and oxidative stress indicators were assessed. Western blot analysis was performed to determine the expression of intestinal tight junction proteins, including occludin and ZO-1. The mRNA expression of the SCFAs receptors olfactory 78 (Olfr78) and G protein-coupled receptor 41 (GPR41) was determined by quantitative real-time PCR. Gut microbiota profiles were established via high-throughput sequencing of the V3-V4 region of the bacterial 16S rRNA gene. SB and SJ significantly ameliorated the severity of renal injury induced by hypertension. The combination also decreased the ratio of Firmicutes/Bacteroidetes, increased the relative abundance of Lactobacillus, and reduced that of Clostridiaceae. The intestinal barrier was improved, and the change in dominant bacteria reduced IS accumulation and further inhibited oxidative stress activation in kidneys. SB and SJ increased SCFAs production, inhibited inflammatory factor release, and regulated blood pressure by decreasing the expression of Olfr78 and increasing that of GPR41, then alleviated kidney damage. This research demonstrated the positive effects of SB and SJ in a rat model of hypertensive nephropathy, indicated that the treatment of SB and SJ by improving the intestinal barrier function, increasing SCFAs, reducing inflammation, decreasing IS, and inhibiting oxidative stress reactions.

Lychee (Litchi chinensis Sonn.) Pulp Phenolics Activate the Short-Chain Fatty Acid-Free Fatty Acid Receptor Anti-inflammatory Pathway by Regulating Microbiota and Mitigate Intestinal Barrier Damage in Dextran Sulfate Sodium-Induced Colitis in Mice

The preventive effect of lychee pulp phenolics (LPP) on dextran sulfate sodium (DSS)-induced colitis of mice and its underlying mechanisms were investigated in this research. LPP supplementation mitigated DSS-induced breakage of the gut barrier as evidenced by the increased tight junction proteins and the enhanced integrity of epithelial cells. Both LPP and 5-ASA treatments could downregulate the expressions of toll-like receptor 4 (TLR-4), NOD protein-like receptor 3 (NLRP3), and proinflammatory cytokines to normal levels. Notably, treatment with LPP at a dosage of 500 mg/kg/day effectively upregulated FFAR2 and FFAR3 expression and contents of short-chain fatty acids (SCFAs), suggesting the activation of the SCFA-FFAR (free fatty acid receptor) pathway. Consistently, the abundances of probiotic taxa and microbiota (Akkermansia, Lactobacillus, Coprococcus, and Bacteroides uniformis) associated with SCFA synthesis were elevated, whereas harmful bacteria (Enterococcus and Aggregatibacter) were suppressed. These data indicate that LPP ameliorates gut barrier damage, activates the microbiota-SCFA-FFAR signaling cascade, and suppresses the TLR4/NLRP3-NF-κB pathway, and therefore, LPP supplementation could be a promising way to protect the intestinal tract.

Microbial sensing in the neonatal pig gut: effect of diet-independent and diet-dependent factors1

There is considerable agreement that the gastrointestinal microbiota contributes to the performance and health of the neonate, and this relationship includes an ability of the host animal to “sense” changes in the microbial community. Identifying the mechanisms used by the host to sense microbiota is one approach to developing methods to manipulate the microbiota to improve pig health and performance. Diet-independent microbial products are molecules unique to the microbial community and sensed by host pattern recognition receptors stimulating inflammation. Common among all members of the microbial community, their presence is unaffected by diet, but the nature of the response does depends on factors affecting the microenvironment in which the molecule is detected. Diet-dependent microbial products arise as products of fermentation of dietary components and include short-chain fatty acids, ammonia, phenols, hydrogen sulfide, amines, and many other compounds. A plethora of sensing mechanisms exists that include enzymatic metabolism as well as membrane receptors that have evolved to respond to microbial products (e.g., short-chain fatty acid receptors), or simply cross-react with microbial products. This review focuses on host mechanisms used to sense the intestinal microbiota and attempts to establish practical considerations for neonatal gut health based on current understanding.

Probiotic Activity of Staphylococcus epidermidis Induces Collagen Type I Production through FFaR2/p-ERK Signaling.

Collagen type I is a key structural component of dermis tissue and is produced by fibroblasts and the extracellular matrix. The skin aging process, which is caused by intrinsic or extrinsic factors, such as natural aging or free radical exposure, greatly reduces collagen expression, thereby leading to obstructed skin elasticity. We investigated the effective fermentation of Cetearyl isononanoate (CIN), a polyethylene glycol (PEG) analog, as a carbon source with the skin probiotic bacterium Staphylococcus epidermidis (S. epidermidis) or butyrate, as their fermentation metabolites could noticeably restore collagen expression through phosphorylated extracellular signal regulated kinase (p-ERK) activation in mouse fibroblast cells and skin. Both the in vitro and in vivo knockdown of short-chain fatty acid (SCFA) or free fatty acid receptor 2 (FFaR2) considerably blocked the probiotic effect of S. epidermidis on p-ERK-induced collagen type I induction. These results demonstrate that butyric acid (BA) in the metabolites of fermenting skin probiotic bacteria mediates FFaR2 to induce the synthesis of collagen through p-ERK activation. We hereby imply that metabolites from the probiotic S. epidermidis fermentation of CIN as a potential carbon source could restore impaired collagen in the dermal extracellular matrix (ECM), providing integrity and elasticity to skin.

The possible mechanism of the protective effect of a sulfated polysaccharide from Gracilaria Lemaneiformis against colitis induced by dextran sulfate sodium in mice

This study aimed to investigate the possible mechanism of the protective effect of a sulfated polysaccharide (SP) from Gracilaria Lemaneiformis against colitis induced by dextran sulfate sodium (DSS). Balb/c mice were gavaged with SP for four weeks, then colon tissue, cecal contents and feces were collected for further analysis. Results showed that SP was effective for inhibiting colon shortening and oedema forming. It could alleviate colonic inflammation via down-regulating the expression of tumor necrosis factor-α (TNF-α), interleukin (IL-6, IL-1β). Besides, it enhanced the intestinal barrier by up-regulating the expression of tight junction proteins Claudin-1 and Zonula occludens-1 (ZO-1) as well as Mucin (MUC-2). The increased expression of short chain fatty acid (SCFA) receptors including G protein-coupled receptor (GPR43, GPR109A) and olfactory receptor (Olfr78), and SCFA production in feces indicated that most of SCFA were absorbed in colon, which could play positive roles in ameliorating colitis. Furthermore, the results of gut microbiota showed that Enterorhabdus, Desulfovibrio, Alistipes, Bacteroides acidifaciens had closest correlations with the strongest protective effects against colitis. Therefore, SP could alleviate DSS-induced colitis via enhancing intestinal barrier, reducing inflammation, activating SCFA receptors and regulating gut microbiota. It could be developed as functional foods which is good for gut health.

Probiotics ameliorate chronic low-grade inflammation and fat accumulation with gut microbiota composition change in diet-induced obese mice models.

Recent reports suggest that obesity is caused by dysbiosis of gut microbiota and that it could be prevented or treated through improvement in the composition and diversity of gut microbiota. In this study, high-fat diet (HFD)-induced obese mice were orally administered with Lactobacillus plantarum K50 (K50) isolated from kimchi and Lactobacillus rhamnosus GG (LGG) as a positive control for 12 weeks. Body weight and weights of epididymal, mesenteric, and subcutaneous adipose tissues and the liver were significantly reduced in K50-treated HFD-fed mice compared with HFD-fed mice. The serum triglyceride level was decreased and high-density lipoprotein cholesterol level was increased in K50-treated HFD-fed mice. The gut microbiota analysis showed that the L. plantarum K50 treatment reduced the Firmicutes/Bacteroidetes ratio and improved the gut microbiota composition. In addition, the level of total short-chain fatty acids (SCFAs) in K50-treated HFD-fed mice was higher than that in HFD-fed mice. A remarkable reduction in the fat content of adipose tissue and liver was also observed in K50-treated HFD-fed mice, accompanied by improvements in gene expression related to lipid metabolism, adipogenesis, and SCFA receptors. K50-treated mice had downregulated expression levels of genes and proteins such as TNFα and IL-1β. Our findings confirm that L. plantarum K50 could be a good candidate for ameliorating fat accumulation and low-grade inflammation in metabolic tissues through gut microbiota improvement.

Effects of Adding Dietary Fiber on the Gut Microbiota, Short-Chain Fatty Acids and Metabolism of Layer Chickens

Dietary fiber is important for the growth performance and health of chickens. However, chickens must rely on fiber-degrading bacteria to grade fiber into monosaccharides due to a lack of endogenous fiber-degrading enzymes. Some of monosaccharides are then fermented into short-chain fatty acids (SCFAs) by SCFA-producing bacteria. SCFAs further regulate the host metabolism via special G protein-coupled receptors (GPRs) such as GPR43. In recent years, more and more research has focused on the impacts of adding dietary fiber on gut microorganisms and microbial metabolites-SCFAs of chickens. However, few works have focused on SCFA receptors and their impacts on metabolism of chickens. Understanding of this would help to explore how the dietary fiber affects chickens’ metabolism via SCFAs and their receptors. Given this, three different levels (0%, 1%, and 2%) of dietary fiber–eubiotic lignocellulose were added to the feed of ISA brown hens (IBH) for 0–8 weeks, with the aim of observing the effects of adding it on the gut microbiota, SCFAs, their receptors and metabolism of chickens. The results showed that the addition of 1% significantly increased the relative abundance of SCFAs-producing bacteria Sutterella, Oscillospira and Lactobacillus panis and the production of SCFAs (P 0.05), resulting in there being no significant difference among groups in the appetite metabolism indexes including glucagon-like peptide-1 (GLP-1) and peptide tyrosine-tyrosine (PYY) and glucose metabolism indexes including blood glucose and liver glycogen of chickens (P > 0.05). The addition of 1% eubiotic lignocellulose is beneficial to increase the relative abundance of some SCFA-producing bacteria and the production of SCFAs at 8 weeks. The effects of added eubiotic lignocellulose on the relative expression of GPR43 mRNA and the metabolism of chickens were slight.

Dietary Fiber, Gut Microbiota, Short-Chain Fatty Acids, and Host Metabolism

With the rapid development of gut microbiological research and high-throughput sequencing technology, we have gained a better understanding of the effects of the gut microbiota and its metabolites such as short-chain fatty acids (SCFAs) on the metabolism of hosts. This effect was found closely related with the consumed dietary fiber by hosts. Dietary fiber has been proven to be very important for hosts. However, hosts such as human, chickens and other monogastric animals cannot digest dietary fiber due to a lack of endogenous fiber-degrading enzymes; therefore, they must rely on gut microorganisms who own endogenous fiber-degrading enzymes such as carbohydrate-active enZymes (CAZymes) encoded by gene. Excellent fiber-degrading bacteria include members of Bacteroidetes phylum such as <i>Bacteroides </i>and <i>Prevotella </i>and members of Firmicutes phylum including <i>Ruminococcus</i>, <i>Fibrobacter</i>, <i>Butyrivibrio</i>, <i>Ruminiclostridium </i>and so on. These fiber-degrading bacteria degrade fiber into monosaccharides via different degrading mechanisms. For instance, Bacteroidetes degrade a dozen kinds of plant fiber using its unique arm-polysaccharide utilization locus (PUL). In contrast to Bacteroidetes, members of the Firmicutes use gram-positive PULs (gp PULs) to process fiber. Some members of the Firmicutes can degrade cellulose and hemicellulose through the cellulosome pathway. And then some oligosaccharides and glucose produced by dietary fiber degradation can be used as carbon and energy sources for microbial growth, thus increasing the diversity of microorganisms. Dietary fiber is the substrate of gut microorganisms. The left monosaccharides are fermented into short-chain fatty acids (SCFAs) by SCFA-producing bacteria including <i>Bifidobacterium</i>, <i>Phascolarctobacterium</i>, <i>Faecalibacterium</i> and so on via different pathways. SCFAs mainly include acetate, propionate and butyrate. SCFAs can further regulate the host's metabolism including energy metabolism, host appetite, liver metabolism and the glucose balance via SCFA receptors including GPR41 and GPR43 or other mechanisms. Therefore, gut microorganisms are also called our “second genome” or “forgotten organs”. In this paper, we provide an overview of the interactions among dietary fiber, gut microbiota, SCFAs and host metabolism.