Recent developments in short-chain fatty acid metabolism.

Bacterial translocation across the bowel wall has recently been proposed as a major problem in the stressed patient. Consequently, there has been considerable interest in fostering bowel wall integrity as a barrier to bacteria and endotoxin. One postulated means to promote this barrier function has been through the provision of the preferred fuels of the bowel wall. Among these are the short-chain fatty acids (SCFAs) which are found to a limited extent in the diet but are primarily produced through the fermentation of non-digestible carbohydrates by the bacterial flora of the colon. In both animal and human studies, SCFAs have been shown to stimulate intestinal mucosal growth. Because non-digestible carbohydrates, after colonic fermentation, are precursors to SCFAs, similar effects to those found with direct provision of SCFAs may be anticipated. Pectin, beta-glucan, and lactulose are among the many available nonabsorbable carbohydrates that could serve as a source of these trophic stimulants to colonic mucosa. Short-chain fatty acids and their precursors deserve extensive and clinical evaluation to define their ultimate role in human disease.     

短链脂肪酸的代谢及其在肠道外科中的应用

短链脂肪酸是碳链为１－６的有机脂肪酸,由饱含中不消化淀粉,纤维多糖等在结肠腔内经厌氧菌酵解生成,主要包括乙酸,丙酸,丁酸等,是结肠腔内重要的有机酸阴离子,通过离子与非离子形式由肠上皮细胞吸收,同时促进水电解吸收。作为结肠粘膜首选的能源底物,ＳＣＦＡ增进钠吸收,促进结肠上皮细胞增殖与粘膜生长,提供代谢能源,增加肠血流,刺激素,是结肠粘膜重要的营养素。     

Regulation of inflammation by short chain fatty acids

The short chain fatty acids (SCFAs) acetate (C(2)), propionate (C(3)) and butyrate (C(4)) are the main metabolic products of anaerobic bacteria fermentation in the intestine. In addition to their important role as fuel for intestinal epithelial cells, SCFAs modulate different processes in the gastrointestinal (GI) tract such as electrolyte and water absorption. These fatty acids have been recognized as potential mediators involved in the effects of gut microbiota on intestinal immune function. SCFAs act on leukocytes and endothelial cells through at least two mechanisms: activation of GPCRs (GPR41 and GPR43) and inhibiton of histone deacetylase (HDAC). SCFAs regulate several leukocyte functions including production of cytokines (TNF-α, IL-2, IL-6 and IL-10), eicosanoids and chemokines (e.g., MCP-1 and CINC-2). The ability of leukocytes to migrate to the foci of inflammation and to destroy microbial pathogens also seems to be affected by the SCFAs. In this review, the latest research that describes how SCFAs regulate the inflammatory process is presented. The effects of these fatty acids on isolated cells (leukocytes, endothelial and intestinal epithelial cells) and, particularly, on the recruitment and activation of leukocytes are discussed. Therapeutic application of these fatty acids for the treatment of inflammatory pathologies is also highlighted.     

Effect of short-chain fatty acids on the human colonic mucosa in vitro.

Fermentable dietary fiber components are known to stimulate colonic crypt proliferation. As these compounds are rapidly degraded to short-chain fatty acids (SCFAs) by the anaerobic microflora, the hypothesis was tested that this trophic effect of fiber may be mediated by SCFAs. Biopsies were taken from normal cecal mucosa of 45 individuals during routine colonoscopy. They were incubated for 3 hours with sodium salts of SCFAs at physiological concentrations (three SCFAs = acetate 60 mmol/L + propionate 25 mmol/L + butyrate 10 mmol/L; acetate 60 mmol/L; propionate 25 mmol/L; butyrate 10 mmol/L) or equimolar NaCl (control). Cell proliferation was measured autoradiographically by subsequent pulse labeling with [3H]thymidine (1 hour). The labeling index (number of labeled cells divided by the total number of cells) was computed for the crypt as a whole and for five equal crypt compartments (compartment 1 = crypt base, compartment 5 = crypt surface). Cecal crypt proliferation was raised significantly in all incubation experiments with SCFAs. Butyrate (10 mmol/L, increase + 89%) and propionate (25 mmol/L, + 70%) were as effective in stimulating proliferation as the combination of three SCFAs (+103%), although the effect of acetate (+31%) was minor. Increasing the butyrate concentration to 25 mmol/L or 60 mmol/L did not result in a further increase of cell labeling. SCFAs stimulated proliferation in the basal three crypt compartments only. An expansion of the proliferative zone to compartments 4 and 5 was not observed. SCFAs, especially butyrate and propionate, are luminal trophic factors for the cecal epithelium.(ABSTRACT TRUNCATED AT 250 WORDS)     

Rapid and Sustained Long‐Term Decrease of Fecal Short‐Chain Fatty Acids in Critically Ill Patients With Systemic Inflammatory Response Syndrome

Background: The gut is an important target organ for injury after severe insult. Short‐chain fatty acids (SCFAs) are end‐products of fermentation of dietary fibers by anaerobic microbiota. They are related to intestinal energy, motility, and transport and to protective effects against infection and inflammation. However, there are few clinical data on SCFAs in critically ill patients. We evaluated serial change in fecal SCFAs in patients with severe systemic inflammatory response syndrome (SIRS). Patients and Methods: This study included 140 intensive care unit (ICU) patients who fulfilled the criteria of SIRS and had a serum C‐reactive protein level of >10 mg/dL. A fecal sample was used for quantitative measurement of fecal SCFA (butyrate, propionate, and acetate) concentrations by high‐performance liquid chromatography. Fecal SCFAs were evaluated weekly for 6 weeks after admission. Data obtained from patients were compared with corresponding data from healthy volunteers. Results: SIRS resulted from infection in 78 patients, trauma in 30, burns in 12, and other causes in 20. Fecal concentrations of butyrate, propionate, and acetate in these patients decreased significantly compared with those in healthy volunteers and remained low throughout the 6 weeks of the patients' ICU stay. Fecal concentrations of SCFAs in the patients with gastrointestinal complications, including enteritis and dysmotility, were lower than those in the patients without gastrointestinal complications. Conclusions: Concentrations of fecal SCFAs in patients with severe SIRS were significantly lower than those in healthy volunteers over a 6‐week period. Maintenance of SCFAs may have therapeutic potential to prevent gastrointestinal complications in critically ill patients.     

The Impact of Short-Chain Fatty Acids on Neonatal Regulatory T Cells

Over the first weeks of life, the neonatal gastrointestinal tract is rapidly colonised by a diverse range of microbial species that come to form the ‘gut microbiota’. Microbial colonisation of the neonatal gut is a well-established regulator of several physiological processes that contribute to immunological protection in postnatal life, including the development of the intestinal mucosa and adaptive immunity. However, the specific microbiota-derived signals that mediate these processes have not yet been fully characterised. Accumulating evidence suggests short-chain fatty acids (SCFAs), end-products of intestinal bacterial metabolism, as one of the key mediators of immune development in early life. Critical to neonatal health is the development of regulatory T (Treg) cells that promote and maintain immunological tolerance against self and innocuous antigens. Several studies have shown that SCFAs can induce the differentiation and expansion of Tregs but also mediate pathological effects in abnormal amounts. However, the exact mechanisms through which SCFAs regulate Treg development and pathologies in early life remain poorly defined. In this review, we summarise the current knowledge surrounding SCFAs and their potential impact on the neonatal immune system with a particular focus on Tregs, and the possible mechanisms through which SCFAs achieve their immune modulatory effect.     

Intestinal Microbiota-Derived Short Chain Fatty Acids in Host Health and Disease

Intestinal microbiota has its role as an important component of human physiology. It produces metabolites that module key functions to establish a symbiotic crosstalk with their host. Among them, short chain fatty acids (SCFAs), produced by intestinal bacteria during the fermentation of partially and non-digestible polysaccharides, play key roles in regulating colon physiology and changing intestinal environment. Recent research has found that SCFAs not only influence the signal transduction pathway in the gut, but they also reach tissues and organs outside of the gut, through their circulation in the blood. Growing evidence highlights the importance of SCFAs level in influencing health maintenance and disease development. SCFAs are probably involved in the management of host health in a complicated (positive or negative) way. Here, we review the current understanding of SCFAs effects on host physiology and discuss the potential prevention and therapeutics of SCFAs in a variety of disorders. It provides a systematic theoretical basis for the study of mechanisms and precise intake level of SCFAs to promote human health.     

Excretion of starch and esterified short-chain fatty acids by ileostomy subjects after the ingestion of acylated starches

BACKGROUND: Short-chain fatty acids (SCFAs) have a role in maintaining bowel health and can assist in the prevention and treatment of colonic disease. The ability of acylated starches to deliver SCFAs to the large bowel has been shown in animal studies but has not been established in humans. OBJECTIVE: The aim was to determine whether cooked, highly acylated starches were resistant to small intestinal digestion in ileostomy volunteers. DESIGN: Volunteers consumed single doses of custards containing 20 g cooked acetylated, propionylated, or butyrylated high-amylose maize starches (HAMSA, HAMSP, and HAMSB, respectively) on each collection day. The amounts of starch and of esterified SCFAs ingested and subsequently excreted in the stoma effluent were measured. Custards containing unacylated high-amylose maize starch (Hylon VII, HAMS) and low-amylose maize starch (3401C, LAMS) were consumed as controls. RESULTS: Between 73% and 76% of the esterified SCFAs survived small intestinal digestion, which showed the potential of acylated starches to deliver specific SCFAs to the large bowel. The resistance of starches to small intestinal digestion as measured by ileal excretion was significantly greater for HAMSA, HAMSP, HAMSB, and HAMS than for LAMS (P < 0.001). The concentration of acetate in stoma digesta was higher than expected in all groups; this additional acid may have been derived from endogenous sources. CONCLUSIONS: Acylated starches are a potentially effective method of delivering significant quantities of specific SCFAs to the colon in humans. These products have potential application in the treatment and prevention of bowel disorders amenable to modulation by SCFAs.     

Intraperitoneal Administration of Short-Chain Fatty Acids Improves Lipid Metabolism of Long–Evans Rats in a Sex-Specific Manner

Short-chain fatty acids (SCFAs) are microbial metabolites, mainly generated by the action of gut microbiota on dietary fibers. Acetate, propionate, and butyrate are the three main SCFAs produced typically in a 60:20:20 molar ratio in the colon. Acetate, propionate, and butyrate, when given individually as supplements, have shown a protective role in obesity and hyperglycemia; however, the sex-specific effects of a mixture of SCFAs, when given in 60:20:20 ratio, on the regulation of lipid metabolism and lipid profile are not known. Male and female Long–Evans rats were given a mixture of SCFAs (acetate, propionate, and butyrate; molar ratio 60:20:20) each day for seven days intraperitoneally; plasma and hepatic lipids, gene expression, and lipidomics profile were analyzed. SCFAs significantly decreased plasma and hepatic triglycerides and cholesterol in males, whereas the fatty acyl composition of cholesteryl esters, triglycerides, and phospholipids was modulated in females. SCFAs decreased the mRNA expression of hepatic acetyl-CoA carboxylase-1 in both males and females. Our findings demonstrate for the first time that SCFAs (60:20:20) improved plasma and hepatic lipid levels and fatty acyl composition in a manner that may provide cardio-protective and anti-inflammatory effects in both sexes, via independent mechanisms.     

Short-chain fatty acids and total parenteral nutrition affect intestinal gene expression

BACKGROUND: The supplementation of total parenteral nutrition (TPN) formulas with short-chain fatty acids (SCFAs) increases glucose uptake and the expression of glucose transporters in parenterally fed animals. Several signals may be involved in intestinal adaptation; however, increased messenger RNA (mRNA) levels for proglucagon and several early-response genes, including c-myc and c-fos, are seen in animals receiving SCFA-supplemented TPN. Although the effects of a mixture of SCFAs are well documented, the relative contribution of individual SCFAs is unknown. Butyrate is a preferred fuel of colonocytes, with documented effects on cellular proliferation and gene expression. Accordingly, this study was undertaken to determine the relative role of butyrate in initiating an adaptive response in nonresected rats receiving TPN. METHODS: Animals received standard TPN for 66 hours, followed by 6 hours of either standard TPN, TPN supplemented with a mixture of SCFAs (acetate, propionate, and butyrate, 60 mmol/L total), or TPN supplemented with butyrate alone (9 mmol/L). An oral control group was fed an elemental diet, similar in macronutrient content to the TPN, so that all animals received the same amount of energy daily. RESULTS: SCFAs increased ileal glucose transporter 2 (GLUT2) mRNA expression compared with the orally fed group. SCFAs also increased proglucagon mRNA expression compared with the TPN group. No changes in Na+K(+)-adenosine triphosphatase or early-response gene expression were found in this study. CONCLUSIONS: In a rat model of TPN, the use of 9 mmol/L butyrate did not have the same effect on GLUT2 and proglucagon expression as a 60-mmol/L mixture of SCFAs. This suggests that the effect of a mixture of SCFAs on intestinal gene expression is not butyrate specific.     

Short-Chain Fatty Acids,Maternal Microbiota and Metabolism in Pregnancy

Short-chain fatty acids (SCFAs), as products of intestinal bacterial metabolism, are particularly relevant in the diagnosis of intestinal dysbiosis. The most common studies of microbiome metabolites include butyric acid, propionic acid and acetic acid, which occur in varying proportions depending on diet, age, coexisting disease and other factors. During pregnancy, metabolic changes related to the protection of energy homeostasis are of fundamental importance for the developing fetus, its future metabolic fate and the mother’s health. SCFAs act as signaling molecules that regulate the body’s energy balance through G-protein receptors. GPR41 receptors affect metabolism through the microflora, while GPR43 receptors are recognized as a molecular link between diet, microflora, gastrointestinal tract, immunity and the inflammatory response. The possible mechanism by which the gut microflora may contribute to fat storage, as well as the occurrence of gestational insulin resistance, is blocking the expression of the fasting-induced adipose factor. SCFAs, in particular propionic acid via GPR, determine the development and metabolic programming of the fetus in pregnant women. The mechanisms regulating lipid metabolism during pregnancy are similar to those found in obese people and those with impaired microbiome and its metabolites. The implications of SCFAs and metabolic disorders during pregnancy are therefore critical to maternal health and neonatal development. In this review paper, we summarize the current knowledge about SCFAs, their potential impact and possible mechanisms of action in relation to maternal metabolism during pregnancy. Therefore, they constitute a contemporary challenge to practical nutritional therapy. Material and methods: The PubMed database were searched for “pregnancy”, “lipids”, “SCFA” in conjunction with “diabetes”, “hypertension”, and “microbiota”, and searches were limited to work published for a period not exceeding 20 years in the past. Out of 2927 publication items, 2778 papers were excluded from the analysis, due to being unrelated to the main topic, conference summaries and/or articles written in a language other than English, while the remaining 126 publications were included in the analysis.     

Non-occupational pneumoconiosis at high altitude villages in central Ladakh.

An epidemiological survey was carried out to investigate the occurrence of non-occupational pneumoconiosis in Ladakh, where there are no mines or industries. The clinicoradiological investigations of 449 randomly selected subjects from three villages showed typical cases of pneumoconiosis associated with progressive massive fibrosis and egg shell calcification of hilar glands. The prevalence of pneumoconiosis in these three villages was 2.0%, 20.1% and 45.3% and it corresponded with the severity of dust storms and the use of chimneys in the kitchens. The dust concentrations in the kitchens with no provision for a chimney were very high. The free silica content of the storms was between 60 and 70%. Exposure to free silica from dust storms and soot from domestic fuels are suggested as causes of these cases of pneumoconiosis.     

Non-occupational pneumoconiosis at high altitude villages in central Ladakh.

An epidemiological survey was carried out to investigate the occurrence of non-occupational pneumoconiosis in Ladakh, where there are no mines or industries. The clinicoradiological investigations of 449 randomly selected subjects from three villages showed typical cases of pneumoconiosis associated with progressive massive fibrosis and egg shell calcification of hilar glands. The prevalence of pneumoconiosis in these three villages was 2.0%, 20.1% and 45.3% and it corresponded with the severity of dust storms and the use of chimneys in the kitchens. The dust concentrations in the kitchens with no provision for a chimney were very high. The free silica content of the storms was between 60 and 70%. Exposure to free silica from dust storms and soot from domestic fuels are suggested as causes of these cases of pneumoconiosis.     

Human Milk Microbiome and Microbiome-Related Products: Potential Modulators of Infant Growth

Infant growth trajectory may influence later-life obesity. Human milk provides a wide range of nutritional and bioactive components that are vital for infant growth. Compared to formula-fed infants, breastfed infants are less likely to develop later-onset obesity, highlighting the potential role of bioactive components present in human milk. Components of particular interest are the human milk microbiota, human milk oligosaccharides (HMOs), short-chain fatty acids (SCFAs), and antimicrobial proteins, each of which influence the infant gut microbiome, which in turn has been associated with infant body composition. SCFAs and antimicrobial proteins from human milk may also systemically influence infant metabolism. Although inconsistent, multiple studies have reported associations between HMOs and infant growth, while studies on other bioactive components in relation to infant growth are sparse. Moreover, these microbiome-related components may interact with each other within the mammary gland. Here, we review the evidence around the impact of human milk microbes, HMOs, SCFAs, and antimicrobial proteins on infant growth. Breastfeeding is a unique window of opportunity to promote optimal infant growth, with aberrant growth trajectories potentially creating short- and long-term public health burdens. Therefore, it is important to understand how bioactive components of human milk influence infant growth.     

Control of food intake by metabolism of fuels: a comparison across species

Research with laboratory species suggests that meals can be terminated by peripheral signals carried to brain feeding centres via hepatic vagal afferents, and that these signals are affected by oxidation of fuels. Pre-gastric fermentation in ruminants greatly alters fuels, allowing mechanisms conserved across species to be studied with different types and temporal absorption of fuels. These fuels include SCFA, glucose, lactate, amino acids and long-chain fatty acid (FA) isomers, all of which are absorbed and metabolised by different tissues at different rates. Propionate is produced by rumen microbes, absorbed within the timeframe of meals, and quickly cleared by the liver. Its hypophagic effects are variable, likely due to its fate; propionate is utilised for gluconeogenesis or oxidised and also stimulates oxidation of acetyl-CoA by anapleurosis. In contrast, acetate has little effect on food intake, likely because its uptake by the ruminant liver is negligible. Glucose is hypophagic in non-ruminants but not ruminants and unlike non-ruminant species, uptake of glucose by ruminant liver is negligible, consistent with the differences in hypophagic effects between them. Inhibition of FA oxidation increases food intake, whereas promotion of FA oxidation suppresses food intake. Hypophagic effects of fuel oxidation also vary with changes in metabolic state. The objective of this paper is to compare the type and utilisation of fuels and their effects on feeding across species. We believe that the hepatic oxidation theory allows insight into mechanisms controlling feeding behaviour that can be used to formulate diets to optimise energy balance in multiple species.     

Modulation of the Gut Microbiota Structure with Probiotics and Isoflavone Alleviates Metabolic Disorder in Ovariectomized Mice

The decrease in ovarian hormone secretion that occurs during menopause results in an increase in body weight and adipose tissue mass. Probiotics and soy isoflavones (SIFs) could affect the gut microbiota and exert anti-obesity effects. The objective of this study was to investigate the effects of probiotics and a diet containing SIF (SIF diet) on ovariectomized mice with menopausal obesity, including the gut microbiome. The results demonstrate that Bifidobacterium longum 15M1 can reverse menopausal obesity, whilst the combination of Lactobacillus plantarum 30M5 and a SIF diet was more effective in alleviating menopausal lipid metabolism disorder than either components alone. Probiotics and SIFs play different anti-obesity roles in menopausal mice. Furthermore, 30M5 alters the metabolites of the gut microbiota that increase the circulating estrogen level, upregulates the expression of estrogen receptor α in abdominal adipose tissue and improves the production of short-chain fatty acids (SCFAs). A SIF diet can significantly alter the structure of the fecal bacterial community and enrich the pathways related to SCFAs production. Moreover, 30M5 and a SIF diet acted synergistically to effectively resolve abnormal serum lipid levels in ovariectomized mice, and these effects appear to be associated with regulation of the diversity and structure of the intestinal microbiota to enhance SCFAs production and promote estrogen circulation.     

Characteristic chromatographic fingerprint study of short-chain fatty acids in human milk,infant formula,pure milk and fermented milk by gas chromatography–mass spectrometry

Human milk, infant formula, pure milk and fermented milk as food products or dietary supplements provide a range of nutrients required to both infants and adults. Recently, a growing body of evidence has revealed the beneficial roles of short-chain fatty acids (SCFAs), a subset of fatty acids produced from the fermentation of dietary fibers by gut microbiota. The objective of this study was to establish a chromatographic fingerprint technique to investigate SCFAs in human milk and dairy products by gas chromatography coupled with mass spectrometry. The multivariate method for principal component analysis assessed differences between milk types. Human milk, infant formula, pure milk and fermented milk were grouped independently, mainly because of differences in formic acid, acetic acid, propionic acid and hexanoic acid levels. This method will be important for the assessment of SCFAs in human milk and various dairy products.     

粪便中6种短链脂肪酸的气相色谱快速检测法

目的 建立粪便中乙酸、丙酸、正丁酸、异丁酸、正戊酸和异戊酸等六种短链脂肪酸（SCFAs）的快速提取及气相色谱定量检测方法。方法 粪便样本分别采用纯水和盐酸溶液（pH = 2）提取,静置、离心后,上清液中的SCFAs采用气相色谱法测定。以正丁醇为内标,保留时间定性,峰面积定量。结果 本法线性关系良好,水提取和酸提取的加标回收率分别为78.8%～115%和85.7%～130%,且无统计学差异（P＞0.05）。比较人和鼠的粪便水提法所得SCFAs含量与参考文献检测结果吻合。结论 本法高效、稳定,可应用于大批粪便样本6种短链脂肪酸的快速测定。