The liver is an important site of energy production and lipid metabolism. However, accumulation of excess fat in the liver promotes development of fibrosis, cirrhosis and hepatocellular cancer. Not much is known about how lipids and lipid metabolism influence liver diseases. Two studies used mice to learn more.

Teratani et al. investigated the effects of a high cholesterol diet on hepatic fibrosis induced by bile duct ligation or carbon tetrachloride, which cause biliary and toxic liver injury.The diet did not affect hepatocytes, but increased levels of cholesterol in hepatic stellate cells (HSCs; liver cells that store lipid and promote fibrogenesis) and increased up-regulation of profibrogenic genes in response to transforming growth factor (TGF)-β.

Although the high-cholesterol diet did not affect expression of the receptor for TGF-β, the authors observed increased levels of the lipopolysaccharide Toll-like receptor (TLR)4, and other alterations in this hepatocyte signaling pathway. Cholesterol did not increase levels of TLR4 mRNA, so the authors to propose that cholesterol prevents degradation of TLR4 protein. This is one of the first studies to show that cholesterol affects HSCs and their fibrogenic abilities.

Moustafa et al. uncovered a unique role for hepatic lipids using a mouse model of cholestatic liver disease, caused by genetic disruption of the ATP-binding cassette sub-family B member 4 (Abcb4−/−). Abcb4 encodes a phospholipid flippase that promotes biliary secretion of phospholipid and protects the biliary epithelium from the damaging effects of bile acids. Mice deficient in Abcb4 develop hepatocellular injury, cholestasis, and liver fibrosis. ABCB4 mutations in humans cause progressive familial intrahepatic cholestasis type 3 (PFIC3).

In the  in Abcb4−/− mice, 24-NorUrsodeoxycholic acid (NorUDCA, a side-chain variant of ursodeoxycholic acid that ameliorates cholestatic liver injury), loss of PPAR-α (PPAR-/-), and the high-fat diet (HFD, in figure below) reduced cholestasis, hepatic inflammation and fibrosis. The improvements coincided with reductions in activities of hepatic phospholipase and triglyceride lipase.

Factors that alter lipid metabolism, leading to liver damage.

These results were surprising because they show that hepatic lipid homeostasis in an important determinant of outcome in a liver disease not characterized by hepatic steatosis. They are also unique in that they demonstrate cholestatic liver disease, at least in Abcb4−/−mice, is improved by increasing, rather than decreasing, hepatic triglyceride levels.

In an editorial that accompanies the articles, Robert Schwab and Jacquelyn Maher ask whether this means that there is some optimal level of hepatic triglyceride—that disease develops if there is too much or too little? They say that the answer is no—instead, the development of liver disease depends on the metabolic activity of hepatic lipid. Excess fatty acids in the liver are dangerous only when they are prevented from being incorporated into triglycerides, and the findings of Moustafa et al. show that liver injury can also occur if lipid droplets are unable to hold on to their triglyceride. Schwab and Maher conclude that these findings incriminate fatty acids as hepatotoxic compounds and support the concept that triglyceride synthesis in hepatocytes is a cytoprotective mechanism.

Although Abcb4−/− mice are a model of human cholestatic liver disease, it is not clear if the lipid-related abnormalities in these mice can be compared to those of patients—even patients with PFIC3. It will be important to determine whether patients with PFIC3 have the same reduction of hepatic triglycerides and increased triglyceride hydrolysis as Abcb4−/− mice. If so, these findings could lead to a new therapeutic approach for this disease.

Read the articles online:
Teratani T, Tomita K, Suzuki T, et al. A high-cholesterol diet exacerbates liver fibrosis in mice via accumulation of free cholesterol in hepatic stellate cells. Gastroenterology 2012;152–164.e10.

Moustafa T, Fickert P, Magnes C, et al. Alterations in lipid metabolism mediate inflammation, fibrosis, and proliferation in a mouse model of chronic cholestatic liver injury. Gastroenterology 2012; 140–151.e12

Read the accompanying editorial.
Schwabe RF, Maher JJ. Lipids in liver disease: looking beyond steatosis. Gastroenterology 2012;8–11.

Celiac disease has been associated with GI cancers in small studies, but there have been no estimates from large populations or based on histopathology analyses.

Elfström et al. collected data from 28 pathology departments in Sweden on biopsy reports from 28,882 individuals with celiac disease, 12,860 with intestinal inflammation and 3705 individuals with latent celiac disease (based on serology test results, but with normal mucosa). They linked the data with those from the Swedish Cancer Registry to identify individuals that eventually developed cancers of the oropharynx, esophagus, stomach, small intestine, large intestine, rectum and anus, liver, or pancreas.

They found that over the study period, patients with these disorders did not have a significantly higher risk of developing GI cancers than the general population, matched for age and sex—in fact, patients with latent celiac disease had a lower absolute cancer risk than the population.

“We saw an association between having a biopsy and GI cancer in the first year, but then after that we saw no increased risk”, said the study’s senior author Jonas F. Ludvigsson in a video abstract:

Video abstract from Jonas Ludvigsson

Ludvigsson believes that the observed increase in cancer within the first year after biopsy analysis resulted from confounding factors—a patient with GI cancer would have symptoms that lead to biopsy analysis and identification of celiac disease or inflammation, and then the cancer.

Small intestinal cancer made up 6%–7% of all GI cancers that developed in individuals with celiac disease, with hazard ratio of 2.2 after the first year of follow up. However, Elfström et al. propose that the increased incidence of small intestinal cancer in these patients, compared with the population, resulted from a combination of surveillance bias or possibly the effects of persistent inflammation.

This was one of the largest studies of cancer risk in children with celiac disease. Of almost 12,000 children with celiac disease, only 4 developed cancer after the first biopsy sample was collected. Although this corresponded to more than 5-fold increase in cancer risk compared with the general pediatric population, the authors urged caution in interpretation of these data, because the increased risk estimate was based on different subtypes of cancer, indicating surveillance bias rather than a specific biologic mechanism.

Overall, Elfström et al. report lower risk estimates for GI cancer than previous studies. They attribute this difference to their use of biopsy data to identify patients with celiac diseases—all patients in Sweden diagnosed with celiac disease undergo biopsy analysis, which reduced selection bias in this particular study. Also, most patients included in this study were diagnosed with celiac disease in the late 1990s or after 2000. The increased use of serologic analyses to diagnose celiac disease during this time period meant that more patients with few or no symptoms of the disease were included in the analysis.

In an editorial that accompanies this article, Rupa Mukherhee et al. state that “up to this point, the prevailing belief has been that patients with severe, inflammatory celiac disease are likely to have a greater potential for malignancy, including small intestinal adenocarcinoma, than patients with milder forms of inflammation or latent celiac disease.” They state that, as a consequence, clinicians have lacked guidance about how to predict or reduce cancer risks, such as through dietary advice or celiac disease–specific cancer screening strategies.

Ludvigsson pointed out that the study was unable to include factors such as body mass index and smoking—important risk factors for cancer—because these data were not recorded in the registries analyzed. Mukherjee says that longer-term studies are needed, along with those to assess risk of other solid organ malignancies, in a similar prospective and population-based manner.

More Information on Celiac Disease:

• NIDDK Website on Celiac Disease

Read the article online.
Elfström P, Granath F, Ye W, et al. Low risk of gastrointestinal cancer among patients with celiac disease, inflammation, or latent celiac disease. Clin Gastroenterol and Hepatol 2012;10:30–36.

Read the accompanying editorial.
Mukherjee R, Kelly CP, Leffler DA. Gastrointestinal cancer in celiac disease: “the first days are the hardest days, don’t you worry anymore?” Clin Gastroenterol and Hepatol 2012;10:4–6.

Read a related Gastroenterology article.
Mårild K, Stephansson O, Montgomery S, et al. Pregnancy outcome and risk of celiac disease in offspring: a nationwide case-control study. Gastroenterology 2012; 142:39-45.e3.

Drugs such as infliximab inhibit the inflammatory cytokine tumor necrosis factor (TNF) and are effective in reducing the symptoms of Crohn’s disease. Many patients experience long periods of remission, and would like to eventually stop taking the drug, because of cost, concerns about long-term safety, or pregnancy.

To determine what happens to patients when patients stop taking the drug, Edouard Louis et al. followed 115 adults with Crohn’s disease who were in stable remission after at least 1 year of treatment with infliximab and an antimetabolite.

Within a year after their therapy was discontinued, almost half the patients experienced a relapse in symptoms (see figure).

Time to relapse for115 patients with Crohn's disease after infliximab therapy was stopped.

However, almost all  of these patients responded to a single re-treatment infusion of infliximab—none experienced a significant acute or delayed infusion reaction.

Louis et al. identified factors that determined patients’ risk of relapse, such as smoking, blood levels of specific factors and measurements of disease severity. They propose that simple parameters such as these might be used to identify patients with a low risk of relapse, for whom withdrawal of infliximab could be considered.

However, this study did not contain a control group, and only included patients considered to be the best responders to infliximab therapy (in deep remission when the drug was stopped). The authors state that larger, controlled studies to compare de-escalation strategies are needed.

Read the article online. This article has accompanying podcast and CME activities.
Louis E, Mary J-Y, Massouille GV, et al. Maintenance of remission among patients with Crohn’s disease on antimetabolite therapy after infliximab therapy is stopped. Gastroenterology 2012;142: 63-70.e5.

Read a related Clinical Gastroenterology and Hepatology article.
Siegel CA, Finlayson SRG, Sands BE, et al. Adverse events do not outweigh benefits of combination therapy for Crohn’s disease in a decision analytic model. Clin Gastroenterol and Hepatol 2012;10:46-51.

Many patients do not receive screening colonoscopies because they are concerned about discomfort during the procedure. So there is much interest in sedation practices and the involvement of anesthesiologists in the procedure.

Sedation for screening colonoscopies was initially provided with midazolam and an opioid, but in the past decade, new options have become available—approximately 25% of patients now receive sedation with propofol instead. Anesthesiologists usually administer propofol, but little was known about the degree to which this specialty has become involved in colonoscopy screening exams.

Vijay Khiani et al. determined how many screening colonoscopies performed over a 5-year period involved an anesthesiologist using the using the linked Surveillance, Epidemiology, and End Results (SEER)-Medicare linked database. The SEER database is an important source for cancer statistics—it provides data from geographic areas that represent approximately 28% of the US population. Khiani et al. analyzed data from 16,268 individuals, 68 years or older, who received screening colonoscopies from 2001 through 2006.

They found that found that anesthesiologist involvement in screening colonoscopies among Medicare beneficiaries increased substantially over this time period—from 11% to 23.4%. Because the numbers of screening colonoscopies doubled over the interval examined, there was actually a multiplicative effect on the absolute numbers of anesthesia-assisted colonoscopies (see figure).

Colonoscopies and anesthesiologist involvement among Medicare fee-for-service patients.

Khiani et al. found that surgeons involved an anesthesiologist in 24.2% of colonoscopies, compared with 18.0% of gastroenterologists and 11.3% of primary care providers. The percentage of colonoscopies that involved an anesthesiologist varied among regions, ranging from 1.6% in San Francisco to 57.8% in New Jersey. Anesthesiologist involvement increased the cost by approximately 20% per screening colonoscopy.

Anesthesiologist involvement could provide many important benefits, including increased comfort and safety, yet there is concern about the cost. Khiani et al. say that, in the absence of an anesthesiologist, there has not been a fee for the sedation of average-risk patients undergoing a screening colonoscopy. Incorporating an anesthesiologist into the colonoscopy increased the costs by $103 per case in this study—an additional $20 million during the study period. In an editorial that accompanies the article, John Vargo estimates that if we assume 100% market penetration of monitored anesthesia care, the costs for such a transition would be $5 billion annually.

But does anesthesia-assisted sedation improve outcomes of endoscopic procedures? Vargo states that that there are no data to support the safety and efficacy this practice. A position statement from a multi-society gastroenterology task force says that administration of propofol by an endoscopist has better efficacy and safety than standard sedation, provided that proper training and patient selection is used. The position statement considered the use of anesthesiologist-administered propofol for healthy individuals undergoing elective endoscopy to be cost prohibitive and provides no improvements to safety or outcomes. However, there has been much controversy over whether the endoscopist or the anesthesiologist is the best person to administer the sedative.

Khiani et al. add that the study did not take into account competition among gastroenterology practices in specific regions or specific volume of cases per session per practitioner, or perform a side-by-side comparison with patients of other third-party payors or non-screening colonoscopy cases. Furthermore, the claims data did not specify whether a nurse anesthetist or anesthesiologist provided services.

They conclude that further research is needed to determine the effects of anesthesiologist involvement on patients and outcomes—especially to determine patients’ perspectives about comfort and their willingness to undergo the procedure with or without an anesthesiologist. An investigation of the potential benefits (such as polyp detection rate) and risks (such as the complication rate) is needed to determine the most safe, comfortable, and cost-effective approach to screening colonoscopies.

Read the article online. This article has accompanying CME activities.
Khiani SV, Soulos P, Gancayco J, et al. Anesthesiologist involvement in screening colonoscopy: temporal trends and cost implications in the medicare population. Clin Gastroenterol and Hepatol 2012;10:58-64.e1

Read the accompanying editorial.
Vargo JJ. A SEER snapshot of anesthesiologist-assisted procedural sedation: in or out of focus? Clin Gastroenterol and Hepatol 2012;10:7–8.e1

Trypsinogen is a pancreatic protein that is converted in acinar cells to the enzyme trypsin—a protease that is important for digestion and that activates other proteases. Patients with pancreatitis have increased levels of trypsinogen and other digestive enzymes, so research has focused for many decades on how these enzymes are regulated and activated to damage the pancreas.

Rajinder Dawra and colleagues created and analyzed mice that do not produce trypsinogen-7, the equivalent gene of human cationic trypsinogen. Surprisingly, the T−/− mice still developed acute pancreatitis following administration of cerulein, a reagent that activates trypsinogen and has other inflammatory effects. The T−/− mice and wild-type mice had similar degrees of local and systemic inflammation during the progression of pancreatitis. They also had comparable levels of acinar cell activation of the transcription factor NF-κB, which has been shown to occur concurrently with trypsinogen activation during early stages of pancreatitis.

However, acinar cell necrosis was reduced by 50% in T−/− mice given cerulein, compared with wild-type mice given cerulein. So loss of trypsingen-7 prevented some, but not all of the pancreatic damage. Dawra et al. conclude that trypsinogen activation leads to acinar cell death during early stages of pancreatitis and is responsible for half of eventual pancreatic injury in patients with this disease.

In an accompanying editorial, Baoan Ji and Craig Logsdon point out that it is not clear if trypsinogen-7 is the only isoform activated by cerulein—reducing the total level of trypsinogen might not have the same effects. The T−/− mice had no phenotypic abnormalities, indicating trypsinogen expression levels of wild-type mice could be in excess of what is actually needed, physiologically. It is also possible that T−/− mice developed mechanisms to compensate for their reduced levels of trypsinogen.

In previous studies, pharmacologic reagents that inhibit trypsinogen activation reduced acute pancreatitis, and mutations in the human gene that encodes cationic trypsinogen have been associated with hereditary pancreatitis. Ji and Logsdon warn that experimental models of acute pancreatitis cause generalized, nonspecific damage, rather than specific activation of trypsinogen. Better models are needed.

Trypsin activation appears to be one component of a complex response of acinar cells to injury (see figure).

The trypsin-based model of pancreatitis (A) and the new, multi-faceted model of pancreatitis (B).

Ji and Logsdon remind us that acute pancreatitis involves not only direct damage to pancreatic tissue, but also edema, coagulation, vascular complications, infiltration of immune cells, and local and systemic inflammation. It is therefore time to broaden the focus of pancreatitis research from trypsinogen activation to other mechanisms that contribute to disease.

More Information on Acute Pancreatitis:

• The National Library of Medicine Website on Acute Pancreatitis

Read the article online.
Dawra R, Sah R, Dudeja V, et al. Intra-acinar trypsinogen activation mediates early stages of pancreatic injury but not inflammation in mice with acute pancreatitis. Gastroenterology 2011;141: 2210-2217.e2

Read the accompanying editorial.
Ji B, Logsdon C. Digesting new information about the role of trypsin in pancreatitis. Gastroenterology 2011;141: 1972–1975.

Chronic abdominal pain is common, yet a challenge to treat, so clinicians have increasingly prescribed opioids for patients with this condition. According to one report from a tertiary care center, 13% of patients with Crohn’s disease and nearly 20% of patients with irritable bowel syndrome reported opioid use.

The widespread use of opioids to treat chronic abdominal pain is a concern, because it is not clear if opioids are effective and because the drugs are frequently misused or abused.

Spencer Dorn and colleagues analyzed 2 national medical databases to identify trends and factors associated with prescription of opioids for chronic abdominal pain. They classified opioid analgesics as drugs from the Multum Therapeutic Classification category for narcotic analgesics and narcotic analgesic combinations; tramadol, classified as a miscellaneous analgesic in this system, was included in the analysis.

Dorn et al. found that although the total number of visits for chronic abdominal pain decreased over time, the percentage of visits at which an opioid was prescribed more than doubled, from 5.9% in the period of 1997–1999 to 12.2% in period of 2006–2008 (see figure).

Decreasing office visits but increasing opioid use, over time

Patients that were 25 to 40 years old were the most likely to receive a prescription, whereas the uninsured and African American patients were the least likely.

The authors speculate that opioid use for chronic abdominal pain has increased because of misunderstandings of recommendations for opioid use, as well as advertising. They said it might also reflect the challenges clinicians face trying to manage patients with chronic disorders, without the time, infrastructure, or incentives necessary to take the integrated approach that experts suggest. Dorn et al. state that “writing a prescription for a pain killer may be the path of least resistance; doing so may both satisfy the patient’s demand for relief and mitigate the clinician’s possible feelings of inadequacy.”

However, the increase is a problem, because opioids have not been adequately assessed for chronic, noncancer-related abdominal pain or been proven to improve functional status or health-related quality of life. Long-term use of opioids can actually induce gastrointestinal symptoms, such as constipation, lower abdominal pain, nausea, and emesis. Some patients even develop narcotic bowel syndrome—chronic or frequently recurring abdominal pain that worsens despite continued or increased opioid dosage.

It is not clear why the number of visits for chronic abdominal pain decreased during the observation period. The authors propose that it might result from a gradual decrease in the prevalence of chronic abdominal pain, or because patients have increasingly sought care in nonambulatory settings.

Dorn et al. propose further studies to determine the reasons for and consequences of these trends.

More Information on Chronic Abdominal Pain:

• The Mayo Clinic Website on Chronic Abdominal Pain

Read the article online.
Dorn SD, Meek PD, Shah ND. Increasing frequency of opioid prescriptions for chronic abdominal pain in us outpatient clinics. Clin Gastroenterol and Hepatol 2011; 9:1078–1085.e1

Patients infected with HCV genotype-1 are usually treated with peginterferon and ribavirin, but approximately 60% do not have a sustained virologic response (SVR, undetectable plasma level of HCV RNA 24 weeks after treatment), and many others cannot tolerate the side effects of peginterferon.

Stefan Zeuzem et al. tested a combination of the HCV polymerase inhibitor BI 207127 and the protease inhibitor BI 201335, each developed by Boehringer Ingelheim, in 31 treatment-naïve patients with chronic HCV, genotype-1 infection. Patients received either 400 mg or 600 mg of BI 207127, 3 times daily, along with 120 mg of BI 201335 and a dose of ribavirin each day for 4 weeks. None of the patients received interferon.

The rate of virologic response (an HCV RNA level below 25 IU/mL) reached 100% by day 22 in the patients given the 600 mg dose of BI 207127, without differences among genotypes—HCV RNA could not even be detected in 71% of the patients by day 29.

One patient in the group given the 400 mg dose of BI 207127 had a virologic breakthrough (a rebound in HCV RNA level) at day 22. The most frequent adverse events were mild gastrointestinal disorders, rash, and photosensitivity, but there were no severe or serious adverse events.

In an editorial that accompanies the article, Prateek Sharma and Anna Lok agree that an interferon-free regimen of direct-acting antiviral agents and ribavirin can suppress HCV for up to 4 weeks. However, they point out that it is not clear if this response, and lack of adverse events, can be maintained for longer time periods.

In a video abstract, Zeuzem states that these findings are a milestone toward different options to achieve viral eradication. “We are looking toward longer treatment exposure with these direct-acting antivirals … with such a safe and tolerable regimen, we hope that 24 weeks may be sufficient to cure patients, without the need for interferon,” he says.

HCV protease inhibitors such as boceprevir and telaprevir are also effective in treating patients chronic HCV genotype-1 infection. However, these drugs must be given with peginterferon and ribavirin, to prevent the development of drug-resistant variants.

The authors propose that the unique structure of BI 207127 precludes the development of resistant viral variants. The drug interferes with a conformational change required for the HCV NS5B polymerase to initiate RNA synthesis; its binding site is an interface between functional domains that restricts sequence polymorphisms. So, BI 207127 seems to have a higher barrier to resistance than other polymerase inhibitors.

Further studies are needed to to determine the exact role of ribavirin in the antiviral activity of this combination. Zeuzem et al. propose that this drug’s weak direct antiviral activity and ability to induce interferon-sensitive genes contribute to its role in the drug combination.

Sharma and Lok conclude that interferon-free regimens are no longer a dream, and that some regimens will also eventually be ribavirin-free. This is good news for patients who cannot take peginteferon or ribavirin because of their interactions with other medications or tolerability issues. However, caution must be taken in selecting which antiviral agents to combine the appropriate dose and duration of therapy for each HCV genotype and subgenotype.

Read the article online. This article has an accompanying podcast and CME activities.
Zeuzem S, Asselah T, Angus P, et al. Efficacy of the protease inhibitor BI 201335, polymerase inhibitor BI 207127, and ribavirin in patients with chronic HCV infection. Gastroenterology 2011;141:2047–2055.

Read the accompanying editorial.
Sharma P, Lok AS. Interferon-free treatment regimens for hepatitis C: are we there yet? Gastroenterology 2011;141:1963–1967.

Although the human appendix is considered to be expendable, it contains gut-associated lymphoid tissue (GALT), which processes antigen and regulates the humoral immune responses. It could therefore have an unappreciated immunomodulatory role in the gut. The presence or absence of an appendix has been associated with several intestinal disorders, and some researchers think it is an important secondary lymphatic organ that controls inflammatory and anti-inflammatory T-cell responses.

Im et al. investigated whether there was a relationship between the presence of absence of an appendix and risk of recurrent C difficile infection, based on data from 254 patients admitted to the hospital for this infection from 2005 to 2007. Using a multivariate analysis, they found that patients with an appendix were at much lower risk for recurrence of C difficile infection than those without (an adjusted relative risk of 0.40).

C difficile is a spore-forming, anaerobic, and gram-positive bacterium that causes gastrointestinal infection resulting in diarrhea and colitis; infections have been increasing in incidence and the severity over the past 10 years. C difficile is a leading cause of death from nosocomial infection, and recurrence is one of the most challenging aspects of its management—approximately 25% of patients experience recurrence despite initial successful treatment.

How might the appendix protect patients from recurring infections with pathogenic bacteria? Im et al. state that the GALT of the human appendix has a higher density of IgA- and IgG-producing B cells than the colon—these antibodies fight C difficile and other bacterial infections. Furthermore, the appendix contains abundant biofilm—adherent colonies of commensal microbes within the extracellular matrix and mucus lining of the bowel epithelium. The authors propose that the appendix serves as a storage location for commensal flora, which can re-inoculate the intestinal tract if they are overtaken by a pathogen or eliminated by an antibiotic.

In an accompanying editorial, Xi Na and Ciaran Kelly propose that biofilms in the appendix accelerate the repopulation of the colonic lumen with the commesal bacteria. The colon’s immune response to C difficile and its toxins might therefore be impaired by appendectomy, which makes the gut more vulnerable to re-infection by pathogenic bacteria (figure).

Risk factors for Clostridium difficile infection and the protective role of the appendix.

Na and Kelly state that the findings of Im et al. raise important questions about the functions of the appendix, its role as a biofilm reservoir, and as an intestinal immune organ.

Im et al. conclude that surgeons should re-assess the practice of performing incidental appendectomies during abdominal and gynecologic surgeries—these might increase patients’ risk for recurrent pathogenic infections.

More Information of Clostridium Difficile Infection:

• Mayo Clinic Website on Clostridium Difficile Infection

Read the article online.
Im GY, Modayil RJ, Lin CT, et al. The appendix may protect against Clostridium difficile recurrence. Clin Gastroenterol and Hepatol 2011; 9:1072–1077.

Read the accompanying editorial.
Na X, Kelly C. The vermiform appendix and recurrent Clostridium difficile infection: a curious connection. Clin Gastroenterol and Hepatol 2011; 9:1018–1019.

Microorganisms account for 90% of the cells in our body (many cannot even be cultured); only 10% of our cells are human. The large microbial mass in the intestine is established at birth, and its composition is determined by a combination of genetic and environmental factors. The makeup of this microbiota has been proposed to affect development of inflammatory bowel diseases and IBS.

Only recently have researchers developed technologies to quantify these microbes. Mirjana Rajilić–Stojanović et al. performed global and deep molecular analysis of fecal samples from 62 adult patients with IBS and 46 healthy adults. In a separate study published in the same issue, Delphine M. Saulnier et al. analyzed 71 stool samples from 22 children with IBS and 22 healthy children using 16S ribosomal RNA gene sequencing.

Both studies found that patients with IBS had a greater abundance of the Firmicutes member Dorea than healthy individuals.

Rajilić–Stojanović et al. reported that adult patients with IBS had a 2-fold greater ratio of Firmicutes to Bacteroidetes than controls, resulting from an approximately 1.5-fold increase in numbers of Dorea, Ruminococcus, and Clostridium spp. They also observed a 2-fold decrease in the number of Bacteroidetes, a 1.5-fold decrease in numbers of Bifidobacterium and Faecalibacterium spp, and, when present, a 4-fold lower average number of methanogens (see figure).

Global phylogenetic tree comparing the intestinal microbiomes of healthy children (interior ring, light red) with those of children with IBS (interior ring, light green). The outer ring shows the groups of bacteria analyzed.

The microbial groups correlated with IBS symptom scores, indicating that several groups of Firmicutes and Proteobacteria might mediate the development of IBS.

However, Saulnier et al. observed that the microbiomes of children with IBS had a significantly greater percentage of the class γ-proteobacteria. One prominent component of this group was Haemophilus parainfluenzae, but a novel, Ruminococcus-like microbe was also associated with IBS. Greater frequency of IBS pain in children correlated with an increased abundance of several bacterial taxa from the genus Alistipes. By contrast, taxa such as the genus Eubacterium and the species Bacteroides vulgatus were more frequently observed in healthy children.

Saulnier et al. were able to use their technology to identify children with IBS and determine their specific subtype, with greater than 95% accuracy. Different subtypes of IBS (IBS with constipation, IBS with diarrhea, etc.) were associated with different bacterial populations, encompassing at least 50–75 different taxa, so this technology might be used in diagnosis.

The authors concluded that qualitative and quantitative differences in specific bacterial components of the gut microbiome are important features of IBS and its subtypes in children. They propose that the role of generic bacterial overgrowth and, more specifically, small intestinal bacterial overgrowth, be evaluated as mechanism of IBS. However, the total microbial load (the 16S rDNA copy number per gram of stool) did not differ significantly between healthy children and those with IBS.

There were some differences between findings of the 2 studies. For example, although Saulnier et al. reported differences in levels of Proteobacteria between children with IBS and controls, this difference was not observed in adults by Rajilić-Stojanović et al. Likewise, in pediatric patients with IBS, a greater frequency of pain was associated with an increase in the genus Alistipes, but in the adult study, levels of Alistipes were significantly higher in controls. These differences might result from the different patient populations analyzed (pediatric vs adult), geographic regions of the studies (Texas vs Finland), or platforms used (next-generation sequencing and Affymetrix arrays vs Agilent arrays).

In an accompanying editorial, Nicholas Tally and Anthony Fodor suggest that microbial niches in the colon and small intestine might exist—there could be specific differences in the mucosal-associated or the luminal microbiota that contribute to development of diseases such as IBS.

Nonetheless, Talley and Fodor concluded that the application of high-throughput technology to IBS is a first step toward identifying each person’s microbial community and individualizing therapy, perhaps with probiotics, prebiotics, and/or antibiotics.

Saulnier et al. propose that analyses of clinical features, dietary and medication history, and genetics will also help us better understand the genetic, metagenomic, and environmental factors that contribute to IBS and other intestinal disorders.

Read the articles online.

Saulnier DM, Riehle K, Mistret T-A, et al. Gastrointestinal microbiome signatures of pediatric patients with irritable bowel syndrome. Gastroenterology 2011;141:1782–1791.

Rajilić–Stojanović M, Biagi E, Heilig HGHJ, et al. Global and deep molecular analysis of microbiota signatures in fecal samples from patients with irritable bowel syndrome. Gastroenterology2011;141:1792–1801.

Read the accompanying editorial.

Talley NJ, Fodor AA. Bugs, stool, and the irritable bowel syndrome: too much is as bad as too little? Gastroenterology2011;141:1555–1559.

Most patients with ulcerative colitis are successfully treated with medication, yet some have severe colitis attacks that can be life threatening. Approximately 10% of patients with colitis therefore receive a colectomy (surgical removal of all or part of the colon) within the first 10 years of diagnosis. However, it is not clear how many people experience complications from this surgery, or what the risk factors are.

Shanika De Silva et al. performed a population-based study to determine the occurrence and severity of postoperative complications and identify factors that affect outcome.

Analyzing 14 years of data, from 666 patients with ulcerative colitis who received colectomies, the authors found that a postoperative complication occurred in 27.0% and the mortality rate was 1.5%. The risk for complications was greatest among patients more than 64 years or with other health complications, such as a history of cardiac disease.

Furthermore, patients with colitis who were admitted to the hospital under emergency conditions and did not respond to medical treatment had worse outcomes when surgery was performed 14 or more days after admission. Patients who underwent emergent surgery because they did not respond to in-hospital medical management, or developed an acute complication, had worse outcomes (2.4% mortality) than patients who had elective surgeries.

Patients who receive immunosuppressants or other drugs for inflammatory bowel diseases (mesalamine, corticosteroids, azathioprine, 6-mercaptopurine, or infliximab) do not have an increased risk for postoperative complications, including infections. Institutions that performed less than 4 colectomies in patients with ulcerative colitis per year had 2-fold greater postoperative mortality than high-volume hospitals that performed surgery on greater than 12 patients per year.

De Silva et al. conclude that it is important to carefully select patients for colectomies. Elderly patients and those with other diseases should be offered comprehensive medical management, and other strategies should be considered before colectomy.

The authors state that elective colectomies have the best outcomes, so gastroenterologists and surgeons should try to optimize management of patients, making timely decisions for surgery in the outpatient setting.

More Information on Colectomy:

• Mayo Clinic Website on Colectomy
• National Library of Medicine Website on Ulcerative Colitis

Read the article online.
De Silva S, Ma C, Proulx M-C, et al. Postoperative complications and mortality following colectomy for ulcerative colitis. Clin Gastroenterol and Hepatol 2011; 9:972–980