J Gastroenterol 2007; 42[Suppl XVII]:41–47
DOI 10.1007/s00535-006-1925-8
Reprint requests to: R.C. Spiller
Role of infection in irritable bowel syndrome
R obin C. S piller
Wolfson Digestive Diseases Centre, University Hospital, Nottingham NG7 2UH, UK
Introduction
Normal ?ora and host defenses
The normal gut is host to several kilograms of bacteria,most of which reside in the colon. Bacterial counts in the stomach number 101–2 colony-forming units (cfu)/ml,while in the jejunum 103–4cfu/ml, largely of pharyngeal organisms, is normal. As one progresses toward the ileocecal valve, counts rise, and within the ileum 105–6 is normal. However, at the ileocecal valve, there is an abrupt increase in numbers, which rise to 1010–13cfu/ml,with a marked change in the nature of organisms, which become anaerobic/facultative anaerobic, with coliforms and anaerobes predominating. Throughout the gut,there are extensive innate defensive mechanisms, which include both gastric acid, bile, lysozyme, and defensins in the upper gut and tight intraepithelial junctions and mucus layers in the lower gut. There is also an acquired immunity based on immunoglobulin secretion (mainly IgA) and cell-mediated responses. Breaches of these defenses by pathogenic organisms produce acute in?ammation with release of cytokines and recruitment of circulating in?ammatory cells. In addition to breaches in the epithelium, there is also extensive dam-age to the lamina propria and submucosa together with the associated nerves. During the process of healing, metaplastic changes occur with increases in enteroendocrine cells, Paneth cells, and chronic in?ammatory cells.1 Furthermore, remodeled nerves often show aberrant expression of receptors and neuropeptides.2
Symptoms of postinfectious irritable bowel syndrome While most patients rapidly recover from infectious gas-troenteritis, about a quarter show persistent distur-bance of bowel habit at 6 months, most commonly increased stool frequency.3 A much smaller number,
Infection by pathogenic organisms leads to mucosal damage and disruption of the gut’s extensive commen-sal ?ora, factors which may lead to prolonged bowel dysfunction. Six to 17% of unselected irritable bowel syndrome (IBS) patients believe their symptoms began with an infection, which is supported by prospective studies showing a 4%–31% incidence of postinfectious IBS-(PI) sfollowing bacterial gastroenteritis. The wide range of incidence can be accounted for by differences in risk factors, which include in order of magnitude;severity of initial illness > bacterial toxigenicity > hypo-chondriasis, depression and neuroticism, and adverse life events in the previous 3 months. PI-IBS has been reported after Campylobacter , Salmonella , and Shigella infections. Serial biopsies after Campylobacter jejuni gastroenteritis show an initial in?ammatory in?ltrate,with an increase in enterochromaf?n (EC) cells, which in most cases subsides over the next 6 months. Those who go on to develop IBS show increased numbers of EC and lymphocyte cell counts at 3 months compared with those who do not develop IBS. Interleukin-1βmRNA levels are increased in the mucosa of those who develop PI-IBS, who also show increased gut perme-ability. Recover can be slow, with approximately 50%still having symptoms at 5 years. Recent studies suggest an increase in peripheral blood mononuclear cell cytokine production in unselected IBS, an abnormality that may be ameliorated by probiotic treatment. The role of small-bowel bacterial overgrowth in IBS is con-troversial, but broad-spectrum antibiotics do have a temporary bene?t in some patients. More acceptable long-term treatments altering gut ?ora are awaited with interest.
Key words: irritable bowel syndrome, infection,
in?ammation
about 10% on average, develop persistent symptoms that meet the Rome II criteria for the diagnosis of irri-table bowel syndrome (IBS), namely abdominal pain and discomfort that is relieved by defecation and/or associated with a change in the stool form or consis-tency.4 Such patients often undergo extensive investiga-tions to exclude disorders of malabsorption and in?ammation. Although there are quantitative changes in mucosal immunocytes, these still lie within the nor-mal range and would be judged normal by most experi-enced histopathologists.
Postinfectious (PI)-IBS is a useful model for under-standing the mechanisms in IBS because it appears in patients with otherwise normal bowel patterns. It is es-sentially a natural experiment, since infection is largely a random event. Compared with other IBS patients, there is a clearly de?ned start date, and symptoms tend to be more homogeneous. Compared with “non-PI-IBS,” the role of psychological abnormalities is less in PI-IBS, with only 25% reporting a history of prior treat-ment for anxiety or depression, compared with nearly 50% in non-PI-IBS.5
De?nition of clinical PI-IBS in clinical practice
Many patients acquire gastroenteritis while away from home, where they encounter ?ora they are otherwise not familiar with. Under these circumstances, it is not uncommon to lack a positive stool culture. Therefore, a useful clinical de?nition of PI-IBS, which we have used before,6 is as follows:
New onset of IBS symptoms meeting the Rome crite-ria, developing acutely after an illness characterized by two or more of the following:
1.fever
2.vomiting
3.acute diarrhea
4.positive stool culture.
The clinical features of PI-IBS are bloating, loose and watery stools, urgency, and the passage of mucus per rectum.3 The incidence of PI-IBS varies according to the series, from as low as 7% to as high as 31%, though the largest studies seem to agree on around 10% (Table 1). It has been reported after Salmonella, Shigella, and Campylobacter gastroenteritis and appears to be a nonspeci?c response. These studies come from Canada, Spain, Korea, China, and the United Kingdom, so PI-IBS does not appear to be unique to any speci?c coun-try or race.
Risk factors for developing PI-IBS
Risk factors include both central and peripheral compo-nents. Peripheral components probably re?ect the se-verity of the mucosal lesion, while central components re?ect past and present psychosocial factors.
Severity of initial injury
One measure of severity is the duration of the initial diarrheal illness. Diarrhea lasting more than 3 weeks gives a relative risk of 11.4 [95% con?dence interval (CI), 2.2–58] compared with diarrhea lasting less than 7 days,3 while in another study a duration of >14 days gave a relative risk of 4.6 (95% CI, 2.1–9.9).7 Speci?c bacte-rial factors cannot be readily compared between spe-cies, but within the Campylobacter species, the presence of an “elongating toxin,” as de?ned by its effect on cultured cell lines, gave a relative risk of 12.8 (95% CI, 1.6–101) for the development of persistent bowel dys-function.8During the healing process, changes in the epithelium are also predictive of the development of PI-IBS, with each one standard deviation increase in enterochromaf?n (EC) cell counts giving a 3.2-fold (95% CI, 1.8–8.2) increase in risk of developing
Table 1.Incidence of postinfectious irritable bowel syndrome
Prospective
studies on
bacterial PI-IBS Follow-up
gastroenteritis(%)(months)n Organism Location McKendrick, 1994311238Salmonella Shef?eld, UK Gwee et al., 199********Mixed Shef?eld, UK Neal et al., 1997376390Bacterial Nottingham, UK Thornley et al., 2001896180 C. jejuni Nottingham, UK Dunlop et al., 20039136747 C. jejuni Nottingham, UK Wang et al., 20047812–24295Shigella Beijing, China Ji, 200576101Shigella Seoul, Korea Mearin, 20051212677Salmonella Catalonia, Spain PI-IBS, postinfectious irritable bowel syndrome; C. jejuni, Campylobacter jejuni
postinfectious symptoms.9EC counts correlate closely with other in?ammatory cells, including lymphocytes, which in animal models drive EC hyperplasia,10 so it is likely that other in?ammatory markers would show similar relationships.
Host factors
Host factors include female sex, which gives a two- to threefold increased risk,3,11 and age >60, which gives a protective effect, with a relative risk of just 0.36 (95% CI, 0.1–0.9).3 Older subjects may have acquired immu-nity, but they also have fewer immunocytes in their rectal mucosa12and may be less reactive to infection. Women show no difference in mucosal immunocyte numbers,12 and it appears, when a multivariate analysis is done, that the sex effect is spurious, owing to confounding by psychological disturbances, which are commoner in women. When these are included in a multivariate model, sex no longer has a predictive effect.11,9
Psychological factors
The presence of depression, which correlates closely with anxiety, gives a relative risk of 3.2 (95% CI, 1.8–8.2)9 for each standard deviation increase in the score on the Hospital and Anxiety Scale,13while hypochon-driasis gives a relative risk of 2.0 (95% CI, 1.7–2.5).14 Gwee et al.11 also found that the presence of adverse life events in the previous 3 months doubled the risk of persistent symptoms, relative risk 2.0 (95% CI, 1.7–2.4). Thus, as with other IBSs, there is an interaction be-tween central and peripheral components, which no doubt varies between patients and accounts for the het-erogeneity between different series, both in symptoms and response to treatment.
Histological changes following infection
Serial biopsy studies show an initial in?ammatory response with increases in CD3 lymphocytes, CD8 intraepithelial lymphocytes, and calprotectin-positive macrophages.1These changes rapidly decline in most subjects, but a small number with persistent symptoms fail to show this decline.1One of the most striking abnormalities is the increased numbers of serotonin-containing EC cells. These are found in the crypts, where on stimulation they release serotonin into the lamina propria. There, the serotonin acts on receptors on both nerve endings and enterocytes. Relevant stimuli include adrenergic stimuli as well as bacterial toxins such as cholera and Escherichia coli enterotoxins and distortion by intraluminal pressure. Recent studies using isolated enteroendocrine cells indicate the pres-ence of numerous receptors, which allow these cells to integrate many different stimuli.15 Patients who develop PI-IBS have a 20% increase in EC cells when assessed 3 months after infection9and a switch in the ratio of 5-hydroxytryptamine (5HT)/peptide YY (PYY)-containing enteroendocrine cells so that 5HT is the pre-dominant component of enteroendocrine granules after the infection, whereas before PYY predominates.1 Abnormalities of serotonin metabolism in PI-IBS
As well as increased numbers, there is evidence of in-creased release of 5HT following a test meal, as can be ascertained from measuring 5HT in platelet-poor plasma (PPP). Compared with controls, PI-IBS patients show increased 5HT in PPP after a 520-Kcal spaghetti-on-toast meal (Fig. 1). These levels are signi?cantly greater than in either controls or constipated IBS pa-tients. Although this may re?ect an increased release from the gut, the origin of 5HT in PPP is unclear, since 5HT is rapidly taken up by platelets and only a very small fraction of 5HT released in the gut is likely to reach peripheral blood. An alternative explanation for the elevated levels is an impairment of the serotonin transporter affecting both the gut and platelets. The action of 5HT is rapidly terminated by the active uptake of this sodium-linked transporter. In the mucosa, the enterocytes provide the largest uptake capacity, where serotonin is metabolized by intracellular monoamine oxidases to 5-hydroxyindoleacetic acid (5HIAA). This water-soluble molecule is then excreted in the urine. Several studies have shown elevation of both plasma 5HT and 5HIAA following a meal in IBS patients with diarrhea.16By measuring not only 5HT levels in the blood but also those in the mucosa, it is possible to estimate the relative amount of 5HT per EC cell in different conditions. When this was done, the ratio of 5HT concentration to EC cell numbers/mm2 was found to increased in constipated IBS, in keeping with im-paired release and hence increased 5HT stores in each EC cell.17 The 5HIAA/5HT ratio in the mucosa is de-pressed both in constipated IBS and to a lesser extent in PI-IBS. The lowered 5HIAA levels are as expected in constipated IBS with a reduced 5HT turnover. How-ever, the reduced ratio in PI-IBS is unexpected given the increased release and implies either an impairment of serotonin reuptake or of enterocyte monoamine oxi-dase activity.
Abnormalities of serotonin transporter
One seminal study has shown marked impairment of serotonin transporter (SERT) immunoreactivity in rec-
tal biopsies from patients with IBS of both the diarrhea (IBS-D) and constipated (C-IBS) variety. This was as-sociated with a decrease in SERT mRNA. However,18these results are controversial, and recent attempts to reproduce them have failed, showing only a modest nonsigni?cant decrease in mRNA in IBS-D and no change in C-IBS.19 Genetic factors are known to in?uence the expression of SERT throughout the body with a promoter polymorphism that predicts reduced function when assessed in an immortalized lymphoblast cell line. Possessing either one or two shortened alleles (s ) predicts reduced serotonin uptake and has been associated with an increased susceptibility to develop depression in response to adverse life events 20 and post-traumatic stress disorder.21 This important gene by environment interaction means that the numerous cross-sectional population studies of the association of SERT polymorphisms and psychiatric disease yield inconsistent results, since they rarely include the environmental factors. Studies of IBS have also been inconsistent, but the largest suggested an excess of the ss but not of the sl genotype in IBS-D.22 However, a recent study did not show any relation between this SERT promoter polymorphism and mRNA for SERT in mucosal biopsies,19 which may suggest that this is not the relevant promoter for the gut as others have sug-gested.23 Any link therefore between this SERT poly-morphism and IBS may not be direct but mediated by its impact on psychological factors such as neuroticism and anxiety.
Evidence of gut in?ammation in IBS
Increased mucosal lymphocyte counts are associated with the development of PI-IBS.9,11 Furthermore, as Table 2 documents, there are now numerous studies that indicate that mucosal biopsies in both PI-IBS and IBS-D show increased numbers of CD3+ lymphocytes.Different researchers have looked at different classes of immunocytes, but there is broad agreement on the in-crease in CD3+ lymphocytes. Chadwick et al.24 also showed increases in CD25+ lymphocytes, indicating the presence of interleukin (IL)-2 receptor, a marker of activated lymphocytes. Other researchers have also examined the presence of mast cells (MC), which have been increased in a number of studies (Table 2). A recent study from Bologna showed increased MC in unselected IBS, which included patients with constipa-tion.25 In addition, two studies have examined the pres-ence of mRNA for IL-1β, a macrophage product that has been shown to be increased in both PI-IBS 26 and IBS-D.7 These in?ammatory cells produce cytokines,which are known to alter enteric neural function and contribute to diarrheal symptoms.27,28
Gut permeability, which is known to be increased by in?ammatory cytokines, has also been shown to be in-creased by bacterial gastroenteritis 1 and in both PI-IBS and IBS-D.29 This increase appears to be long lasting,since the Walkerton, Ontario, study of 10012 cases of infective gastroenteritis due to E. coli O157 and Campylobacter jejuni found increased permeability 2years after the infectious event in those who developed PI-IBS.30
Plasma 5HT following a 520kcal test meal in patients with IBS and healthy controls
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51=n ()51=n )
51=)
s e t u n i m (e m i t 0
010203040
506075H T (n m o l /L )
Fig. 1.Increased postprandial 5-hydroxytryptamine (5HT ) levels in platelet-poor plasma in postinfectious ir-ritable bowel syndrome (PI-IBS ). C-IBS ,constipation IBS. From Dunlop et al. Clin Gastroenterol Hepatol 2004;3:349–57.17Reproduced by kind permission of the editor of Clinical Gastroenterology &Hepatology
Evidence of systemic immune activation in IBS Peripheral blood mononuclear cell cytokine production has recently been shown to be elevated in IBS by a number of researchers.31–34 Some of these cytokine ab-normalities may be driven by psychological stress, since experimental stress has been shown to increase some cytokines, including IL-6 and interferon.35 IBS patients have also been shown to have a depressed IL-10/ IL-12 ratio compared with controls, an abnormality that is corrected by treatment with a probiotic, Bi?dobacterium infantis.32These cytokine abnormali-ties may have relevance to the extraintestinal symptoms that are often so prominent in IBS.36
Interaction between in?ammation and
impaired SERT
Several animal studies have indicated that in?ammation leads to downregulation of SERT.10,37Whether this downregulation is speci?c or merely a feature of mu-cosal injury has not been determined. The implications are that low-grade in?ammation could lead to an in-crease in mucosal serotonin availability, and this might account for the symptomatic improvement noted with 5HT
3
antagonists in IBS-D.38Alternatively, in?ammation may increase the local release of 5HT as a result of tissue injury and the release of adenosine, which is known to be capable of stimulating 5HT re-lease from EC cells.39
Small-bowel bacterial overgrowth in IBS?
There have been several reports of small-bowel bacte-rial overgrowth (SIBO) in IBS as detected using the lactulose breath test.40 The criteria used by the research-ers were somewhat inconsistent but rely on the concept that small-bowel bacterial overgrowth will result in a double peak of hydrogen excretion as the lactulose bolus encounters successfully ?rst small intestinal and then colonic bacteria. Unfortunately, as Riorden et al.41 showed using a lactulose breath test combined with scintigraphy,41 the double peak is quite unreliable. Thus, in a study of 28 patients in whom the lactulose breath hydrogen test was combined with scintigraphy and cul-ture of jejunal aspirate, the lactulose breath tests de-tected only 38% of true SIBO (jejunal culture >105cfu/ ml). Furthermore, only 17% of those with positive jeju-nal cultures showed a double peak, and single peaks were seen in 21% of subjects with true SIBO. Finally, 50% of double peaks were seen in subjects with a sterile small bowel.
However, even when the subjects studied did not have bacterial overgrowth, a randomized control trial of neomycin given for just 10 days showed a transient improvement 1 week after treatment ceased, an effect which was greatest for those whose breath hydrogen fell the most.40Others have also reported transient symp-tomatic bene?t with antibiotics such as metronidazole.42 The mechanism of bene?t is unclear, but may be similar to that seen in diets that exclude sources of poorly ab-sorbed carbohydrate, which have been shown to lead to a reduction in 24-h hydrogen and methane gas excre-tion.43 However, antibiotic treatments seem unlikely to be useful, as symptoms promptly return on stopping antibiotics and chronic antibiotic therapy is invariably associated with the development of bacterial resistance. Furthermore, other authors have suggested that the consumption of antibiotics actually increases the risk of subsequently developing IBS symptoms.44
Table 2.Histological ?ndings in mucosal biopsies in IBS of various subtypes
Author, year, type of IBS Site Mast cells CD3 lymph Macrophage EC cells Weston et al., 1993,49 IBS-D T ileum+++NA O’Sullivan et al., 2000,50 IBS-D Cecum++NA NA Gwee et al., 1999,11PI-IBS Rectum?++IL-1 mRNA↑NA Spiller et al., 2000,1PI-IBS Rectum?++++ Chadwick et al., 2002,24 IBS-D Colon?++NA Dunlop et al., 2003,5 IBS-D (not PI-IBS)Rectum++++?Dunlop et al., 2003,9PI-IBS Rectum?++++ Wang et al., 2004,7PI-IBS & IBS-D T ileum++IL-1 mRNA↑NA
Colon?+NA Barbara et al., 2004,25 C-IBS & IBS-D Colon+++NA Park et al., 2006,51 IBS-D Rectum++?IBS, irritable bowel syndrome with diarrhea; C-IBS, irritable bowel syndrome with constipation; EC, enterochromaf?n; IL, interleukin; NA, not assessed
Possible role for probiotics
A more attractive alternative would be to manipulate the colonic ?ora by the use of probiotics. These prepa-rations have a number of potentially valuable proper-ties, including the inhibition of other bacteria and the reduction of symptoms during acute infection. Further-more, some probiotics are known to exert anti-in?ammatory effects through downregulating systemic immunity.45As recent meta-analyses indicate, not all probiotics are equal,46,47but two recent large studies have suggested a symptomatic bene?t in IBS with Bi?dobacterium infantis,32,48 and in one study there was an associated normalization of the immune response.32 Whether this effect will prove useful and how to target it effectively to the right type of patient remains to be established.
Implications for treatment
Not all patients develop IBS after infection, and not all have evidence of in?ammation or abnormal ?ora. Even the best current treatment for IBS, the 5HT3 antago-nists, still have a number needed to treat of seven,38 indicating clearly that “most treatments don’t work for most patients,” to quote the chairman of a famous pharmaceutical company. As we further understand the mechanisms of IBS, the aim must be to identify easily measurable objective markers that will allow classi?cation of IBS patients into more homogenous groups in a way that current symptom-based systems do not. Only then can we expect the current poor therapeu-tic response to be improved as we target treatments to underlying causes.
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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） 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
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...
“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.
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） 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 【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；
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
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+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） 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。
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.
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 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，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/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