Abstract：
Short-chain fatty acids refer to organic carboxylic acids with less than 6 carbon atoms, which can be quickly absorbed by animal, and participate in animal metabolism to provide energy, maintain intestinal integrity, regulate intestinal flora and regulate immune function. It is kind of feed additive with various physiological functions and have no toxic side. This review summarizes regulation mechanism of short-chain fatty acids on intestinal health and its application in animal production. The aim of this review is to provide a theoretical reference for the application of short-chain fatty acids in
animal production.
1.Characteristics and metabolic pathways of SCFAs
1.1 Characteristics of SCFAs
SCFAs are fatty acids with less than 6 carbon atoms, small and unstable molecular structure, also known as volatile fatty acids (VFA), mainly including acetic acid, propionic acid, butyric acid, valeric acid and isovaleric acid. Generally, there are two sources of SCFAs in animals: one is directly acquired from exogenous sources, and the other is through the hindgut
Microbial fermentation produces SCFAs, which is also the main way for animals to obtain SCFAs. For ruminants, SCFAs are an important source of energy, with a content of 90-150 mmol/l in the rumen fluid, and SCFAs produced by the rumen of cattle throughout the day and night can account for 0%-70% of the energy required by the body. For non-ruminants, SCFAs are mainly composed of dietary fiber fermented by microorganisms in the colon (pig) or cecum (poultry), and are the main energy substance of intestinal epithelial cells, providing 60% to 70% of their energy requirements. An important substance to maintain the intestinal health of animals. After SCFAs are absorbed by the intestinal tract, acetic acid and propionic acid are transported to the liver, mainly to participate in the energy metabolism of the animal body, while butyric acid mainly provides energy for the intestinal mucosa. The health of the intestinal epithelium is largely dependent on butyrate, which is
The main energy supply material of intestinal mucosa, followed by acetic acid and propionic acid. The intestinal mucosa has important barrier functions, including mechanical barrier, chemical barrier, biological barrier and immune barrier, among which the immune barrier is the most important. The main energy substance of the intestinal mucosa is not glucose, but glutamic acid and glutamine
Amino acids represented by butyric acid, or short-chain fatty acids represented by butyric acid. When the energy is insufficient, it will cause intestinal mucosal atrophy and even necrosis and shedding of intestinal villi, seriously affecting the health of animals. Therefore, SCFAs play an important role in maintaining intestinal health and intestinal mucosal integrity in animals.
Supplementing animals with SCFAs can alleviate the problem of intestinal mucosal energy deficiency caused by insufficient glutamine supply, and has good economic benefits.
1.2 Metabolic pathways of SCFAs
More than 90% of SCFAs in the animal body exist in the form of ions. For ruminants, the absorption of SCFAs is mainly carried out in the rumen, mainly converted into energy substances for the body to use, utilized by the rumen epithelium or transported to the liver for metabolism. Non-ruminants are mainly fermented by microorganisms in the gut, mainly in the colon, and 90% to 95% of SCFAs produced are acetic acid, propionic acid and butyric acid, and the rest only account for 5% to 10%. After butyric acid is produced, it is mainly consumed as an energy substance of the intestinal epithelium, and a small amount of remaining butyric acid enters the liver to participate in gluconeogenesis, ketone body and triglyceride synthesis, indirectly affecting the body’s glucose and lipid metabolism. Acetate and propionate are mainly transported to the liver after production. Acetate can be used in the synthesis of cholesterol, long-chain fatty acids, glutamic acid, glutamine, and β-hydroxybutyric acid in the liver, and can also be taken up and utilized by tissues such as muscle, heart, and brain. Propionic acid mainly performs gluconeogenesis in the liver, can inhibit the synthesis of cholesterol, and has an inhibitory effect on the synthesis of fat.
2 Regulation and mechanism of SCFAs on animal intestinal health
The intestinal tract is an important place for animals to digest, absorb and metabolize nutrients, and it is also an important barrier for the body to resist external environmental stimuli. The health of the animal intestinal tract is very important. SCFAs are closely related to animal energy metabolism, and can participate in the energy supply of intestinal epithelium and affect the intestinal environment. SCFAs can promote animal intestinal development, improve animal immune function, and protect animal health by regulating intestinal energy, intestinal barrier, and body metabolism.
2.1 Regulation of intestinal energy by SCFAs
SCFAs are closely related to the energy metabolism of the body, and have a positive impact on the health of the intestinal tract of animals. For ruminants, SCFAs are an important source of energy, and the SCFAs produced by the cow’s rumen throughout the day and night can account for 60% to 70% of the energy required by the body. For non-ruminants, colonic fermentation
The produced SCFAs can provide 60%-70% energy for the colonic epithelium. Normally, the gut utilizes butyrate preferentially, followed by propionate and acetate. Studies have found that glucose and glutamine are the energy substances that animals preferentially use in the foregut, while butyric acid is the primary energy substance in the colon. butyric acid
It can carry out energy metabolism through β-oxidation in the hydroxymethylglutaryl-CoA cycle and is the main energy source of intestinal mucosal epithelial cells. SCFAs can increase the height of intestinal villi and the ratio of villi height/crypt depth, increase the activity of intestinal disaccharidase, increase the contact area between the intestinal tract and food, promote the development of the intestinal tract, and enhance the digestion and absorption of nutrients by animals. It can be seen that supplementing animals with SCFAs can provide energy for the intestinal mucosa of animals, maintain the shape of the intestinal tract, promote the development of the intestinal mucosa, and ensure the health of the intestinal tract.
At present, the regulation mechanism of SCFAs on energy is still unclear, and more focus on molecular aspects. Studies have found that the concentration of SCFAs in different tissues is different, and the portal blood, peripheral blood and gastrointestinal tract are about 400, 100, and 100 mmol/l, respectively, indicating that SCFAs have different energy regulation effects in different tissues. Microbiota have a strong role in maintaining NADH/NAD+ and ATP levels in the colon because colonocytes use microbiota-produced butyrate as their main energy source. The most affected pathway in colonocytes was the butyrate metabolic pathway, followed by the oxidative metabolic pathway. Butyrate can regulate the energy of the body through two pathways: ① Increase peroxisome proliferator-activated receptor gamma coactivator-1α (PPARγ coactivator-1α, PGC-1α) and adenosine monophosphate in liver and muscle Activate the expression of protein kinase; ② Promote the activity and expression of mitochondrial uncoupling protein and PGC-1α in brown fat, intensify fatty acid oxidation, and increase body heat production. In addition, studies have found that SCFAs can regulate host energy metabolism and body health by activating intestinal gluconeogenesis (IGN).
2.2 Regulation of SCFAs on intestinal barrier
The intestinal barrier of animals is an important barrier against the invasion of foreign pathogens, including four major barriers: mechanical barrier, chemical barrier, immune barrier and microbial barrier. Any damage to the barrier function will lead to the metabolic disorder of the body, affect the health of the intestinal tract of animals, and then lead to the decline of production performance.
2.2.1 Regulation of mechanical barrier by SCFAs
Tight junctions are complexes composed of a variety of proteins, mainly including transmembrane proteins [Claudins, Occludin, JAM] and cytoplasmic proteins (Claudin, ZO). Intestinal mechanical barrier properties are closely related. Increasing the expression of tight junction-related proteins plays an important role in maintaining the mechanical barrier of animal intestines and inhibiting pathogenic substances from invading the body. Propionic acid can significantly promote the expression of Occludin-1, G protein-coupled receptor 5A (GPRC5A) and other genes, indicating that propionic acid can maintain cell permeability, strengthen the mechanical barrier function of the intestinal tract, and improve the health of animals. Tong et al found that propionic acid can increase the expression of intestinal tight link proteins ZO-1, Occludin, and cadherin, promote the growth of intestinal epithelial cells, and improve intestinal barrier function. Intestinal transmembrane resistance (Transepithelial electrical resistance ⁃ tance, TER) and FITC-labeled dextran 4 kDa (Fluorescein
isothiocyanate dextran 4 kDa, FD4) is an important indicator reflecting extracellular permeability and intestinal barrier. Wang et al. found that sodium butyrate can improve the intestinal morphology of weaned piglets, increase jejunum TER, reduce FD4, improve intestinal damage caused by weaning stress, and enhance intestinal barrier function. Huang et al. found that sodium butyrate significantly increased the expression of Occludin protein in the jejunum and colon of weaned piglets, and reduced the occurrence of diarrhea by reducing intestinal permeability. Ding Yaping found that SCFAs can promote the proliferation of intestinal mucosal cells in rats and inhibit the proliferation of tumor cells.
Proliferation, enhance the nutrition of intestinal mucosal cells, and protect the intestinal mechanical barrier. The mechanism may be to adjust the proliferation cycle of colonic mucosal cells, thereby affecting their proliferation activity. Bai et al. reported that sodium butyrate can reduce the expression of tight junction proteins ZO-1 and Occludin-5, reduce intestinal
Permeability, enhances the mechanical barrier function of intestinal epithelial cells. Ding Ying’s research found that different levels of SCFAs can increase the expression of Claudin-1 gene in broiler jejunum by increasing extracellular regulated protein kinases (ERK1/2)
and p38 mitogen-activated protein kinase (p38 mitogen-activated protein kinase, p38MAPK) expression to increase the expression of
In summary, the regulation of the intestinal mechanical barrier of SCFAs animals is mainly by promoting the expression of tight junction proteins Claudin, Occludin and ZOs and other related genes in the intestine, reducing intestinal permeability, promoting the proliferation of intestinal mucosal cells, and improving animal health. Mechanical barrier function of the intestinal tract. ZO-1, Caludin-1, Claudin-8 and Occludin to enhance intestinal barrier function.
2.2.2 Regulation of chemical barriers by SCFAs
The intestinal chemical barrier is mainly composed of a mucus layer covering the intestinal epithelial cells. Intestinal microorganisms, host inflammatory mediators, and intestinal secretions (gastric acid, glycoproteins, digestive enzymes, etc.) can all affect the intestinal chemical barrier. Mucin (MUC) is secreted by epithelial cells and is the most important molecule in the mucus layer. It can prevent harmful macromolecular substances from entering the epithelial cell layer and plays an important role in the intestinal chemical barrier. SCFAs can promote the activation of inflammasomes in intestinal epithelial cells, promote the production of anti-inflammatory factors, up-regulate the gene expression of MUC1, MUC2, MUC3 and MUC4 in the intestine and the secretion of pancreatic enzymes in pancreatic juice, and strengthen the intestinal chemical barrier function. Gaudier et al found that at the transcriptional level, butyric acid can specifically regulate the expression of MUC genes in intestinal goblet cells, and significantly up-regulate the expression of mucus proteins MUC2, MUC3 and MUC5AC genes. Butyric acid has different regulatory effects on different mucin genes. The expression of MUC3 gene is regulated by butyric acid itself, possibly through the histone deacetylase (Histone deacetylase, HDAC) pathway. Butyrate metabolites may be involved in gene regulation of MUC2 and MUC5AC.
It can be seen that butyric acid can promote the secretion of intestinal mucus mucin and enhance the intestinal chemical barrier function. Diao et al. found that intragastric administration of SCFAs to weaned piglets can reduce the expression of pro-apoptotic genes Bax and Caspase-3 in intestinal cells, reduce the apoptosis index of cells, and stimulate the expression of intestinal mucin MUC1 and MUC2 genes through the MAPK signaling pathway. Strengthens the chemical barrier function of intestinal epithelial cells. Bai et al. reported that SCFAs can increase the expression of phosphatase and tensin homologue deleted on chromosome 10 (PTEN), and promote the expression and Induces the differentiation of cancer cells and enhances the chemical barrier function of intestinal epithelial cells.
The above results indicate that SCFAs regulate the chemical barrier mainly by promoting the expression of mucin MUC-related genes, reducing the apoptosis index of intestinal cells and the enzyme activity of intestinal secretions, etc. Genes are regulated to enhance the chemical barrier function of animal intestines.
2.2.3 Regulation of SCFAs on the immune barrier
The intestine is not only the main place for digestion and absorption in animals, but also the largest immune organ in animals. SCFAs can affect the proliferation, differentiation and apoptosis of intestinal cells through multiple ways, participate in the immune regulation of the body, and improve the immune barrier function of the body. SCFAs can significantly increase the level of immunoglobulin (IgA) in colostrum of sows, and then improve the immunity of piglets through vertical transmission. Niu Haihua’s research found that sodium butyrate can promote the development of piglets’ immune organs such as pancreas and spleen, increase the content of serum IgG, IgM and plasma cell IgA+ in mucosa, and improve the immune function of weaned piglets. The regulation of sodium butyrate on the immune function and anti-inflammatory ability of piglets may be related to its acidification performance. Low acidity can promote the development of immune organs, promote the secretion of bile, improve the intestinal microbial environment, and produce physiologically active substances. Wang et al found that adding sodium butyrate can reduce the contents of histamine, tryptase, tumor necrosis factor α (TNF-α), interferon γ (IFN-γ) and interleukin (IL-6) in the jejunal mucosa of weaned piglets , which may signal through JNK (c-Jun NH2-terminal kinase, c-Jun NH2-terminal kinase)
path to complete. SCFAs can regulate intestinal inflammatory response through freefatty acid receptor 2 (FFA2). Carretta et al. found that butyric acid can activate neutrophils, induce Ca2+ influx, and make ERK1/ 2 and p38MAPK phosphorylation, regulate ruminant innate immune response, while Ca2 + , ERK1/2 and MAPK are involved in the activation of FFA2. Xiong et al. found that butyric acid can alleviate the intestinal inflammatory response of piglets caused by E. coli challenge, and the regulation mechanism of butyric acid on inflammation is completed by inhibiting HDAC to affect the expression of host defense peptides (HDP). Sodium butyrate can alleviate the inflammatory response caused by lipopolysaccharide (LPS) by reducing the expression of IL-6 and IL-8, and can be used as an effective anti-inflammatory agent. Butyrate can activate the GPR109A receptor to induce the secretion of IL-18 in colonic epithelial cells. GPR109A can induce Treg cell differentiation through IL-10 and acetaldehyde dehydrogenase 1A1 (acetaldehyde dehydrogenase 1A1, ALDH1A1), and enhance dendritic cells and macrophages. Anti-inflammatory effect of cells, inhibits intestinal inflammatory response. Studies by Chen et al. have shown that intravenous injection of sodium butyrate to growing pigs can significantly reduce the pro-inflammatory factors IL-6, IL-8,
The expression of IL-12p40 and TNF-α promotes the secretion of intestinal sIgA, increases the expression of anti-inflammatory factors IL-10 and epidermal growth factor (epidermal growth factor, EGF), and strengthens the intestinal immune barrier. Xu et al. obtained the same results. Sodium butyrate significantly reduced the expression of inflammatory factors IL-6, IL-8, IFN-γ, TNF-β and HDAC in the ileum of newborn piglets, and reduced the intestinal inflammatory response. HDACs, controlling histone acetylation status and regulating the transcription of multiple genes act on cells to regulate immune function. SCFA can regulate the mammalian target of rapamycin (mTOR) pathway by inhibiting HDAC, increase p70 S6 kinase acetylation and rS6 phosphorylation levels, and helper T cell 1 (Th1), Th17 and secretion T cell ratio of IL-10. Lin et al. reported that SCFAs can induce and activate nuclear factor κB (nuclear factor kappa-B, NF-κB) through Toll-like receptors (Toll-like receptors5, TLR5), TLR2/1, TLR4 and TLR9, thereby promoting the expression of TNF-α. Secretion, inhibition of monocyte chemotactic protein 1 (monocyte chemotactic protein 1, MCP-1) and IL-8 production. Tong et al found that propionic acid can inhibit the expression of pro-inflammatory factors IL-1β, IL-6 and TNF-α in the intestine, and may regulate the inflammatory response through STAT3 (signal transducer and activator of transcription) signal transduction . Oxidative stress can destroy the immunity of animal gut, sodium butyrate can significantly
Significantly reduce the content of malondialdehyde (MDA) and TNF-α in serum and intestinal mucosa, increase the content of IFN-γ in serum, enhance the body’s antioxidant capacity, and improve immune function. It can be seen that SCFAs regulate the immune function of animals through multiple channels, and promote the development of immune organs and immune substances in animals.
It can enhance the expression of anti-inflammatory cytokines, reduce the expression of pro-inflammatory cytokines, and enhance the antioxidant capacity, thereby enhancing the immune barrier function of animals.
2.2.4 Regulation of SCFAs on the microbial barrier
There are a large number of microbial flora living in the intestinal tract of animals, and these microbial flora play an important role in the health and immunity of animals. A stable intestinal flora is crucial to the physiological function and health of animals, and the microbial barrier composed of intestinal microorganisms is an important part of the intestinal barrier. SCFAs can release H+ in the intestinal tract, reducing the pH value of the intestinal tract to a certain extent. The acidic environment of the intestinal tract is conducive to the growth of beneficial bacteria such as Lactobacillus, while inhibiting the proliferation of harmful bacteria such as Escherichia coli. The acidic intestinal environment affects the metabolism of pathogenic microorganisms, which is of great significance for maintaining the balance of intestinal flora in animals. Adding SCFA to the diet can reduce the number of harmful bacteria such as Escherichia coli and Salmonella in the intestine, increase the number of beneficial bacteria such as lactic acid bacteria in the intestine, stabilize the structure of the intestinal flora, and strengthen the intestinal microbial barrier function. Studies by Li Hongjin and others have shown that sodium butyrate can reduce the content of harmful bacteria in the intestinal tract, increase the content of beneficial bacteria, stabilize the intestinal flora of weaned piglets, and promote intestinal development. Van Immerseel et al. found that SCFAs could significantly reduce the content of Salmonella in cecal digesta of broilers. Zhang et al. found that cecal infusion of propionate in growing pigs increased the abundance of Bacteroidetes in the colon, decreased the abundance of Firmicutes, and increased the abundance of Prevotella and Bacteroides. Chen et al found that butyric acid can significantly increase the diversity and richness of the flora of growing pigs. Can
It can be seen that SCFAs can strengthen the intestinal microbial barrier function by increasing the content of beneficial bacteria in the intestine and reducing the content of harmful bacteria. The mechanism may be mainly through the release of H+ by SCFAs to reduce the intestinal pH.
2.3 Regulation of SCFAs on body metabolism
SCFAs play important roles in maintaining the intestinal environment, electrolyte balance, and providing energy to host cells and gut microbiota. Studies have shown that SCFAs participate in the metabolic process of the body by stimulating hormones and nerve signals in various tissues, regulating energy homeostasis and lipid metabolism. Oral administration of propionate in obese patients can significantly increase the plasma peptide (postprandial plasma peptide, PYY) and glucagon-like peptide (GLP-1) released by colonocytes in vivo, and increase the response of muscle and adipose tissue to glucose. Absorption of glucose, insulin secretion, reduction of glucagon, reduction of energy intake of the body through the regulation of glucose metabolism and fat metabolism, and reduction of patient weight. SCFAs can regulate the body’s carbohydrate and fat metabolism by regulating gastrointestinal hormones such as leptin, PYY, GLP-1 and GLP-2. SCFAs can increase the expression of gastrointestinal hormones PYY and GLP by regulating GPR, increase the absorption of glucose by muscle and fat, increase the secretion of insulin and reduce the production of glucagon. Studies by Lu et al. have shown that SCFAs can increase the body’s energy consumption, improve glucose tolerance, and regulate body fat content and body weight by changing the expression of GPR43 and GPR41. Studies by Jiao et al. have shown that SCFAs can reduce the mRNA expression of fatty acid synthesis genes fatty acid synthase (FAS) and acetyl-CoA carboxylase (ACC), increase the mRNA expression of lipolysis gene carnitine palmitoyltransferase-1α (CPT-1α), and reduce the mRNA expression of different tissues. Lipid synthesis, reducing body fat
deposition of fat.
3 Application of SCFAs in animal production
3.1 Effects on growth performance
SCFAs have various physiological functions such as regulating intestinal flora, intestinal immunity, and improving growth performance, and have been widely used in animal production. Dietary supplementation of SCFAs has less consistent effects on animal growth performance. In pig production, the addition of sodium butyrate can significantly increase the daily gain, feed intake and feed conversion rate of weaned piglets and growing pigs, and significantly reduce the rate of diarrhea. It has also been found that oral administration of SCFAs can reduce the average daily feed intake of weaned piglets, with no significant effect on the growth performance of growing pigs. In poultry production, the addition of acetic acid can significantly increase the body weight and feed conversion rate of broilers, and improve the intestinal histology of broilers. At the age of 2 to 6 weeks, the addition of 0.3% showed better growth performance, and Ahsan et al. The results were consistent. The results of Sikandar et al. showed that adding sodium butyrate could significantly reduce the feed-to-weight ratio of broilers, but it was also reported that adding acetic acid in drinking water had no effect on the growth performance of broilers. In ruminant production, Guilloteau et al. found that adding sodium butyrate to milk replacer can be quickly absorbed by the calf intestinal tract and improve the growth rate and feed conversion rate of calves, which may be related to improving the gastrointestinal tract of ruminants. It is related to digestion ability and improvement of digestive enzyme activity. However, Beiranvand et al. found that adding sodium propionate to the diet had no effect on the growth performance of calves. It has also been reported that propionate can increase body weight gain in ruminants but the effect is not significant, or that propionate can significantly increase the body weight of weaned calves. It can be seen that the research results of SCFAs on production performance are inconsistent, so more experimental data accumulation is needed. From the above results, we can see that the inconsistency of production performance may be related to the type of SCFAs added (acetic acid, propionic acid, butyric acid, acid salt), the way of adding (mixing, oral, powder or coating), the way of compatibility (SCFAs complex with or with other nutrients) and the amount of addition. Subsequent research should focus more on the study of different types of SCFAs on animal production performance, the synergistic research of multiple SCFAs, the mixed compatibility between SCFAs and other nutrients, etc. The specific application research and application effect are still to be determined For further research.
3.2 Effects on gut health
SCFAs have positive effects on the gut health of animals. Sodium butyrate can significantly increase intestinal tight junction protein, improve intestinal morphology, and improve the antioxidant capacity and immune capacity of weaned piglets. Reduce the content of harmful bacteria in the intestine, increase the content of beneficial bacteria, reduce the apoptosis of intestinal epithelial cells, improve the intestinal barrier function, and promote the development of the intestinal tract of weaned piglets. Adding sodium butyrate down-regulates the expression of pro-inflammatory factors in the intestine of growing pigs, increases the secretion of colonic sIgA, and enhances immunity. Shorten the return rate of sows, increase the levels of triglycerides, prolactin, leptin, TNF-α, and IgA in colostrum, and improve the immunity and growth rate of piglets. Tributyrin (which can be decomposed by pancreatic lipase to produce butyric acid) can alleviate the intestinal damage caused by LPS challenge in broilers and increase the activity of intestinal disaccharidase. Significantly increases shell thickness and tends to increase egg weight. Sodium butyrate can promote the development of immune organs (thymus, spleen) of broilers, improve intestinal morphology, enhance immune function, and 1 g/kg can be used to replace the use of antibiotics. 500 mg/kg of acetic acid or propionic acid can increase the activity of amylase, trypsin and chymotrypsin in the small intestine, reduce the number of E. coli in the intestine, and promote the digestion and absorption capacity of the intestine. In ruminants, sodium butyrate can improve the intestinal morphology of calf jejunum, enhance the proliferation of intestinal cells, reduce the apoptosis of mucosal cells, and improve the intestinal health of calves. Inhibit the activation of NF-κB and the synthesis of pro-inflammatory factors in goat rumen epithelial cells, relieve inflammatory damage, reduce the apoptosis rate of cells, and protect the integrity and barrier function of goat rumen epithelial cells. The above data show that SCFAs can improve the intestinal morphology of animals, improve the intestinal flora structure of animals, maintain the integrity of the intestinal tract, and promote the development of the intestinal tract. Further research and development is required.
4 Conclusion
In general, SCFAs are important metabolites of intestinal microorganisms, which have various biological functions such as providing energy for animals, maintaining intestinal integrity, regulating intestinal flora, and regulating immune function. Adding SCFAs to feed can improve the disease resistance of animals, and has broad application prospects in animal husbandry production. At present, most of the additions of SCFAs are single additions, mainly the addition of butyric acid, and most of them are used in monogastric animals. There are relatively few studies on different addition amounts, addition forms, compatibility principles, and synergy with other nutrients, and it is difficult to propose specific solutions in production practice. Therefore, it is necessary to strengthen the research on the mechanism and effect of SCFAs in animal practice, to study the mixed compatibility of different types of SCFAs and the synergistic effect with other functional nutrients. Additives provide new ideas and bring huge benefits to animal intestinal health and production.
