短链脂肪酸调控骨代谢的作用及机制的研究进展

肠道菌群紊乱可导致宿主病理性骨质流失,其通过产生的代谢物从肠道扩散到体循环对骨代谢发挥重要的调控作用。短链脂肪酸（Short Chain Fatty Acids,SCFAs）是肠道细菌产生的代谢物家族中最受关注的代谢产物,近年来研究表明,SCFAs在骨代谢相关疾病的发生发展中具有重要调节作用。本文就其在骨骼系统中的作用、调节骨组织中细胞的机制及作为靶点防治骨代谢疾病骨质疏松的研究进行综述,并为此新兴且具有前景的研究领域在未来的基础研究和转化研究提供展望。     

Urea and short-chain fatty acids metabolism in Holstein cows fed a low-nitrogen grass-based diet

Three ruminally cannulated and multicatheterised lactating dairy cows were used to investigate the effect of different supplement strategies to fresh clover grass on urea and short-chain fatty acid (SCFA) metabolism in a zero-grazing experiment with 24-h blood and ruminal samplings. Fresh clover grass was cut every morning and offered from 0800 to 1500 h. Maize silage was fed at 1530 h. The three treatments, arranged in a Latin square, differed by timing of feeding rolled barley and soya-bean hulls relative to fresh clover grass. All diets had the same overall composition. Treatments were soya-bean hulls fed at 0700 h and barley fed at 1530 h (SAM), barley fed at 0700 h and soya-bean hulls fed at 1530 h (BAM), and both soya-bean hulls and barley fed at 1530 h (SBPM). The grass had an unexpectedly low content of crude protein (12.7%) and the cows were severely undersupplied with rumen degradable protein. The treatment effects were numerically small; greater arterial ammonia concentration, net portal flux of ammonia and net hepatic flux of urea during part of the day were observed when no supplementary carbohydrate was fed before grass feeding. A marked diurnal variation in ruminal fermentation was observed and grass feeding increased ruminal concentrations of propionate and butyrate. The net portal fluxes of propionate, butyrate, isovalerate and valerate as well as the net hepatic uptake of propionate, butyrate, valerate and caproate increased after feeding at 0700 h. The hepatic extraction of butyrate showed a relatively large depression with grass feeding with nadir at 1200 to 1330 h. The increased net portal absorption and the decreased hepatic extraction resulted in an approximately six-fold increase in the arterial blood concentration of butyrate. The gut entry rate of urea accounted for 70 ± 10% of the net hepatic production of urea. Saliva contributed to 14% of the total amount of urea recycled to the gut. Urea recycling to the gut was equivalent to 58% of the dietary nitrogen intake. Despite the severe undersupply of rumen degradable protein, the portal-drained viscera did not extract more than 4.3% of the urea supplied with arterial blood. This value is in line with the literature values for cows fed diets only moderately deficient in rumen degradable protein and indicates that cows maximise urea transfer across gut epithelia even when the diet is moderately deficient in rumen degradable protein.     

肠道菌群多糖利用及代谢

宿主与肠道共生菌之间存在一种互利共生的关系.肠道共生菌可以代谢宿主自身不能消化的多糖.进入肠道内的多糖是影响肠道共生菌生理状态和组成的重要因素,这些多糖主要来自饮食和宿主的粘膜分泌物.人类饮食中含有几十种不同的膳食多糖,其中大多数不能被人类基因组中编码的酶降解,并进入大肠,供肠道共生菌利用.肠道共生菌将这些不易消化的多...     

The interplay between host cellular and gut microbial metabolism in NAFLD development and prevention

Metabolism regulation centred on insulin resistance is increasingly important in nonalcoholic fatty liver disease (NAFLD). This review focuses on the interactions between the host cellular and gut microbial metabolism during the development of NAFLD. The cellular metabolism of essential nutrients, such as glucose, lipids and amino acids, is reconstructed with inflammation, immune mechanisms and oxidative stress, and these alterations modify the intestinal, hepatic and systemic environments, and regulate the composition and activity of gut microbes. Microbial metabolites, such as short-chain fatty acids, secondary bile acids, protein fermentation products, choline and ethanol and bacterial toxicants, such as lipopolysaccharides, peptidoglycans and bacterial DNA, play vital roles in NAFLD. The microbe–metabolite relationship is crucial for the modulation of intestinal microbial composition and metabolic activity. The intestinal microbiota and their metabolites participate in epithelial cell metabolism via a series of cell receptors and signalling pathways and remodel the metabolism of various cells in the liver via the gut–liver axis. Microbial metabolic manipulation is a promising strategy for NAFLD prevention, but larger-sampled clinical trials are required for future application.     

Fermentation of prebiotics by human colonic microbiota in vitro and short-chain fatty acids production: a critical review

Prebiotics are known for their health benefits to man, including reducing cardiovascular disease and improving gut health. This review takes a critical assessment of the impact of dietary fibres and prebiotics on the gastrointestinal microbiota in vitro. The roles of colonic organisms, slow fermentation of prebiotics, production of high butyric and propionic acids and positive modulation of the host health were taken into cognizance. Also, the short-chain fatty acids (SCFAs) molecular signalling mechanisms associated with their prebiotic substrate structural conformations and the phenotypic responses related to the gut microbes composition were discussed. Furthermore, common dietary fibres such as resistant starch, pectin, hemicelluloses, β-glucan and fructan in context of their prebiotic potentials for human health were also explained. Finally, the in vitro human colonic fermentation depends on prebiotic type and its physicochemical characteristics, which will then affect the rate of fermentation, selectivity of micro-organisms to multiply, and SCFAs concentrations and compositions.     

Characterization of gut microbiota and short-chain fatty acid in breastfed infants with or without breast milk jaundice

This study aims to investigate the gut microbiota and metabolites in breastfed infants with breast milk jaundice (BMJ) using gut microbiome–metabolomics. Breastfed newborns diagnosed with BMJ and those without BMJ (control group) were enrolled. Faecal samples were collected from the participants and subjected to high-throughput sequencing of the 16s rDNA V3 and V4 regions of the gut flora and metabolomics of short-chain fatty acids (SCFAs). Proteobacteria, Fimicutes and Actinobacteria were the main bacteria at the phylum level. Eshcerichia-Shigella and Enterobacteriacea were the main bacteria at the genus level. The difference between the two groups was compared. Compared to the control group, the amount of Streptococcus was significantly increased while the amount of Enterococcus was significantly decreased in the faeces from infants with BMJ. Functional prediction analysis of 16S found that biosynthesis of penicillin and cephalosporin significantly increased in the BMJ group. Gas chromatography–mass spectrometry detection of SCFAs revealed that levels of acetic acid and propionic acid were significantly lower in the BMJ group than in the control group. The reduced levels of acetic acid and propionic acid may be related to the increase in Streptococcus and decrease in Enterococcus, both of which may contribute to BMJ.     

Responses of feeding prebiotics on nutrient digestibility, faecal microbiota composition and short-chain fatty acid concentrations in dogs: a meta-analysis

The effects of prebiotics on digestibility, short-chain fatty acid (SCFA) concentrations and bacterial populations in the faeces and immunity in dogs were evaluated by meta-analyses. Overall, data from 15 published studies containing 65 different treatment means of 418 observations from different breeds of dogs were included in the data set. Feeding of prebiotics to dogs did not affect the nutrient intake (P > 0.10), nor did prebiotics change (P > 0.10) the digestibility of dry matter (DM) and fat. However, crude protein (CP) digestibility tended to decrease quadratically (P = 0.06) with increasing dosages of prebiotics, although the degree of prediction was low (R(2) = 0.33). The concentration of total SCFA (P = 0.08; R(2) = 0.90) tended to increase linearly, whereas concentration of acetate (R(2) = 0.25), propionate (R(2) = 0.88) and butyrate (R(2) = 0.85) increased quadratically with increasing dosage of prebiotics in the faeces of dogs. The numbers of beneficial bifidobacteria (P < 0.01; R(2) = 0.62) increased quadratically, but lactobacilli (P < 0.01; R(2) = 0.66) increased linearly with increasing supplementation of prebiotics. The changes in healthy bacterial numbers were affected by the interaction of initial bacterial numbers and dose of prebiotics; bacterial numbers increased relatively more when initial bacterial numbers were low. Dietary composition did not influence the response of prebiotics on lactobacilli and bifidobacterial numbers in this study. The numbers of pathogenic Clostridium perfringens and Escherichia coli were not affected by prebiotics. Prebiotics did not affect the serum immunoglobulin (Ig) concentrations such as IgG, IgA and IgM in dogs. Although prebiotics may tend to have an adverse effect on CP digestibility, prebiotics at doses up to 1.40% food intake (DM basis) might increase the beneficial bacterial populations and SCFA concentrations in the faeces of dogs. Thus, the feeding of prebiotics has a great prospective to improve the intestinal health of dogs.     

短链脂肪酸在宿主能量代谢方面的调节作用

肠道菌群数量庞大,对宿主多种生理活动具有重要调节作用。现有研究发现,肠道菌群主要通过调节其产生的不同代谢产物,参与宿主物质代谢反应,改变能量代谢水平,影响机体炎症反应。在诸多代谢产物中,短链脂肪酸（醋酸盐、丙酸盐、丁酸盐等）具有重要调节作用,对机体代谢功能方面具有深远影响。本文结合国内外相关研究文献,综述了短链脂肪酸在调节机体能量代谢方面的相关研究,以期为进一步阐明其在机体能量代谢方面的作用提供科学依据。     

The interplay between diet,gut microbes,and host epigenetics in health and disease

The mechanisms linking the function of microbes to host health are becoming better defined but are not yet fully understood. One recently explored mechanism involves microbe-mediated alterations in the host epigenome. Consumption of specific dietary components such as fiber, glucosinolates, polyphenols, and dietary fat has a significant impact on gut microbiota composition and function. Microbial metabolism of these dietary components regulates important epigenetic functions that ultimately influences host health. Diet-mediated alterations in the gut microbiome regulate the substrates available for epigenetic modifications like DNA methylation or histone methylation and/or acetylation. In addition, generation of microbial metabolites such as butyrate inhibits the activity of core epigenetic enzymes like histone deacetylases (HDACs). Reciprocally, the host epigenome also influences gut microbial composition. Thus, complex interactions exist between these three factors. This review comprehensively examines the interplay between diet, gut microbes, and host epigenetics in modulating host health. Specifically, the dietary impact on gut microbiota structure and function that in-turn regulates host epigenetics is evaluated in terms of promoting protection from disease development.     

The gut microbiota modulates host amino acid and glutathione metabolism in mice

The gut microbiota has been proposed as an environmental factor that promotes the progression of metabolic diseases. Here, we investigated how the gut microbiota modulates the global metabolic differences in duodenum, jejunum, ileum, colon, liver, and two white adipose tissue depots obtained from conventionally raised (CONV‐R) and germ‐free (GF) mice using gene expression data and tissue‐specific genome‐scale metabolic models (GEMs). We created a generic mouse metabolic reaction (MMR) GEM, reconstructed 28 tissue‐specific GEMs based on proteomics data, and manually curated GEMs for small intestine, colon, liver, and adipose tissues. We used these functional models to determine the global metabolic differences between CONV‐R and GF mice. Based on gene expression data, we found that the gut microbiota affects the host amino acid (AA) metabolism, which leads to modifications in glutathione metabolism. To validate our predictions, we measured the level of AAs and N‐acetylated AAs in the hepatic portal vein of CONV‐R and GF mice. Finally, we simulated the metabolic differences between the small intestine of the CONV‐R and GF mice accounting for the content of the diet and relative gene expression differences. Our analyses revealed that the gut microbiota influences host amino acid and glutathione metabolism in mice.     

Antibiotic resistance determinants in the interplay between food and gut microbiota

A complex and heterogeneous microflora performs sugar and lactic acid fermentations in food products. Depending on the fermentable food matrix (dairy, meat, vegetable etc.) as well as on the species composition of the microbiota, specific combinations of molecules are produced that confer unique flavor, texture, and taste to each product. Bacterial populations within such "fermented food microbiota" are often of environmental origin, they persist alive in foods ready for consumption, eventually reaching the gastro-intestinal tract where they can interact with the resident gut microbiota of the host. Although this interaction is mostly of transient nature, it can greatly contribute to human health, as several species within the food microbiota also display probiotic properties. Such an interplay between food and gut microbiota underlines the importance of the microbiological quality of fermented foods, as the crowded environment of the gut is also an ideal site for genetic exchanges among bacteria. Selection and spreading of antibiotic resistance genes in foodborne bacteria has gained increasing interest in the past decade, especially in light of the potential transferability of antibiotic resistance determinants to opportunistic pathogens, natural inhabitants of the human gut but capable of acquiring virulence in immunocompromised individuals. This review aims at describing major findings and future prospects in the field, especially after the use of antibiotics as growth promoters was totally banned in Europe, with special emphasis on the application of genomic technologies to improve quality and safety of fermented foods.     

Role of free fatty acid receptors in the regulation of energy metabolism

Free fatty acids (FFAs) are energy-generating nutrients that act as signaling molecules in various cellular processes. Several orphan G protein-coupled receptors (GPCRs) that act as FFA receptors (FFARs) have been identified and play important physiological roles in various diseases. FFA ligands are obtained from food sources and metabolites produced during digestion and lipase degradation of triglyceride stores. FFARs can be grouped according to ligand profiles, depending on the length of carbon chains of the FFAs. Medium- and long-chain FFAs activate FFA1/GPR40 and FFA4/GPR120. Short-chain FFAs activate FFA2/GPR43 and FFA3/GPR41. However, only medium-chain FFAs, and not long-chain FFAs, activate GPR84 receptor. A number of pharmacological and physiological studies have shown that these receptors are expressed in various tissues and are primarily involved in energy metabolism. Because an impairment of these processes is a part of the pathology of obesity and type 2 diabetes, FFARs are considered as key therapeutic targets. Here, we reviewed recently published studies on the physiological functions of these receptors, primarily focusing on energy homeostasis.     

Analyses of short-chain fatty acids and exhaled breath volatiles in dietary intervention trials for metabolic diseases

As an alternative to pharmacological treatment to diseases, lifestyle interventions, such as dietary changes and physical activities, can help maintain healthy metabolic conditions. Recently, the emerging analyses of volatile organic compounds (VOCs) from breath and short-chain fatty acids (SCFAs) from plasma/feces have been considered as useful tools for the diagnosis and mechanistic understanding of metabolic diseases. Furthermore, diet-induced changes of SCFAs in individuals with diagnosed metabolic abnormalities have been correlated with the composition changes of the gut microbiome. More interestingly, the analysis of exhaled breath (breathomics) has gained attention as a useful technique to measure the human VOC profile altered as a result of dietary interventions. In this mini-review, we examined recent clinical trials that performed promising dietary interventions, SCFAs analysis in plasma/feces, and VOC profile analysis in exhaling breath to understand the relationship between dietary intervention and metabolic health.     

肠道微生物多样性与能量代谢调控及肥胖关系的研究进展

肠道微生物与宿主之间相互选择,构成了一个相对稳定的超有机体。宿主基因型和遗传关系影响肠道微生物的生态学特征,而肠道微生物发酵肠道内多糖,为宿主提供可吸收利用的养分,增强肠道对养分吸收的能力。同时,肠道微生物还影响一些转录因子的活性,调控宿主基因的表达,增强宿主甘油三酯的合成和脂肪沉积,减少脂肪酸氧化分解,调控宿主能量代谢。     

Simple inhibitors of histone deacetylase activity that combine features of short-chain fatty acid and hydroxamic acid inhibitors

Butyric acid and trichostatin A (TSA) are anti-cancer compounds that cause the upregulation of genes involved in differentiation and cell cycle regulation by inhibiting histone deacetylase (HDAC) activity. In this study we have synthesized and evaluated compounds that combine the bioavailability of short-chain fatty acids, like butyric acid, with the bidentate binding ability of TSA. A series of analogs were made to examine the effects of chain length, simple aromatic cap groups, and substituted hydroxamates on the compounds' ability to inhibit rat-liver HDAC using a fluorometric assay. In keeping with previous structure-activity relationships, the most effective inhibitors consisted of longer chains and hydroxamic acid groups. It was found that 5-phenylvaleric hydroxamic acid and 4-benzoylbutyric hydroxamic acid were the most potent inhibitors with IC₅₀'s of 5 μM and 133 μM respectively.     

Use of Gifu Anaerobic Medium for culturing 32 dominant species of human gut microbes and its evaluation based on short-chain fatty acids fermentation profiles

Recently, a “human gut microbial gene catalogue,” which ranks the dominance of microbe genus/species in human fecal samples, was published. Most of the bacteria ranked in the catalog are currently publicly available; however, the growth media recommended by the distributors vary among species, hampering physiological comparisons among the bacteria. To address this problem, we evaluated Gifu anaerobic medium (GAM) as a standard medium. Forty-four publicly available species of the top 56 species listed in the “human gut microbial gene catalogue” were cultured in GAM, and out of these, 32 (72%) were successfully cultured. Short-chain fatty acids from the bacterial culture supernatants were then quantified, and bacterial metabolic pathways were predicted based on in silico genomic sequence analysis. Our system provides a useful platform for assessing growth properties and analyzing metabolites of dominant human gut bacteria grown in GAM and supplemented with compounds of interest.