Altered Gut Flora Research Articles

Mercury in first-cut baby hair of children with autism versus typically-developing children

Children with autism were examined to determine amounts of mercury (Hg) in their baby hair and the factors that might affect Hg body burden. US children with autism (n = 78) and matched controls (n = 31) born between 1988 and 1999 were studied. Hg in first-cut baby hair was determined using cold vapor atomic fluorescence spectrometry (CVAFS). Twenty samples were split and also measured with Neutron Activation Analysis (NAA). Logistic regression analysis showed that compared to children with higher levels of mercury (above 0.55 mcg g−1), children with lower levels of mercury in their hair (below 0.55 mcg g−1) were 2.5-fold more likely to manifest with autism. Children with autism had similar mercury exposure as controls from maternal seafood and maternal dental amalgams. Children with autism also had 2.5-fold higher incidence of oral antibiotic use during their first 18 months of life. Their mothers were possibly more likely to use oral antibiotics during pregnancy or nursing. The amount of Hg in the baby hair of children with autism showed a significant correlation with the number of maternal dental amalgams. The lower level of Hg in the baby hair of children with autism indicates an altered metabolism of Hg, and may be due to a decreased ability to excrete Hg. This is consistent with usage of higher amounts of oral antibiotics, which are known to inhibit Hg excretion in rats due to alteration of gut flora, and may exert a similar effect in humans. Higher usage of oral antibiotics in infancy may also partially explain the high incidence of chronic gastrointestinal problems seen in individuals with autism.

Effect of the orlistat on serum endotoxin lipopolysaccharide and adipocytokines in South Asian individuals with impaired glucose tolerance

Orlistat has been shown to increase adiponectin and reduce progression to type 2 diabetes in obese Caucasians. Some effects of orlistat are thought to be independent of weight loss by altering gut flora and the production of endotoxin lipopolysaccharide (LPS). We studied the effect of dietary treatment with and without orlistat in South Asian individuals with impaired glucose tolerance (IGT) on adiponectin and inflammatory markers including LPS. South Asian individuals were randomised to either dietary treatment with orlistat or dietary treatment alone. At the end of 12 months, a comparison was made between the two groups for differences in anthropomorphic measurements and serum markers. Three hundred and five individuals underwent oral glucose tolerance test of whom 40 had IGT. Complete baseline and 1-year data was available for 31 patients. After 1 year, patients in the orlistat group demonstrated a greater but insignificant decrease in weight (4.5 +/- 0.1 kg), and a significant increase in adiponectin (6.73 +/- 3.2 microg/ml) and decrease in LPS (4.55 +/- 1.98 EU/ml) compared with- the diet-alone group. In the orlistat group the reduction in LPS was correlated with the increase in adiponectin (p < 0.005). The increase in adiponectin levels in the orlistat group would suggest that orlistat may reduce the progression to type 2 diabetes in South Asian individuals by raising serum adiponectin. The finding that LPS levels are also reduced by orlistat and that this reduction correlates with the increase in adiponectin raises the possibility that the increase in adiponectin may be mediated via an effect on LPS levels.

Probiotic use in the critically ILL

Probiotics are "live microbes which when administered in adequate amounts confer a health benefit to the host" (FAO/WHO joint group). Their potential role in bio-ecological modification of pathological internal milieu of the critically ill is under evaluation. Probiotics are available as single microbial strain (e.g., Bacillus clausii, Lactobacillus) or as a mix of multiple strains of Lactobacillus (acidophilus, sporogenes, lactis, reuteri RC-14, GG, and L. plantarum 299v), Bifidobacterium (bifidum, longum, infantis), Streptococcus (thermophillus, lactis, fecalis), Saccharomyces boulardii etc. Lactobacilli and Bifidobacteria are gram-positive, anaerobic, lactic acid bacteria. These are normal inhabitant of human gut and colonize the colon better than others. Critical illness and its treatment create hostile environment in the gut and alters the micro flora favoring growth of pathogens. Therapy with probiotics is an effort to reduce or eliminate potential pathogens and toxins, to release nutrients, antioxidants, growth factors and coagulation factors, to stimulate gut motility and to modulate innate and adaptive immune defense mechanisms via the normalization of altered gut flora. Scientific evidence shows that use of probiotics is effective in prevention and therapy of antibiotic associated diarrhea. However, available probiotics strains in currently used doses do not provide much needed early benefits, and need long-term administration to have clinically beneficial effects (viz, a reduction in rate of infection, severe sepsis, ICU stay, ventilation days and mortality) in critically ill surgical and trauma patients. Possibly, available strains do not adhere to intestinal mucosa early, or may require higher dose than what is used. Gap exists in our knowledge regarding mechanisms of action of different probiotics, most effective strains--single or multiple, cost effectiveness, risk-benefit potential, optimum dose, frequency and duration of treatment etc. More information is needed on safety profile of probiotics in immunocompromised state of the critically ill in view of rare reports of fungemia and sepsis and a trend toward possible increase in nosocomial infection. At present, despite theoretical potential benefits, available evidence is not conclusive to recommend probiotics for routine use in the critically ill.

Alterations in intestinal microbial flora and human disease

To highlight the evidence supporting the role of altered commensal gut flora in human disease. While the contribution of the indigenous gut microbial community is widely recognized, only recently has there been evidence pointing to indigenous flora in disease. This review discusses recent evidence pointing to the role of altered commensal gut flora in such common conditions as irritable bowel syndrome and inflammatory bowel disease. Recent studies document the intricate relationship between the vast population of microbes that live in our gut and the human host. Since increased intestinal permeability and immune activation are consequences of an altered host-gut microbial relationship, what are the clinical effects of this shift in relationship? We focus on the example of an abnormal expansion of gut microbial flora into the small bowel or small intestinal bacterial overgrowth and discuss the effects of bacterial overgrowth on the human host in acute pancreatitis, bacterial gastroenteritis, irritable bowel syndrome, inflammatory bowel disease, hepatic encephalopathy, and fibromyalgia and burn injury. The identification of the underlying role of altered commensal gut microbiota in these and other human diseases could lead to novel diagnostic and therapeutic strategies that would improve clinical outcome.

Thymocytes, Pre‐B Cells, and Organ Changes in a Mouse Model of Chronic Ethanol Ingestion—Absence of Subset‐Specific Glucocorticoid‐Induced Immune Cell Loss

The well-known immune deficiency of the chronic alcoholic dictates the need for a long-term rodent ethanol administration model to evaluate the baseline immunologic effects of chronic ethanol abuse, and investigate the genetic determinants of those effects. Much published work with rodents has shown clearly that acute ethanol administration and short-term ethanol-containing liquid diets both cause elevated corticosterone and can cause significant thymocyte, pre-B cell and peripheral lymphocyte losses. Such losses may mask more subtle alterations in immune homeostasis, and in any case are generally short-lived compared with the span of chronic ethanol abuse. Thus, it is important to have a model in which long-term immune alterations can be studied free of corticosteroid-induced cell losses. We have utilized chronic 20% (w/v) ethanol in water administration to several mouse strains for prolonged periods of time and evaluated serum corticosterone, immunologic stress parameters, and other organ changes by standard methods. We now confirm earlier reports that chronic ethanol in water administration to mice does not produce net elevations of corticosterone, although diurnal variation is altered. Importantly, there is neither selective loss of immune cell populations known to be corticosteroid sensitive, CD4+CD8+ thymocytes and pre-B cells, nor are changes observed in the histologic appearance of the thymus. Nonetheless, there are significant chronic ethanol effects in other tissues, including reduced heart weight, mild hepatic steatosis, alterations of gut flora, increased serum peptidoglycan, and as published elsewhere, immune system abnormalities. This model of ethanol administration is convenient, sustainable for up to 1 year, demonstrably feasible in several mouse strains, permits good weight gains in most strains, and results in significant changes in a number of organs. The administration method also will permit modeling of long-term steady abuse punctuated by major binges, and is suitable for supplementation studies using water soluble additives. Overall, the method is useful for a wide range of studies requiring a chronic low-stress method of ethanol administration.

Irritable bowel syndrome and bloating

Gaseous symptoms in irritable bowel syndrome (IBS) including eructation, flatulence, and bloating occur as a consequence of excess gas production, altered gas transit, abnormal perception of normal amounts of gas within the gastrointestinal tract, or dysfunctional somatic muscle activity in the abdominal wall. Because of the prominence of gaseous complaints in IBS, recent investigations have focussed on new insights into pathogenesis and novel therapies of bloating. The evaluation of the IBS patient with unexplained gas and bloating relies on careful exclusion of organic disease with further characterisation of the underlying condition with directed functional testing. Treatment of gaseous symptomatology in IBS should be targeted to pathophysiologic defects whenever possible. Available therapies include lifestyle alterations, dietary modifications, enzyme preparations, adsorbents and agents which reduce surface tension, treatments that alter gut flora, and drugs that modulate gut transit.

Mercury, Lead, and Zinc in Baby Teeth of Children with Autism Versus Controls

This study determined the level of mercury, lead, and zinc in baby teeth of children with autism spectrum disorder (n = 15, age 6.1 ± 2.2 yr) and typically developing children (n = 11, age = 7 ± 1.7 yr). Children with autism had significantly (2.1-fold) higher levels of mercury but similar levels of lead and similar levels of zinc. Children with autism also had significantly higher usage of oral antibiotics during their first 12 mo of life, and possibly higher usage of oral antibiotics during their first 36 mo of life. Baby teeth are a good measure of cumulative exposure to toxic metals during fetal development and early infancy, so this study suggests that children with autism had a higher body burden of mercury during fetal/infant development. Antibiotic use is known to almost completely inhibit excretion of mercury in rats due to alteration of gut flora. Thus, higher use of oral antiobiotics in the children with autism may have reduced their ability to excrete mercury, and hence may partially explain the higher level in baby teeth. Higher usage of oral antibiotics in infancy may also partially explain the high incidence of chronic gastrointestinal problems in individuals with autism.

Role of infection in irritable bowel syndrome

Infection by pathogenic organisms leads to mucosal damage and disruption of the gut's extensive commensal flora, 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) following 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 > hypochondriasis, 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 inflammatory infiltrate, with an increase in enterochromaffin (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-1beta mRNA levels are increased in the mucosa of those who develop PI-IBS, who also show increased gut permeability. 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 controversial, but broad-spectrum antibiotics do have a temporary benefit in some patients. More acceptable long-term treatments altering gut flora are awaited with interest.

The Effect of a Nonabsorbed Oral Antibiotic (Rifaximin) on the Symptoms of the Irritable Bowel Syndrome

Alterations in gut flora may be important in the pathophysiology of the irritable bowel syndrome (IBS). To determine whether the nonabsorbed antibiotic rifaximin is more effective than placebo in reducing symptoms in adults with IBS. Double-blind, randomized, placebo-controlled study. 2 tertiary care medical centers. 87 patients who met Rome I criteria for IBS and were enrolled from December 2003 to March 2005. Participants who met enrollment criteria were randomly assigned to receive 400 mg of rifaximin 3 times daily for 10 days (n = 43) or placebo (n = 44). Eighty participants completed rifaximin therapy or placebo, and follow-up data were available for at least 34 participants per study group at any time point thereafter. A questionnaire was administered before treatment and 7 days after treatment. The primary outcome was global improvement in IBS. Patients were then asked to keep a weekly symptom diary for 10 weeks. Over the 10 weeks of follow-up, rifaximin resulted in greater improvement in IBS symptoms (P = 0.020). In addition, rifaximin recipients had a lower bloating score after treatment. The major limitations of the study were its modest sample size and short duration and that most patients were from 1 center. Rifaximin improves IBS symptoms for up to 10 weeks after the discontinuation of therapy.

Advances in critical care management of hepatic failure and insufficiency

Chronic liver disease is becoming an increasingly frequent diagnosis for patients in the intensive care setting with such diagnoses as symptomatic ascites, spontaneous bacterial peritonitis, hepatorenal syndrome, or fulminant hepatic failure. To review frequent diagnoses for patients with chronic liver disease admitted to the intensive care unit and discuss current concepts in management and investigational modalities. Patients with new-onset ascites in the intensive care setting should undergo immediate ultrasound to rule out acute thrombosis. A transjugular intrahepatic portosystemic shunt is indicated when control of the refractory ascites or hepatic hydrothorax is required. In patients with hepatorenal syndrome, hemodialysis can be used as a bridge to liver transplantation. Otherwise, hepatorenal syndrome carries a high mortality. When hepatic encephalopathy is present, a precipitating cause should be sought and treated, if identified. Although bioartificial support systems are under active investigation, standard treatment for hepatic encephalopathy is lactulose and alteration of gut flora. Patients with fulminant hepatic failure should be stabilized and transferred to the intensive care unit of a liver transplant center and supported with appropriate airway management, close neurologic evaluation, glucose monitoring, and correction of coagulopathy when there is overt bleeding or an invasive procedure is planned. Intracranial pressure monitoring is recommended to maintain an adequate cerebral perfusion pressure of >60 mm Hg. Review of the literature demonstrates that certain critically ill patients with chronic liver disease may benefit from invasive modalities such as transjugular intrahepatic portosystemic shunting, hemodialysis, and in some cases, liver transplantation, which may be offered only at tertiary care centers.

Clostridium difficile Associated Disease. Acid Suppression

Purpose: There has been a recent rise in incidence of Clostridium difficile associated disease (CDAD) in hospitalized patients, especially with identification of new virulent strains. The recent wide spread use of acid suppressing agents may play an important role in altering gut flora and substantially increasing susceptibility to CDAD. The aim of this study was to identify the use of acid suppressing agents, as a risk factor, in patients diagnosed with C. difficile infection. Methods: This was a retrospective, cross sectional review of US veterans hospitalized in NY Harbor Healthcare system, over one year period (5/2005 to 5/2006). All patients with complaints of diarrhea, with positive stool toxin for Clostridium difficile over a period of one year were identified. The data was collected regarding age, gender, acid suppressing agent use and antibiotic use. Information was also gathered, whether the use of acid suppressing agent was chronic as out patient or acute as inpatient, at least 1 week prior to diagnosis of CDAD. Results: A total of 136 subjects were identified with positive stool toxin for C. difficile over a period of one year. Ninety six percent of the subjects were men. The mean age of the subjects was 71 ± 1.2 (± SEM). Seventy eight percent of patients were on acid suppressing agents: 68% were on proton pump inhibitors and 10% were on H2 receptor antagonists. In the group of subjects on acid suppressing agents 31% were on chronic acid suppression as out patient and 64% were on acid suppression during the hospitalization. Recent history of antibiotic use was present in 88% of subjects. 67% of the subjects had simultaneous use of acid suppressing agents and antibiotic use which was significantly (p <.05) higher then subjects who were either only on antibiotic or acid suppressing agent alone. Conclusions: CDAD is on the rise in hospitalized patients, especially in elderly age group. The known risk factors, age, concomitant medical condition, immune suppression, antibiotic use, have remained unchanged. The recent wide spread use of acid suppressing agents may be one of the factors, increasing the risk of acquiring Clostridium Difficile infection. We observed from our cohort analysis that combined acid suppression and antibiotic use is present in significant number of patients diagnosed with C. difficile. These results need to be further tested in a prospective randomized controlled trial.

Communication Regarding Metabonomic Identification of Two Distinct Phenotypes in Sprague-Dawley (Crl:CD(SD)) Rats

In a recent publication, we reported the identification and characterization of two distinct phenotypes in SpragueDawley rats obtained from the Charles River Raleigh facility (Robosky et al., 2005). The phenotypes were designated as HIP (high hippuric acid level in urine) and CA (high chlorogenic acid metabolites level in urine). The endogenous urinary metabolic profile of each phenotype was distinct and stable over the period from February 2004 through February 2005. The phenotypic difference is most likely due to altered gut flora that play a role in the metabolism of aromatic acids. Since this time, the phenotype was monitored in SpragueDawley rats from Charles River Raleigh facility Room 9 and Room 10 by analyzing urine samples using the same methods. The September 2005 data indicate a shift in the urinary endogenous metabolic profile of urine from Room 9 rats, previously having the CA phenotype (Fig. 1). The urinary levels of hippuric acid and chlorogenic acid metabolites are now similar in Room 9 and Room 10 rats, and the metabolite levels are characteristic of the HIP phenotype. The observed shift in the CA phenotype was not totally unexpected. A lack of ‘‘normal’’ gut flora speciation was suggested as a possible explanation of the variant CA phenotype observed in rats from Room 9 in the manuscript. It therefore seems possible that during the period from February 2005 to September 2005 a more typical gut flora was established in the Room 9 colony. Of the colonies investigated in the original manuscript, the Room 9 colony represented the most recently initiated colony (December 2002). If this hypothesis is correct, what is surprising is the length of time required for the repopulation of normal gut flora within Room 9 (several years) and the rapidity with which the phenotype changed from the aberrant phenotype (CA) to the more typical HIP phenotype (several months). These findings in no way invalidate the findings of the original manuscript and highlight a variable not often considered in toxicology studies or any other type of study for that matter. The gut flora are difficult, if not impossible, to completely characterize. However, metabonomics evaluation presents a new opportunity to indirectly measure gut flora composition and its contribution to systems biology. While the impact of gut flora on toxicology as well as other biological investigations has been recognized in principle for quite some time, we believe that this subject is entering an era of renewed interest and importance.

Probiotics in Paediatric Disorders

It is well established that alterations in gut flora are responsible for infectious diseases, especially in paediatric cases. An infant’s gut is sterile at the time of birth and the type of flora that develop depends on the type of feed provided to the newborn baby. Critical changes occur in the gut flora of an infant after birth and during weaning. Probiotics, the nutritional foods containing live microbes, effectively modulate gut flora and have been shown to have beneficial effects in a multitude of paediatric disorders. This review encompasses information regarding the development of intestinal flora in neonates, various paediatric disorders related to abnormal gut flora and application of probiotics in paediatric disorders and the mode of action of probiotics. We also outline a plethora of microbial strains and paediatric commercial patented preparations. The safety profile and tolerability of probiotics is also discussed at length. Future research will need to focus on mechanistic studies to explore molecular mechanisms of host-microbe interaction, use of genetic engineering, microarrays and proteomic technologies to produce advanced probiotic strains. Modified manufacturing conditions and newer pharmaceutical techniques or delivery systems can be used to enhance the stability and resistance of probiotics to gastric pH and to achieve targeted and sustained delivery.

Altered Gut Flora and Environment in Patients with Severe SIRS

The gut is considered an important target organ of injury after severe insult such as sepsis, trauma, and shock. The impact of bacterial translocation or mesenteric lymph on systemic inflammatory response and multiple organ damage has been investigated in animals, but dynamic changes in the gut flora and environment have not been fully clarified in critically ill patients. In the present study, we quantitatively evaluated changes in the gut microflora and environment in patients with severe systemic inflammatory response syndrome (SIRS). Twenty-five patients with severe SIRS, who fulfilled the criteria for SIRS, had a serum CRP level >10 mg/dL, and were treated in the intensive care unit for more than 2 days, were included in our study. SIRS was a result of sepsis in 18 patients, trauma in 6, and burn in 1. A fecal sample was used for quantitative evaluation of microflora (bacterial counts of 10 key groups including Bifidobacterium and Lactobacillus) by plate or tube technique and of the gut environment (pH and 9 organic acids by high speed liquid chromatography). Data obtained from patients were compared with corresponding data from healthy volunteers. Analysis of fecal flora confirmed that patients with severe SIRS had significantly lower total anaerobic bacterial counts (especially 2-4 log fewer "beneficial" Bifidobacterium and Lactobacillus) and 2 log higher "pathogenic" Staphylococcus and Pseudomonas group counts than those of healthy volunteers. Concentrations of total organic acids (especially "beneficial" short-chain fatty acids such as acetic acid, propionic acid, and butyric acid) in the feces were significantly decreased in the patients, whereas pH was markedly increased. The gut flora and environment are significantly altered in patients with severe SIRS. Abnormal gut flora and environment may affect systemic inflammatory response after severe insult.

Lactulose breath testing, bacterial overgrowth, and IBS: just a lot of hot air?

Lactulose breath testing, bacterial overgrowth, and IBS: just a lot of hot air?

Inflammatory bowel disease in children and adolescents: Working Group Report of the First World Congress of Pediatric Gastroenterology, Hepatology, and Nutrition.

Inflammatory bowel disease in children and adolescents: Working Group Report of the First World Congress of Pediatric Gastroenterology, Hepatology, and Nutrition.

Influence of intestinal flora on the development of fibrosis and cirrhosis in a rat model1

The gut flora play a significant role in the disposition of many foreign substances, as well as producing nutrients and toxins that may be absorbed and reach the liver. This study examines the influence of antibiotic-induced alterations in gut flora on the development of hepatic fibrosis in a rat model. Thirty-six male Porton rats were fed alcohol (3.9 g/kg per day) in the drinking water and exposed to carbon tetrachloride (CCl4) vapor (80 p.p.m.) for 6 h each night, five nights per week. Half were also given neomycin (330 mg/kg per day) and polymyxin B (105 mg/kg per day) in the drinking water. Fecal cultures were carried out at 0, 3, 8 and 13 weeks; rats were killed at 14 weeks. Coded liver section were assessed for fibrosis using a graded scale (0, no abnormal fibrosis to 4, early or established cirrhosis). Rats that received antibiotics had significantly higher fibrosis scores than those that did not (mean score 2.4 vs 1.4, P < 0.01, ordinal logistic regression). Three rats, all of which were in the antibiotic group, were cirrhotic. Rats that had received antibiotics fell into three groups. Four had overgrowth of Proteus mirabilis; in these the fibrosis scores (mean 1.5) were similar to those in the rats that did not receive antibiotic. In six, no organisms could be cultured; fibrosis scores of these (mean 2.3) were slightly elevated (P = 0.03), but this was mainly because of a single rat in this subgroup being cirrhotic. The remaining eight had overgrowth of Morganella morganii; these had significantly (P < 0.001) elevated fibrosis scores. Furthermore, in this subgroup, fibrosis scores were significantly correlated (Spearman's r = 0.82, P = 0.01) with the number of weeks of Morganella colonization. Antibiotic treatment exacerbated fibrosis in the alcohol/CCl4 rat model; this effect appeared to be related to the type of gut flora and may be endotoxin-mediated.

A perspective on the safety of antibacterials used to treat urinary tract infections

The safety of antibacterials used to treat urinary tract infections is reviewed. The types of side-effects found relate to the gastrointestinal tract, the female genital tract, and the skin, with miscellaneous complaints such as headache also occurring. Gastrointestinal effects are by far the most common and may be induced by direct irritation of the bowel, alteration of gut flora, direct stimulation of smooth muscle or alteration of bacterial metabolism of bile acid. Rare toxic effects specific to individual agents are also observed. There is no perfect treatment for urinary tract infections but from the point of view of safety, beta-lactams, nitrofurantoin and for fomycin, while causing a significant incidence of minor side-effects, are only very rarely associated with serious toxicity.

Limitations of 3-phenylpropionylglycine in early screening for medium-chain acyl-coenzyme A dehydrogenase deficiency

Screening for medium-chain acyl-coenzyme A dehydrogenase (MCAD) deficiency by urinary 3-phenylpropionylglycine may not be reliable in early infancy because young infants are not colonized with adult-type colonic flora. In this study we delineated the microbes that produce 3-phenylpropionic acid, the precursor of 3-phenylpropionylglycine. We found that the use of some antibiotics may alter gut flora, thereby confounding this method of screening for MCAD deficiency.

Molecular genetic approaches to the analysis of colorectal cancer

After lung cancer, colorectal tumours are the most common in Western society. In the UK over 19 000 people a year die of colorectal cancer and the involvement of both environmental and genetic factors has been suggested for the high incidence of this disease. A number of studies have focused on the role of dietary fibre, vitamin A deficiency and alterations in gut flora due to dietary changes, but the involvement of any of these factors has yet to be fully substantiated by epidemiological studies. Colorectal cancer is an ideal system for investigating the multistage progression of tumours. A number of clearly defined stages have been described at the histological level (Figure 1). Normal colonic surface epithelium comprises simple columnar epithelium with tubular glands in the lamina propria arranged regularly in rows with large numbers of mucus secreting goblet cells. This smooth surface undergoes a number of changes during tumour formation. Initially, hyperplastic regions of rapidly growing epithelium are seen; these lead to the formation of polyps or adenomas, which are outgrowths into the lumen of the colon. Polyps do not necessarily progress to form tumours but it is thought that all tumours arise from such growths. They vary in shape and size from large pedunculated growths to barely visible flatish outgrowths. A number of different conditions have been associated with polyps (Table 1). The final stage in the cancer process is