Probiotics in the defence and metabolic balance

P r o c e e d i n g s o f t h e N u t r i t i o n S o c i e t y

The 3rd International Immunonutrition Workshop was held at Platja D’Aro,Girona,Spain on 21–24October 2009

3rd International Immunonutrition Workshop

Session 8:Probiotics in the defence and metabolic balance of the

organism

Gut microbiota in obesity and metabolic disorders

Yolanda Sanz *,Arlette Santacruz and Paola Gauf?n

Microbial Ecophysiology and Nutrition Group,Institute of Agrochemistry and Food Technology (IATA),Spanish National

Research Council (CSIC),Valencia,Spain

Obesity is a major public health issue as it is causally related to several chronic disorders,including type-2diabetes,CVD and cancer.Novel research shows that the gut microbiota is involved in obesity and metabolic disorders,revealing that obese animal and human subjects have alterations in the composition of the gut microbiota compared to their lean counterparts.Moreover,transplantation of the microbiota of either obese or lean mice in?uences body weight in the germ-free recipient mice,suggesting that the gut ecosystem is a relevant target for weight management.Indigenous gut microbes may regulate body weight by in?uencing the host’s metabolic,neuroendocrine and immune functions.The intestinal microbiota,as a whole,provides additional metabolic functions and regulates the host’s gene expression,improving the ability to extract and store energy from the diet and contributing to body-weight gain.Imbalances in the gut microbiota and increases in plasma lipopolysaccharide may also act as in?ammatory factors related to the development of atherosclerosis,insulin resistance and body-weight gain.In contrast,speci?c probiotics,prebiotics and related metabolites might exert bene?cial effects on lipid and glucose metabolism,the production of satiety peptides and the in?ammatory tone related to obesity and associated metabolic disorders.This knowledge is contributing to our understanding of how environmental factors in?uence obesity and associated diseases,providing new opportunities to design improved dietary intervention strategies to manage these disorders.

Gut microbiota:Obesity:Chronic in?ammation:Type-2diabetes:Probiotics:Prebiotics

Obesity is one of the major current public health problems because of its increasing prevalence and association with important chronic disorders (1).These include type-2dia-betes mellitus,atherosclerosis,CVD,non-alcoholic fatty liver disease and cancer.Obesity is the result of a long-term positive imbalance between energy intake and expenditure,which is regulated by multiple pathways involving metabolites,hormones and neuropeptides.High-fat diet-induced obesity and metabolic disorders are also associated with a state of chronic low-grade in?ammation and increased susceptibility to infection,due to malfunc-tion of the immune system.Obese individuals have increased macrophage in?ltration in the adipose tissue along with the production of in?ammatory adipokines,cytokines and associated immune factors.In?ammatory immune mediators (e.g.C-reactive protein,TNF a ,IL-6and monocyte chemotactic protein 1)and some adipokines (e.g.leptin)are usually elevated in obese mice and human subjects,whereas the production of the anti-in?ammatory and insulin-sensitizing adipokine adiponectin is reduced (2).In fact,chronic activation of the innate immune system is regarded as a risk factor for the development of obesity and associated disorders;this activation might partly depend on the immunomodulatory effects exerted by diet-ary compounds in the gut and beyond (2).

The human intestinal tract is populated by a vast number of bacterial species that reach concentrations ranging from 107to 1012cells/g intestinal content,from the small

Abbreviation:LPS,lipopolysaccharide.

*Corresponding author:Yolanda Sanz,fax +34963636301,email yolsanz@iata.csic.es

Proceedings of the Nutrition Society (2010),69,434–441doi:10.1017/S0029665110001813

g The Authors 2010First published online 14June 2010

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intestine to the colon.This microbial community develops with its host throughout life by establishing mutualistic symbiotic relationships which favour their co-existence (3).The collective genome (microbiome)of the gut microbiota contains at least 100times as many genes as the human genome,providing additional features and contributing to human physiological diversity (4,5).In particular,the gut microbiota has been considered to be a possible causative factor of metabolic conditions as well as a therapeutic target in recent years (5).Herein,the proposed modes of action of the gut microbiota in obesity and associated-metabolic disorders and the effects of interventions with the probiotic,prebiotics and synbiotics are reviewed.

Obesity,weight loss and gut microbiota composition Obesity is associated with phylum and group-speci?c changes in the microbiota,and with reduced bacterial diversity (6,7).Increases in the relative abundance of Fir-micutes and reductions in Bacteroidetes have been asso-ciated with obesity by comparisons between the distal gut microbiota of genetically obese ob/ob mice (leptin de-?cient)and their lean (ob /+or +/+)littermates using DNA sequencing techniques (8).A higher proportion of Archaea was also found on the caecal microbiota of these genetically obese mice in comparison with their lean littermates (9).Diet-induced obesity in mice has also been associated with an increased proportion of Eubacterium dolichum ,belonging to the Firmicutes division (10).Com-pared to lean rats,obese Zucker rats (fa /fa )showed reduced Bi?dobacterium counts quanti?ed by ?uorescence in situ hybridization and increased abundance of Halomo-nas and Sphingomonas ,detected by PCR and denaturing gradient gel electrophoresis (7).Obesity induced by a high-fat diet was also associated with lower Bi?dobacterium numbers in caecal content in mice (11).

Similar alterations in the relative proportions of Firmi-cutes and Bacteroidetes in faeces have been associated with human obesity (12).In addition,obese human adults submitted to a hypoenergic diet (either low carbohydrate-or low-fat diet)showed signi?cant increases in the faecal proportions of Bacteroidetes parallel to weight loss over a 1-year-long intervention (12).Furthermore,a lower proportion of Bacteroidetes and a higher proportion of Actinobacteria have been associated with obesity by com-parisons between the faecal microbiota of obese and lean twin human subjects (6).A larger-scale intervention trial has recently demonstrated that both an energy-restricted diet and increased physical activity induce changes in the gut microbiota structure of obese adolescents,correlated with weight loss and BMI Z -score reductions (13,14).Clostridium histolyticum ,Clostridium lituseburense and Eubacterium rectale–Clostridium coccoides proportions dropped sig-ni?cantly,while those of the Bacteroides–Prevotella group increased after the intervention in those adolescents that experienced signi?cant weight reduction (8.1%of their body weight)as determined by ?uorescence in situ hybri-dization (13).When the microbiota was analysed by quanti-tative real-time PCR,increased Bacteroides fragilis and Lactobacillus group numbers and reduced C.coccoides

and Bi?dobacterium longum group numbers were detected in those adolescents that experienced important weight loss after the intervention (14).Moreover,the effectiveness of lifestyle intervention on body-weight loss seems to be in?uenced by the composition of the individual’s micro-biota (14).Alterations in the faecal microbiota composition also seem to precede overweight in children,early in life.Children maintaining normal weight showed an increased number of Bi?dobacterium ,whereas children becoming overweight showed an increased number of Staphylo-coccus aureus in faeces during infancy (15).

Perturbations in the composition of gut microbiota associated with genetic or diet-induced obesity seem to be reversible by oral transfer of the gut microbiota from lean or obese mice to a germ-free recipient (10,16)or by the administration of prebiotic substrates to animal models at least over short-term periods (17).Studies on the evolution of mammals and their gut microbes by DNA sequencing also indicate that the diet is a fundamental promoter of change in gut bacterial diversity (18).Altogether,this evidence supports the hypothesis that the modulation of gut microbiota via dietary intervention is a potential strategy to help manage obesity and metabolic-associated disorders (10,16,17),although actual proof is still limited.

Role of the gut microbiota in nutrient metabolism

and energy storage The intestinal microbiota develops an important biochem-ical activity within the human body by providing ad-ditional metabolic functions (4)and regulating the diverse aspects of cellular differentiation and gene expression via host–microbe interactions (19).In fact,comparisons between germ-free mice and mice colonized by the conventional distal gut microbiota showed that the microbiota,as a whole,increases the host’s ability to extract energy from the diet and store this energy in adipocytes,contributing to body-weight gain (20).The intestinal microbiota provides enzymes involved in the utilization of non-digestible car-bohydrates and host-derived glycoconjugates,deconjuga-tion and dehydroxylation of bile acids,cholesterol reduction and biosynthesis of vitamins (K and B group),isoprenoids and amino acids (e.g.lysine and threo-nine)(4,19).In particular,the ability of the commensal microbiota to utilize complex dietary polysaccharides which would otherwise be inaccessible to human subjects and to generate SCFA seems to contribute to the ability of the host to harvest energy from the diet (20).This may represent 10%daily energy supply in omnivores and up to 70%in herbivores (21).Speci?c components of the com-mensal microbiota also regulate serum lipids and choles-terol by taking part in bile-acid recycling and metabolism.Bacterial enzymes mainly catalyse the deconjugation and dehydroxylation of bile acids,which alter the solubiliza-tion and absorption of dietary lipids throughout the intes-tine (22).Faecal commensal bacteria also reduce cholesterol to coprostanol and,thus,increase its excretion in faeces (23).In addition,the commensal microbiota and its metab-olites regulate the expression of genes involved in the processing and absorption of dietary carbohydrates and

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complex lipids in the host,favouring fat storage (20,24).The expression of a monosaccharide transporter (Na +/glucose co-transporter)has been induced in Bi?dobacterium the-taiotaomicron mono-colonized mice,leading to increased absorption of dietary monosaccharides and SCFA and,thereby,promoting de novo synthesis of lipids in the liver (24).In fact,the colonization of germ-free mice by the conventional microbiota leads to increased liver expression of key enzymes (acetyl-CoA carboxylase and fatty acid synthase)involved in de novo fatty acid biosynthetic pathways and the transcriptional factors (carbohydrate response element-binding protein and sterol regulatory element-binding protein-1)involved in hepatocyte lipo-genic responses to insulin and glucose (20).Furthermore,microbial colonization reduces the levels of circulating fasting-induced adipose factor in the gut,skeletal muscle and liver levels of phosphorylated AMP-activated protein kinase,which jointly contribute to reducing fat oxidation and enhancing fat storage (25).

Role of the gut microbiota in neurohormonal function The gut microbiota could also interact with the production and function of hormones and neuropeptides synthesized by the nervous system and enteroendocrine cells of the gastrointestinal tract mucosa and peripheral organs (adi-pose tissue,pancreas and liver),which are critical to the regulation of energy balance.

Colonization of the germ-free intestine of mice by con-ventional microbiota stimulates adipokine leptin synthesis,with a proportional increase in body fat and insulin resist-ance (20).Although leptin is the dominant long-term signal informing the brain of energy stores and inhibiting food intake,leptin de?ciency is not a common cause of obesity but leptin resistance is (26).Obese subjects usually have increased serum leptin levels associated with increased hunger and reduced energy expenditure.Increased leptin levels could also induce the production of pro-in?amma-tory T-helper 1-type cytokines and contribute to the in?am-matory tone associated with obesity (26).SCFA,which are mainly produced by the gut microbiota,act as ligands for G protein-coupled receptors,such as Gpr41,expressed in the intestine,colon and adipocytes,which upon activation stimulate the expression of peptide hormones (e.g.leptin and peptide tyrosine–tyrosine)involved in appetite and energy metabolism (27).In particular,Gpr41-de?cient mice show a reduced expression of peptide tyrosine–tyrosine,which modulates gut motility and reduced harvest of energy from the diet,in a microbiota-dependent manner.Autoantibodies against key appetite-regulating neuropep-tides and peptide hormones (e.g.alpha-melanocyte-stimu-lating hormone,neuropeptide Y,agouti-related protein,ghrelin and leptin)have also been detected in the sera of human subjects and rats (28).The sequence homology found between these neuropeptides and proteins from some members of the intestinal microbiota would suggest that the microbiota could in?uence their production and,therefore,eating behaviour.Mice infected with Helico-bacter pylori showed delayed gastric emptying,increased visceral perception and abnormal feeding patterns (29).

Feeding behaviour remained altered for up to 2months post-infection,possibly due to altered gastric mechan-osensitivity,increased postprandial cholecystokinin release inducing satiety and increased TNF a expression in the central nervous system (30).However,the administration of Lactobacillus strains after H.pylori eradication normalized the feeding behaviour (31).

Interactions between the gut microbiota composition and stress-related hormones,which affect energy balance,have also been identi?ed.Stress at late stages during pregnancy,parallel to elevated cortisol plasma levels,was found to lead to reductions in faecal Bi?dobacterium counts in infant monkeys (32).Stress induced in male rat pups by maternal separation early in life also led to increased plasma corticosterone and the systemic immune response with alterations in the faecal microbiota com-pared to the control group (33).In germ-free mice,higher plasma adrenocorticotropic hormone and elevated corti-costerone were detected in response to restraint stress as compared to conventional mice (34).However,the excessive hypothalamic–pituitary–adrenal stress response in germ-free mice was reversed by inoculation with a Bi?do-bacterium infantis strain.Glucocorticoids are well known for their critical role in metabolism and,in particular,alterations in tissue-speci?c cortisol levels in?uencing lipogenic and gluconeogenetic pathways in fat and liver,associated with obesity and the development of insulin-resistance (35).

Role of the gut microbiota in immune function Obesity induced by high-fat diets and the associated metabolic disorders are characterized by a state of low-grade in?ammation which has been related to alterations in the gut microbiota composition and increased plasma lipopolysaccharide (LPS)levels (11,36).Mice fed a high-fat diet exhibited a signi?cant increase in plasma LPS,which was termed ‘metabolic endotoxemia’,associated with changes in the gut microbiota (reductions in Bi?dobacter-ium and E.rectale/C.coccoides ).A mouse model chroni-cally infused with a dose of LPS to reach the same plasma LPS levels as those measured in the high-fat-diet-fed mice also mimicked the phenotype of high-fat-fed mice.This was characterized by fasting hyperglycaemia,obesity,steatosis,adipose tissue macrophages in?ltration,hepatic insulin resistance and hyperinsulinemia.Furthermore,mice knocked out in CD14,a key molecule in Toll-like receptor 4signalling,were completely resistant to the development of in?ammation induced by both high-fat feeding and chronic LPS administration in the visceral and sub-cutaneous adipose depots,the liver and the muscle (36).In contrast,the inhibition of the gut microbiota by antibiotic administration (nor?oxacin and ampicillin)in two different mouse models of insulin resistance resulted in reduced serum LPS levels,low-grade in?ammation,obesity and type-2diabetes (15).Altogether,these ?ndings demonstrate the link between the gut microbiota,LPS and certain metabolic disorders.In human subjects,increased LPS plasma levels have also been associated with an elevated BMI and high-fat feeding (37,38).These increased LPS

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concentrations were suf?cient to activate the synthesis of in?ammatory cytokines (e.g.TNF a )by monocytes in vitro .Therefore,metabolic endotoxemia has also been con-sidered a possible factor contributing to the postprandial in?ammatory state,which could favour certain chronic disorders,including type-2diabetes and atherosclerosis in human subjects (38).

The colonization of the germ-free mouse intestine also regulates the expression of serum amyloid A proteins,which are mediators of in?ammation and metabolism and whose serum levels are increased in subjects with obesity,chronic hyperglycaemia,insulin resistance and CVD (39).The serum amyloid A3protein expression was signi?cantly augmented in adipose and colonic tissues by the presence of intestinal microbes,when comparing germ-free and conventionally raised mice.The authors propose that LPS,and potentially other products of gut bacteria,activate Toll-like receptors and mediate signalling through MyD88and NF-k B to promote increased serum amyloid A3and pro-in?ammatory cytokine expression (e.g.TNF a ),thereby exacerbating the chronic low-grade in?ammation associated with obesity (39).

Effects of probiotics and prebiotics on obesity and

metabolic disorders in animals A summary of trials evaluating different modes of action of classical probiotics (Lactobacillus and Bi?dobacterium strains),prebiotics or a combination thereof synbiotics,on diverse biomarkers of body-weight balance,immunity and metabolism in conventional animals and animal models of obesity,diabetes and hyperlipidemia is shown in Table 1.For example,feeding rats with skim milk fermented by Lactobacillus gasseri SBT2055led to reduction in adipo-cyte size and increased numbers of small adipocytes in white adipose tissue,also reducing serum leptin concen-trations compared with control rats,suggesting that the probiotic plays a role in regulating adipose tissue growth (40).Dietary supplementation of high fructose-induced diabetes and streptozotocin-induced diabetes in rats with a probiotic product (dahi)containing Lactoba-cillus acidophilus NCDC14and Lactobacillus casei NCDC19improved the biomarkers of glucose and lipid metabolism and delayed or suppressed glucose intolerance,hyperglycaemia,hyperinsulinemia,dyslipidemia and oxi-dative stress (41,42).The administration of either Lactoba-cillus paracasei NCC2461or Lactobacillus rhamnosus NCC4007to germ-free mice colonized with human baby microbiota also decreased plasma concentrations of VLDL and LDL and stimulated glycolysis (43).Similarly,when the same murine model was administered galactosyl oligo-saccharides combined with L.rhamnosus NCC4007as a synbiotic,the levels of plasma lipoproteins,hepatic TAG and kidney lipids were reduced (44).It seems that the re-duction in TAG in the liver was mainly due to the prebiotic,while the decrease in plasma lipoproteins was mainly due to the probiotic L.rhamnosus .This synbiotic also induced a remarkable stimulus to both growth and activity of bi?-dobacteria and,in particular,of B.longum (44).

The oral administration of the probiotic product VSL#3to wild-type male C57BL6mice fed a high-fat diet

signi?cantly improved their insulin resistance,hepatic natural killer T cell depletion and hepatic steatosis induced by the high-fat diet.This effect was natural killer T cell dependent,resulting from the attenuation of the TNF a and I k B kinase in?ammatory signalling and leading to im-proved sensitivity in insulin signalling (45).

Inulin-type prebiotics have also been demonstrated to modulate lipid and glucose metabolism in different animal models.Oligofructose decreases food intake,fat mass development and hepatic steatosis in normal and obese rats and mice;moreover,it exerts an anti-diabetic effect in streptozotocin-treated rats and high-fat-fed mice (46,47).The positive effects of oligofructose on diverse metabolic parameters are partly explained by its ability to regulate the expression of anorexigenic peptides,such as GLP-1that promotes satiety,as well as other gastrointestinal peptides (such as peptide tyrosine-tyrosine and ghrelin),which could jointly be involved in controlling food intake as detected in rats (46).Moreover,the administration of oligofructose to high-fat-fed mice increased the intestinal Bi?dobacterium numbers and normalized the endotoxemia and in?ammatory tone associated with the high-fat diet (17).Furthermore,the administration of oligofructose to geneti-cally obese mice (ob/ob )induced speci?c changes in the gut microbiota,characterized by increases in Lactobacillus ,Bi?dobacterium and C.coccoides–E.rectale groups,which led to reductions in intestinal permeability and an im-provement in tight-junction integrity and in?ammatory markers (plasma LPS and cytokines)(48).These effects were associated with increases in portal plasma GLP-2levels and its precursor (the proglucagon mRNA),in the jejunum and colon.

Effects of probiotics and prebiotics on obesity and

metabolic disorders in human subjects A summary of human clinical trials that have evaluated different effects of probiotic,prebiotic and synbiotic intake on biomarkers of lipid and glucose metabolism,blood pressure and body weight is shown in Table 2.Sup-plementation of hypercholesterolemic patients with the pro-biotic bacteria Lactobacillus plantarum 299v signi?cantly lowered serum concentrations of LDL cholesterol and ?brinogen (49).A functional food product containing the same strain,L.plantarum 299v,also decreased different biomarkers of CVD risk in heavy smokers (49),(Table 2).Monocytes isolated from the subjects treated with L.plantarum 299v also showed signi?cantly reduced adhesion to native and stimulated human umbilical vein endothelial cells,suggesting that the probiotic product could reduce CVD risk (49).A yoghurt supplemented with L.acidophilus 145,B.longum 913and oligofructose in-creased HDL cholesterol concentrations and decreased the ratio of LDL:HDL cholesterol in comparison with control yoghurt in women (50).However,the administration of other probiotic strains did not exert signi?cant effects on serum lipids,cholesterol or lipoproteins (51,52).The effects of probiotic supplementation together with dietary coun-selling exerted positive effects on glucose metabolism in normoglycaemic pregnant women (53).Blood glucose

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concentrations were the lowest in the diet/probiotic group during pregnancy and over the 12months’postpartum period.Glucose tolerance was also better in the diet/probiotic group compared with the control/placebo group during the last trimester of pregnancy and over the 12-month postpartum period (53).In human subjects,inulin-type fructans have also generally been found effective on normalization of metabolic disorder biomarkers,although the results have not been as consistent as those reported in animals (54).Supplementation of inulin to subjects under a moderately high-carbohydrate,low-fat diet led to de-creased hepatic lipogenesis and plasma TAG con-centrations,suggesting an effect on the reduction of atherosclerosis risk factors (55).Oligofructose intake also led to slightly signi?cant effects on postprandial insulin response,but not on lipid metabolism in individuals

with mild hypercholesterolemia (56).An infant formula containing galactosyl-oligosaccharides and long chain fructo-oligosaccharides in a ratio of 9:1did not exert sig-ni?cant effects on total cholesterol and LDL cholesterol in infants compared with those receiving a control infant formula (57).Daily consumption of oligofructose decreased the basal hepatic glucose production in healthy subjects,without any effect on insulin-stimulated glucose metab-olism (58).However,this prebiotic had no effect on glucose and lipid metabolism in type-2diabetics (59).In a pilot study with 10human subjects,oligofructose treatment also increased satiety following breakfast and dinner,reduced hunger and prospective food consumption follow-ing dinner (60).A long-term study (12months)including 100subjects revealed that those who received the pre-biotic supplement had a smaller increase in BMI,BMI

Table 1.Effects of probiotics,prebiotics and synbiotics on biomarkers of body weight,immunity and metabolism in animals

Probiotic/prebiotic/dose Animal model Duration Outcome

Reference

L.gasseri SBT2055milk

fermented with 6·107cfu/g Male Sprague–Dawley rats 28d

?Adipocyte size in mesenteric white adipose tissue,?number of small adipocytes in mesenteric and retroperitoneal adipose tissues and ?serum leptin 40

L.acidophilus NCDC14and L.casei NCDC19in dahi product (108cfu/g)

High fructose-induced diabetes in male Wistar rats

8weeks ?Plasma glucose,glycosylated haemoglobin,insulin,total cholesterol,TAG,LDL-cholesterol,

VLDL-cholesterol and free fatty acids and liver glycogen.41

?Thiobarbituric acid-reactive substances and ?reduced glutathione in liver and pancreas.L.acidophilus NCDC14and L.casei NCDC19in dahi product (7.3·109cfu/g)

Streptozotocin-induced diabetes in Wistar rats

28d ?Incremental peaks and delayed reduction of

insulin secretion during oral glucose tolerance test 42

?Oxidative damage in pancreatic tissues by inhibiting lipid peroxidation and formation of nitric oxide and ?glutathione content and activities of superoxide dismutase,catalase and glutathione peroxidase L.paracasei NCC2461and L.rhamnosus NCC4007(108cfu/d)

Female germ-free mice C3H colonized with human baby ?ora 14d ?Plasma VLDL-and LDL-cholesterol;?TAG 43

?Faecal excretion of bile acids

?Acetate and butyrate in the caecum ?Acetate/propionate in the liver

L.paracasei NCC2461or L.rhamnosus NCC4007(108cfu/d)with GOS (3%)Female germ-free mice C3H colonized with human baby ?ora 14d ?Propionate and butyrate in caecum with L.rhamnosus 62

?Isobutyrate in caecum with L.paracasei ?Liver TAG and ?glycogen with L.paracasei L.rhamnosus GG (108cfu/d)

with GOS (3%)

Female germ-free mice C3H colonized with human baby ?ora 14d ?Hepatic lipids and serum lipoproteins 44

?Bi?dobacterium and B.longum

VSL#3(B.breve,https://www.sodocs.net/doc/666337798.html,ctis,L.acidophilus,L.plantarum,L.paracasei,L.bulgaricus and S.thermophilus )(1.5·109cfu/d)Male C57BL6mice with steatosis and insulin resistance induced by a high-fat diet 28d ?Hepatic NKT cell numbers and ?in?ammatory

signalling improving steatosis and insulin resistance.

45

Oligofructose (10%)

Streptozotocin-treated diabetic male Wistar rats

6weeks

?Food intake

46

?Glucose tolerance and insulin secretion ?Portal and colonic GLP-1(7–36)

Oligofructose (10%)High fat diet fed male C57bl6/J mice 4weeks ?Energy intake,epididymal fat mass and body-weight gain;?Glycaemia

47Oligofructose (10g%)

High fat fed male C57bl6/J mice

14weeks

?Endotoxemia and plasma and adipose tissue pro-in?ammatory cytokines

17

?

Glucose tolerance and glucose-induced insulin secretion

Oligofructose (10%)ob/ob mice C57BL/64weeks

?Intestinal permeability

48

?In?ammatory markers (LPS,cytokines,etc.)?

Portal plasma GLP-2levels and the jejunum and colon precursor proglucagon mRNA.

cfu,colony-forming units;GOS,galactosyl-oligosaccharides;LPS,lipopolysaccharide;NKT,natural killer T cells;?,increase;?,decrease.

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Z -score and total fat mass,compared with the control group (61).

Conclusions

A number of ecological studies have uncovered the as-sociation between the composition of the gut microbiota and body weight and the prominent role played by the diet in these interactions.Mechanistic studies have also revealed that the gut microbiota may perform speci?c functions in the metabolic,neurohormonal and immune dysfunction associated with obesity.In this scenario,the use of dietary strategies targeting the gut ecosystem emerges as an additional tool to control metabolic dis-orders.A small number of trials have demonstrated that the administration of probiotics,prebiotics and their combina-tion (synbiotics)exert positive effects in vivo ,which are often more remarkable in animals than in human subjects.Nevertheless,the ?ndings indicate that advances in this ?eld could be of value to improve intervention strategies to manage obesity and its associated metabolic disorders.

Acknowledgements

This work was supported by grants AGL2008-01440/ALI and Consolider Fun-C -Food CSD2007-00063from the Spanish Ministry of Science and Innovation and AP 124/09

from Consejer?

′a de Sanidad (Valencia,Spain).The schol-arships to A.S.from CONACYT (Mexico)and to P.G.from CONICET (Argentina)are fully acknowledged.This review was drafted by Y.S.and discussed and approved by all authors.Authors declare no con?ict of interest.

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Table 2.Effects of probiotics,prebiotics and synbiotics on biomarkers of body weight regulation and metabolic disorders in human subjects Probiotic/prebiotic (dose/d)Administration pattern/

duration Study-design*Outcome

Reference

L.plantarum 299v (5.0·107cfu/d fermented milk)

Hypercholesterolaemic patients/6weeks

Heavy smokers /6weeks CRDB ?Plasma LDL-cholesterol and ?brinogen 49CRDB ?Systolic blood pressure,leptin and ?brinogen,F(2)-isoprostanes and IL-663L.acidophilus 145(106-8cfu/g),B.longum 913(at least 105cfu/g)and oligofructose (1%)in yoghurt with S.thermophilus and Lactococcus lactis (300g/d)

Healthy women,

15normocholesterolemic and 14hypercholesterolemic Three periods of 7weeks:(1)control for all,(2)and (3)control–symbiotic exchange

CO

?Plasma HDL-cholesterol and ?LDL/HDL cholesterol ratio Total cholesterol and LDL-cholesterol NS

50

L.fermentum PCC (2·109cfu/capsule;2capsules/d)

Hypercholesterolemic patients/10weeks CDB

Plasma total cholesterol,HDL-cholesterol,and TAG and liver enzymes NS 51

L.acidophilus DDS-1B.longum

UABL-14(109cfu)plus oligofructose (10–15mg)per capsule;3capsules/d

55normocholesterolemic subjects 2months or 2menstrual cycles CRSB Plasma concentrations of total cholesterol,HDL-cholesterol,LDL-cholesterol and TAG NS 52

L.rhamnosus GG and https://www.sodocs.net/doc/666337798.html,ctis Bb12

(109cfu each/d)plus dietary counselling Intake by women from ?rst trimester of pregnancy onwards CRSB/?Blood glucose concentrations and ?glucose tolerance during pregnancy

and over the 12-month postpartum period 53

Inulin (10g/d)

Non-obese healthy subjects for 3weeks CRDB ?Plasma TAG,?Hepatic lipogenesis 55CO Plasma cholesterol NS

Oligofructose (10.6g/d)

Subjects with

hypercholesterolemia for 2months

CRDB ?Postprandial insulin response 56

CO Lipids NS

GOS and lcoligofructose (9:1)(0.6g/100ml)

Infants till 6months of age CRDB Plasma cholesterol and LDL cholesterol NS 57Oligofructose (20g/d)Healthy subjects for 4weeks DB CO ?Basal hepatic glucose production

58Insulin-stimulated glucose metabolism NS Oligofructose (20g/d)Type 2diabetics for 4weeks DB Glucose and lipids NS

59Oligofructose (16g/d)Healthy,non-obese subjects for 2weeks

CRSB ?Satiety following breakfast and dinner 60?Hunger and prospective food

Oligofructose (8g/d)

Healthy,non-obese subjects for 12months

CRDB

?BMI BMI Z -score and total fat mass

61

cfu,colony-forming units;GOS,galactosyl-oligosaccharides;lcoligofructose,long-chain insulin type;NS,no signi?cant effects;?,increase;?,decrease.*C,placebo-controlled;R,randomized;DB,double-blind;SB,single-blind trial;CO,cross-over.

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The way常见用法

The way 的用法 Ⅰ常见用法： 1)the way+ that 2)the way + in which（最为正式的用法） 3)the way + 省略（最为自然的用法） 举例：I like the way in which he talks. I like the way that he talks. I like the way he talks. Ⅱ习惯用法： 在当代美国英语中，the way用作为副词的对格，“the way+ 从句”实际上相当于一个状语从句来修饰整个句子。 1)The way =as I am talking to you just the way I’d talk to my own child. He did not do it the way his friends did. Most fruits are naturally sweet and we can eat them just the way they are—all we have to do is to clean and peel them. 2）The way= according to the way/ judging from the way The way you answer the question, you are an excellent student. The way most people look at you, you’d think trash man is a monster. 3）The way =how/ how much No one can imagine the way he missed her. 4）The way =because

The way的用法及其含义(二)

The way的用法及其含义（二） 二、the way在句中的语法作用 the way在句中可以作主语、宾语或表语： 1.作主语 The way you are doing it is completely crazy.你这个干法简直发疯。 The way she puts on that accent really irritates me. 她故意操那种口音的样子实在令我恼火。The way she behaved towards him was utterly ruthless. 她对待他真是无情至极。 Words are important, but the way a person stands, folds his or her arms or moves his or her hands can also give us information about his or her feelings. 言语固然重要,但人的站姿,抱臂的方式和手势也回告诉我们他(她)的情感。 2.作宾语 I hate the way she stared at me.我讨厌她盯我看的样子。 We like the way that her hair hangs down.我们喜欢她的头发笔直地垂下来。 You could tell she was foreign by the way she was dressed. 从她的穿著就可以看出她是外国人。 She could not hide her amusement at the way he was dancing. 她见他跳舞的姿势，忍俊不禁。 3.作表语 This is the way the accident happened.这就是事故如何发生的。 Believe it or not, that's the way it is. 信不信由你, 反正事情就是这样。 That's the way I look at it, too. 我也是这么想。 That was the way minority nationalities were treated in old China. 那就是少数民族在旧中

(完整版)the的用法

定冠词the的用法： 定冠词the与指示代词this ,that同源,有“那(这)个”的意思,但较弱,可以和一个名词连用,来表示某个或某些特定的人或东西. (1)特指双方都明白的人或物 Take the medicine.把药吃了. (2)上文提到过的人或事 He bought a house.他买了幢房子. I've been to the house.我去过那幢房子. (3)指世界上独一无二的事物 the sun ,the sky ,the moon, the earth (4)单数名词连用表示一类事物 the dollar 美元 the fox 狐狸 或与形容词或分词连用,表示一类人 the rich 富人 the living 生者 (5)用在序数词和形容词最高级,及形容词等前面 Where do you live?你住在哪? I live on the second floor.我住在二楼. That's the very thing I've been looking for.那正是我要找的东西. (6)与复数名词连用,指整个群体 They are the teachers of this school.(指全体教师) They are teachers of this school.(指部分教师) (7)表示所有,相当于物主代词,用在表示身体部位的名词前 She caught me by the arm.她抓住了我的手臂. (8)用在某些有普通名词构成的国家名称,机关团体,阶级等专有名词前 the People's Republic of China 中华人民共和国 the United States 美国 (9)用在表示乐器的名词前 She plays the piano.她会弹钢琴. (10)用在姓氏的复数名词之前,表示一家人 the Greens 格林一家人(或格林夫妇) (11)用在惯用语中 in the day, in the morning... the day before yesterday, the next morning... in the sky... in the dark... in the end... on the whole, by the way...

“the way+从句”结构的意义及用法

“tｈｅwａｙ+从句”结构的意义及用法 首先让我们来看下面这个句子: Ｒead the foｌloｗｉnｇpassagｅａnd talkａbout ｉt wi ｔh your classmaｔes．Try tｏｔeｌl whaｔyｏu thiｎk ｏf Tom aｎd ｏｆｔhe ｗay the chiｌｄrenｔrｅated ｈim. 在这个句子中，ｔhe waｙ是先行词,后面是省略了关系副词that或in whｉch的定语从句。 下面我们将叙述“the ｗaｙ+从句”结构的用法。 1.tｈe wａy之后，引导定语从句的关系词是tｈat而不是hoｗ,因此，<<现代英语惯用法词典＞＞中所给出的下面两个句子是错误的：Ｔhｉs is ｔｈeｗayｈowｉtｈａppened. This is the way how he ａlwａｙs treats me. 2．在正式语体中,thaｔ可被in which所代替;在非正式语体中，ｔhat则往往省略。由此我们得到theｗay后接定语从句时的三种模式：1) tｈe ｗaｙ＋ｔhａt-从句２）the way +ｉn whiｃh－从句3) the ｗay +从句 例如：Ｔｈe way(in whiｃh ，thａt) ｔhｅｓｅｃomｒade ｓloｏｋａｔｐrobｌems is wrong．这些同志看问题的方法

不对。 Ｔｈｅｗａy(that ,ｉn ｗhiｃh)yoｕ’ｒe doinｇit is comple ｔeｌy crａzy.你这么个干法,简直发疯。 Wｅａdmiｒｅd him for thｅｗay ｉｎｗhｉch he fａｃeｓdiｆficultieｓ． Waｌlａｃe ａｎd Ｄarwiｎｇreed ｏn the way ｉｎwhi ｃh ｄｉfｆｅrｅnt forms ｏf life had ｂegｕn.华莱士和达尔文对不同类型的生物是如何起源的持相同的观点。 Thｉs is ｔｈe ｗaｙ（tｈａｔ) hｅdｉd it. I lｉkeｄｔhe waｙ(ｔhat) ｓｈeｏｒganized ｔhe ｍeetｉng． 3.theｗay(tｈat)有时可以与hｏw(作“如何”解）通用。例如： That’s tｈe ｗaｙ(tｈaｔ) shｅspoke. = Tｈat’s how shｅspoke.

way 用法

表示“方式”、“方法”，注意以下用法： 1.表示用某种方法或按某种方式，通常用介词in(此介词有时可省略)。如： Do it (in) your own way. 按你自己的方法做吧。 Please do not talk (in) that way. 请不要那样说。 2.表示做某事的方式或方法，其后可接不定式或of doing sth。 如： It’s the best way of studying [to study] English. 这是学习英语的最好方法。 There are different ways to do [of doing] it. 做这事有不同的办法。 3.其后通常可直接跟一个定语从句(不用任何引导词)，也可跟由that 或in which 引导的定语从句，但是其后的从句不能由how 来引导。如： 我不喜欢他说话的态度。 正：I don’t like the way he spoke. 正：I don’t like the way that he spoke. 正：I don’t like the way in which he spoke. 误：I don’t like the way how he spoke. 4.注意以下各句the way 的用法： That’s the way (=how) he spoke. 那就是他说话的方式。 Nobody else loves you the way(=as) I do. 没有人像我这样爱你。 The way (=According as) you are studying now, you won’tmake much progress. 根据你现在学习情况来看，你不会有多大的进步。 2007年陕西省高考英语中有这样一道单项填空题： ——I think he is taking an active part insocial work. ——I agree with you_____. A、in a way B、on the way C、by the way D、in the way 此题答案选A。要想弄清为什么选A，而不选其他几项，则要弄清选项中含way的四个短语的不同意义和用法，下面我们就对此作一归纳和小结。 一、in a way的用法 表示：在一定程度上，从某方面说。如： In a way he was right.在某种程度上他是对的。注：in a way也可说成in one way。 二、on the way的用法 1、表示：即将来(去)，就要来(去)。如： Spring is on the way.春天快到了。 I'd better be on my way soon.我最好还是快点儿走。 Radio forecasts said a sixth-grade wind was on the way.无线电预报说将有六级大风。 2、表示：在路上，在行进中。如： He stopped for breakfast on the way.他中途停下吃早点。 We had some good laughs on the way.我们在路上好好笑了一阵子。 3、表示：(婴儿)尚未出生。如： She has two children with another one on the way.她有两个孩子，现在还怀着一个。 She's got five children，and another one is on the way.她已经有5个孩子了，另一个又快生了。 三、by the way的用法

The way的用法及其含义(一)

The way的用法及其含义（一） 有这样一个句子：In 1770 the room was completed the way she wanted. 1770年，这间琥珀屋按照她的要求完成了。 the way在句中的语法作用是什么？其意义如何？在阅读时，学生经常会碰到一些含有the way 的句子，如：No one knows the way he invented the machine. He did not do the experiment the way his teacher told him.等等。他们对the way 的用法和含义比较模糊。在这几个句子中，the way之后的部分都是定语从句。第一句的意思是，“没人知道他是怎样发明这台机器的。”the way的意思相当于how；第二句的意思是，“他没有按照老师说的那样做实验。”the way 的意思相当于as。在In 1770 the room was completed the way she wanted.这句话中，the way也是as的含义。随着现代英语的发展，the way的用法已越来越普遍了。下面，我们从the way的语法作用和意义等方面做一考查和分析： 一、the way作先行词，后接定语从句 以下3种表达都是正确的。例如：“我喜欢她笑的样子。” 1. the way+ in which +从句 I like the way in which she smiles. 2. the way+ that +从句 I like the way that she smiles. 3. the way + 从句(省略了in which或that) I like the way she smiles. 又如：“火灾如何发生的，有好几种说法。” 1. There were several theories about the way in which the fire started. 2. There were several theories about the way that the fire started.

way 的用法

way 的用法 【语境展示】 1. Now I’ll show you how to do the experiment in a different way. 下面我来演示如何用一种不同的方法做这个实验。 2. The teacher had a strange way to make his classes lively and interesting. 这位老师有种奇怪的办法让他的课生动有趣。 3. Can you tell me the best way of working out this problem? 你能告诉我算出这道题的最好方法吗？ 4. I don’t know the way (that / in which) he helped her out. 我不知道他用什么方法帮助她摆脱困境的。 5. The way (that / which) he talked about to solve the problem was difficult to understand. 他所谈到的解决这个问题的方法难以理解。 6. I don’t like the way that / which is being widely used for saving water. 我不喜欢这种正在被广泛使用的节水方法。 7. They did not do it the way we do now. 他们以前的做法和我们现在不一样。 【归纳总结】 ●way作“方法，方式”讲时，如表示“以……方式”，前面常加介词in。如例1； ●way作“方法，方式”讲时，其后可接不定式to do sth.，也可接of doing sth. 作定语，表示做某事的方法。如例2，例3；

the-way-的用法讲解学习

t h e-w a y-的用法

The way 的用法 "the way+从句"结构在英语教科书中出现的频率较高, the way 是先行词, 其后是定语从句.它有三种表达形式:1) the way+that 2)the way+ in which 3)the way + 从句(省略了that或in which),在通常情况下, 用in which 引导的定语从句最为正式,用that的次之,而省略了关系代词that 或 in which 的, 反而显得更自然,最为常用.如下面三句话所示,其意义相同. I like the way in which he talks. I like the way that he talks. I like the way he talks. 一.在当代美国英语中,the way用作为副词的对格,"the way+从句"实际上相当于一个状语从句来修饰全句. the way=as 1)I'm talking to you just the way I'd talk to a boy of my own. 我和你说话就象和自己孩子说话一样. 2)He did not do it the way his friend did. 他没有象他朋友那样去做此事. 3)Most fruits are naturally sweet and we can eat them just the way they are ----all we have to do is clean or peel them . 大部分水果天然甜润,可以直接食用,我们只需要把他们清洗一下或去皮.

way的用法总结大全

way的用法总结大全 way的用法你知道多少，今天给大家带来way的用法，希望能够帮助到大家，下面就和大家分享，来欣赏一下吧。 way的用法总结大全 way的意思 n. 道路,方法,方向,某方面 adv. 远远地，大大地 way用法 way可以用作名词 way的基本意思是“路,道,街,径”,一般用来指具体的“路,道路”,也可指通向某地的“方向”“路线”或做某事所采用的手段,即“方式,方法”。way还可指“习俗,作风”“距离”“附近,周围”“某方面”等。 way作“方法,方式,手段”解时,前面常加介词in。如果way前有this, that等限定词,介词可省略,但如果放在句首,介词则不可省略。

way作“方式,方法”解时,其后可接of v -ing或to- v 作定语,也可接定语从句,引导从句的关系代词或关系副词常可省略。 way用作名词的用法例句 I am on my way to the grocery store.我正在去杂货店的路上。 We lost the way in the dark.我们在黑夜中迷路了。 He asked me the way to London.他问我去伦敦的路。 way可以用作副词 way用作副词时意思是“远远地,大大地”,通常指在程度或距离上有一定的差距。 way back表示“很久以前”。 way用作副词的用法例句 It seems like Im always way too busy with work.我工作总是太忙了。 His ideas were way ahead of his time.他的思想远远超越了他那个时代。 She finished the race way ahead of the other runners.她第一个跑到终点,远远领先于其他选手。 way用法例句

the_way的用法大全教案资料

t h e_w a y的用法大全

The way 在the way+从句中, the way 是先行词, 其后是定语从句.它有三种表达形式:1) the way+that 2)the way+ in which 3)the way + 从句(省略了that或in which),在通常情况下, 用in which 引导的定语从句最为正式,用that的次之,而省略了关系代词that 或 in which 的, 反而显得更自然,最为常用.如下面三句话所示,其意义相同. I like the way in which he talks. I like the way that he talks. I like the way he talks. 如果怕弄混淆，下面的可以不看了 另外，在当代美国英语中,the way用作为副词的对格,"the way+从句"实际上相当于一个状语从句来修饰全句. the way=as 1)I'm talking to you just the way I'd talk to a boy of my own. 我和你说话就象和自己孩子说话一样. 2)He did not do it the way his friend did. 他没有象他朋友那样去做此事. 3)Most fruits are naturally sweet and we can eat them just the way they are ----all we have to do is clean or peel them . 大部分水果天然甜润,可以直接食用,我们只需要把他们清洗一下或去皮. the way=according to the way/judging from the way 4)The way you answer the qquestions, you must be an excellent student. 从你回答就知道,你是一个优秀的学生. 5)The way most people look at you, you'd think a trashman was a monster. 从大多数人看你的目光中,你就知道垃圾工在他们眼里是怪物. the way=how/how much 6)I know where you are from by the way you pronounce my name. 从你叫我名字的音调中,我知道你哪里人. 7)No one can imaine the way he misses her. 人们很想想象他是多么想念她. the way=because 8) No wonder that girls looks down upon me, the way you encourage her. 难怪那姑娘看不起我, 原来是你怂恿的

the way 的用法

The way 的用法 "the way+从句"结构在英语教科书中出现的频率较高, the way 是先行词, 其后是定语从句.它有三种表达形式:1) the way+that 2)the way+ in which 3)the way + 从句(省略了that或in which),在通常情况下, 用in which 引导的定语从句最为正式,用that的次之,而省略了关系代词that 或in which 的, 反而显得更自然,最为常用.如下面三句话所示,其意义相同. I like the way in which he talks. I like the way that he talks. I like the way he talks. 一.在当代美国英语中,the way用作为副词的对格,"the way+从句"实际上相当于一个状语从句来修饰全句. the way=as 1)I'm talking to you just the way I'd talk to a boy of my own. 我和你说话就象和自己孩子说话一样. 2)He did not do it the way his friend did. 他没有象他朋友那样去做此事. 3)Most fruits are naturally sweet and we can eat them just the way they are ----all we have to do is clean or peel them . 大部分水果天然甜润,可以直接食用,我们只需要把他们清洗一下或去皮.

the way=according to the way/judging from the way 4)The way you answer the qquestions, you must be an excellent student. 从你回答就知道,你是一个优秀的学生. 5)The way most people look at you, you'd think a trashman was a monster. 从大多数人看你的目光中,你就知道垃圾工在他们眼里是怪物. the way=how/how much 6)I know where you are from by the way you pronounce my name. 从你叫我名字的音调中,我知道你哪里人. 7)No one can imaine the way he misses her. 人们很想想象他是多么想念她. the way=because 8) No wonder that girls looks down upon me, the way you encourage her. 难怪那姑娘看不起我, 原来是你怂恿的 the way =while/when(表示对比) 9)From that day on, they walked into the classroom carrying defeat on their shoulders the way other students carried textbooks under their arms. 从那天起,其他同学是夹着书本来上课,而他们却带着"失败"的思想负担来上课.

The way的用法及其含义(三)

The way的用法及其含义（三） 三、the way的语义 1. the way=as（像） Please do it the way I’ve told you.请按照我告诉你的那样做。 I'm talking to you just the way I'd talk to a boy of my own.我和你说话就像和自己孩子说话一样。 Plant need water the way they need sun light. 植物需要水就像它们需要阳光一样。 2. the way=how（怎样，多么） No one can imagine the way he misses her.没人能够想象出他是多么想念她！ I want to find out the way a volcano has formed.我想弄清楚火山是怎样形成的。 He was filled with anger at the way he had been treated.他因遭受如此待遇而怒火满腔。That’s the way she speaks.她就是那样讲话的。 3. the way=according as （根据） The way you answer the questions, you must be an excellent student.从你回答问题来看，你一定是名优秀的学生。 The way most people look at you, you'd think a trash man was a monster.从大多数人看你的目光中,你就知道垃圾工在他们眼里是怪物。 The way I look at it, it’s not what you do that matters so much.依我看，重要的并不是你做什么。 I might have been his son the way he talked.根据他说话的样子，好像我是他的儿子一样。One would think these men owned the earth the way they behave.他们这样行动，人家竟会以为他们是地球的主人。

way的用法

一．Way：“方式”、“方法” 1.表示用某种方法或按某种方式 Do it (in) your own way. Please do not talk (in) that way. 2.表示做某事的方式或方法 It’s the best way of studying [to study] English.。 There are different ways to do [of doing] it. 3.其后通常可直接跟一个定语从句(不用任何引导词)，也可跟由that 或in which 引导的定语从句 正：I don’t like the way he spoke. I don’t like the way that he spoke. I don’t like the way in which he spoke.误：I don’t like the way how he spoke. 4. the way 的从句 That’s the way (=how) he spoke. I know where you are from by the way you pronounce my name. That was the way minority nationalities were treated in old China. Nobody else loves you the way(=as) I do. He did not do it the way his friend did. 二．固定搭配 1. In a/one way：In a way he was right. 2. In the way /get in one’s way I'm afraid your car is in the way， If you are not going to help，at least don't get in the way. You'll have to move－you're in my way. 3. in no way Theory can in no way be separated from practice. 4. On the way (to……) Let’s wait a few moments. He is on the way Spring is on the way. Radio forecasts said a sixth-grade wind was on the way. She has two children with another one on the way. 5. By the way By the way，do you know where Mary lives? 6. By way of Learn English by way of watching US TV series. 8. under way 1. Elbow one’s way He elbowed his way to the front of the queue. 2. shoulder one’s way 3. feel one‘s way 摸索着向前走；We couldn’t see anything in the cave, so we had to feel our way out 4. fight/force one’s way 突破。。。而前进The surrounded soldiers fought their way out. 5.. push/thrust one‘s way（在人群中）挤出一条路He pushed his way through the crowd. 6. wind one’s way 蜿蜒前进 7. lead the way 带路，领路；示范 8. lose one‘s way 迷失方向 9. clear the way 排除障碍，开路迷路 10. make one’s way 前进，行进The team slowly made their way through the jungle.

the way的用法大全

在the way+从句中, the way 是先行词, 其后是定语从句.它有三种表达形式:1) the way+that 2)the way+ in which 3)the way + 从句(省略了that或in which),在通常情况下, 用in which 引导的定语从句最为正式,用that的次之,而省略了关系代词that 或in which 的, 反而显得更自然,最为常用.如下面三句话所示,其意义相同. I like the way in which he talks. I like the way that he talks. I like the way he talks. 如果怕弄混淆，下面的可以不看了 另外，在当代美国英语中,the way用作为副词的对格,"the way+从句"实际上相当于一个状语从句来修饰全句. the way=as 1)I'm talking to you just the way I'd talk to a boy of my own. 我和你说话就象和自己孩子说话一样. 2)He did not do it the way his friend did. 他没有象他朋友那样去做此事. 3)Most fruits are naturally sweet and we can eat them just the way they are ----all we have to do is clean or peel them . 大部分水果天然甜润,可以直接食用,我们只需要把他们清洗一下或去皮. the way=according to the way/judging from the way 4)The way you answer the qquestions, you must be an excellent student. 从你回答就知道,你是一个优秀的学生. 5)The way most people look at you, you'd think a trashman was a monster. 从大多数人看你的目光中,你就知道垃圾工在他们眼里是怪物. the way=how/how much 6)I know where you are from by the way you pronounce my name. 从你叫我名字的音调中,我知道你哪里人. 7)No one can imaine the way he misses her. 人们很想想象他是多么想念她. the way=because 8) No wonder that girls looks down upon me, the way you encourage her. 难怪那姑娘看不起我, 原来是你怂恿的 the way =while/when(表示对比) 9)From that day on, they walked into the classroom carrying defeat on their shoulders the way other students carried textbooks under their arms.

“the-way+从句”结构的意义及用法知识讲解

“the way+从句”结构的意义及用法 首先让我们来看下面这个句子： Read the following passage and talk about it with your classmates. Try to tell what you think of Tom and of the way the children treated him. 在这个句子中，the way是先行词，后面是省略了关系副词that 或in which的定语从句。 下面我们将叙述“the way+从句”结构的用法。 1．the way之后，引导定语从句的关系词是that而不是how,因此，<<现代英语惯用法词典>>中所给出的下面两个句子是错误的：This is the way how it happened. This is the way how he always treats me. 2. 在正式语体中，that可被in which所代替；在非正式语体中，that则往往省略。由此我们得到the way后接定语从句时的三种模式：1) the way +that-从句2) the way +in which-从句3) the way +从句 例如：The way(in which ,that) these comrades look at problems is wrong.这些同志看问题的方法不对。

The way(that ,in which)you’re doing it is completely crazy.你这么个干法，简直发疯。 We admired him for the way in which he faces difficulties. Wallace and Darwin greed on the way in which different forms of life had begun.华莱士和达尔文对不同类型的生物是如何起源的持相同的观点。 This is the way (that) he did it. I liked the way (that) she organized the meeting. 3.the way(that)有时可以与how(作“如何”解)通用。例如： That’s the way (that) she spoke. = That’s how she spoke. I should like to know the way/how you learned to master the fundamental technique within so short a time. 4．the way的其它用法：以上我们讲的都是用作先行词的the way，下面我们将叙述它的一些用法。

定冠词the的12种用法

定冠词the的12种用法 定冠词the 的12 种用法，全知道?快来一起学习吧。下面就和大家分享，来欣赏一下吧。 定冠词the 的12 种用法，全知道? 定冠词the用在各种名词前面，目的是对这个名词做个记号，表示它的特指属性。所以在词汇表中，定冠词the 的词义是“这个，那个，这些，那些”，可见，the 即可以放在可数名词前，也可以修饰不可数名词，the 后面的名词可以是单数，也可以是复数。 定冠词的基本用法： (1) 表示对某人、某物进行特指，所谓的特指就是“不是别的，就是那个!”如： The girl with a red cap is Susan. 戴了个红帽子的女孩是苏珊。 (2) 一旦用到the，表示谈话的俩人都知道说的谁、说的啥。如：

The dog is sick. 狗狗病了。(双方都知道是哪一只狗) (3) 前面提到过的，后文又提到。如： There is a cat in the tree.Thecat is black. 树上有一只猫，猫是黑色的。 (4) 表示世界上唯一的事物。如： The Great Wall is a wonder.万里长城是个奇迹。(5) 方位名词前。如： thenorth of the Yangtze River 长江以北地区 (6) 在序数词和形容词最高级的前面。如： Who is the first?谁第一个? Sam is the tallest.山姆最高。 但是不能认为，最高级前必须加the，如： My best friend. 我最好的朋友。 (7) 在乐器前。如： play the flute 吹笛子

Way的用法

Way用法 A:I think you should phone Jenny and say sorry to her. B:_______. It was her fault. A. No way B. Not possible C. No chance D. Not at all 说明：正确答案是A. No way，意思是“别想！没门！决不！” 我认为你应该打电话给珍妮并向她道歉。 没门！这是她的错。 再看两个关于no way的例句： （1）Give up our tea break? NO way! 让我们放弃喝茶的休息时间？没门儿！ （2）No way will I go on working for that boss. 我决不再给那个老板干了。 way一词含义丰富，由它构成的短语用法也很灵活。为了便于同学们掌握和用好它，现结合实例将其用法归纳如下： 一、way的含义 1. 路线

He asked me the way to London. 他问我去伦敦的路。 We had to pick our way along the muddy track. 我们不得不在泥泞的小道上择路而行。 2. （沿某）方向 Look this way, please. 请往这边看。 Kindly step this way, ladies and gentlemen. 女士们、先生们，请这边走。 Look both ways before crossing the road. 过马路前向两边看一看。 Make sure that the sign is right way up. 一定要把符号的上下弄对。 3. 道、路、街，常用以构成复合词 a highway（公路），a waterway（水路），a railway（铁路），wayside（路边）

way与time的特殊用法

way/time的特殊用法 1、当先行词是way意思为”方式.方法”的时候,引导定语从句的关系词有下列3种形式： Way在从句中做宾语 The way that / which he explained to us is quite simple. Way在从句中做状语 The way t hat /in which he explained the sentence to us is quite simple. 2、当先行词是time时,若time表示次数时,应用关系代词that引导定语从句,that可以省略; 若time表示”一段时间”讲时,应用关系副词when或介词at/during + which引导定语从句 1.Is this factory _______ we visited last year? 2.Is this the factory-------we visited last year? A. where B in which C the one D which 3. This is the last time _________ I shall give you a lesson. A. when B that C which D in which 4.I don’t like the way ________ you laugh at her. A . that B on which C which D as 5.He didn’t understand the wa y ________ I worked out the problem. A which B in which C where D what 6.I could hardly remember how many times----I’ve failed. A that B which C in which D when 7.This is the second time--------the president has visited the country. A which B where C that D in which 8.This was at a time------there were no televisions, no computers or radios. A what B when C which D that