Clostridium Difficile-induced Colitis Research Articles

Treatment with butyrate alleviates dextran sulfate sodium and Clostridium difficile-induced colitis by preventing activity of Th17 cells via regulation of SIRT1/mTOR in mice

Inflammatory bowel disease (IBD) patients are particularly vulnerable to infection with Clostridium difficile infection (CDI).Available treatments of IBD with CDI have not effective. Butyrate, the metabolites of microbiota, plays a vital role in maintaining immune homeostasis and potential drugs for treatment of IBD with CDI. The aim of this study was to investigate the effect of butyrate on IBD with CDI. Mice were given dextran sulfate sodium (DSS) and were infected with C. difficile (CD). Butyrate was treated during the study period. Butyrate protected from DSS+CD induced colitis by improving weight loss, survival, colon shorten, activity index score, and suppressing the expression of proinflammatory cytokines including IL-6, IL-17, TNF-α, IL-1β as well as regulating Th17/Treg balance through activation of SIRT1/mTOR. Besides, SR1001, an inhitor of the orphan nuclear receptors retinoic acid-related receptor γt, which is a transcription factor specific to the formation of Th17 cells can suppress the Th17 development and alleviate the DSS+CD induced colitis in mice. Notably, the therapeutic effect of butyrate was revered when disease mice treated with butyrate and Ex-527, a SIRT1 inhibitor. Taken together, we demonstrate that butyrate alleviates dextran sulfate sodium and clostridium difficile induced colitis by preventing Th17 through activation of SIRT1/mTOR.

Treating From the Inside Out: Relevance of Fecal Microbiota Transplantation to Counteract Gut Damage in GVHD and HIV Infection.

The gastrointestinal (GI) tract is a complex and well-balanced milieu of anatomic and immunological barriers. The epithelial surface of the GI tract is colonized by trillions of microorganisms, known as the gut microbiota, which is considered an “organ” with distinctive endocrine and immunoregulatory functions. Dysregulation of the gut microbiota composition, termed dysbiosis, has been associated with epithelial damage and translocation of microbial products into the circulating blood. Dysbiosis, increased gut permeability and chronic inflammation play a major role on the clinical outcome of inflammatory bowel diseases, graft-vs.-host disease (GVHD) and HIV infection. In this review, we focus on GVHD and HIV infection, conditions sharing gut immune damage leading to dysbiosis. The degree of dysbiosis and level of epithelial gut damage predict poor clinical outcome in both conditions. Emerging interventions are therefore warranted to promote gut microbiota homeostasis and improve intestinal barrier function. Interventions such as anti-inflammatory medications, and probiotics have toxicity and/or limited transitory effects, justifying innovative approaches. Fecal microbiota transplantation (FMT) is one such approach where fecal microorganisms are transferred from healthy donors into the GI tract of the recipient to restore microbiota composition in patients with Clostridium difficile-induced colitis or inflammatory bowel diseases. Preliminary findings point toward a beneficial effect of FMT to improve GVHD and HIV-related outcomes through the engraftment of beneficial donor bacteria, notably those producing anti-inflammatory metabolites. Herein, we critically review the potential for FMT in alleviating dysbiosis and gut damage in patients with GVHD or HIV-infection. Understanding the underlying mechanism by which FMT restores gut function will pave the way toward novel scalable and targeted interventions.

Butyrate Protects Mice from Clostridium difficile-Induced Colitis through an HIF-1-Dependent Mechanism

Antibiotic-induced dysbiosis is a key factor predisposing intestinal infection by Clostridium difficile. Here, we show that interventions that restore butyrate intestinal levels mitigate clinical and pathological features of C.difficile-induced colitis. Butyrate has no effect on C.difficile colonization or toxin production. However, it attenuates intestinal inflammation and improves intestinal barrier function in infected mice, as shown by reduced intestinal epithelial permeability and bacterial translocation, effects associated with the increased expression of components of intestinal epithelial cell tight junctions. Activation of the transcription factor HIF-1 in intestinal epithelial cells exerts a protective effect in C.difficile-induced colitis, and it is required for butyrate effects. We conclude that butyrate protects intestinal epithelial cells from damage caused by C.difficile toxins via thestabilization of HIF-1, mitigating local inflammatory response and systemic consequences of the infection.

Critical role of MAVS in the protection against Clostridium difficile-induced colitis

Clostridium difficile (C. difficile) is an opportunistic bacteria that flourishes in intestinal flora is altered by antibiotic use and can cause large intestinal colitis if left untreated. The mechanism of MAVS-mediated innate immune signaling in response to C. difficile infection remains unclear. This knowledge gap was addressed in the present research by administration of an antibiotic cocktail to WT and MAVS-deficient (MAVS−/−) mice for five days, followed by the oral administration of C. difficile VPI 10,463 strain (1 × 107 colony forming units). Subjects were subsequently observed for another eight days for signs of colitis. Colon and cecum tissue samples were harvested from naive and infected mice two days post-infection for histopathologic analysis. Colon tissue samples were harvested to analyze cytokine gene expression and RegIIIβ/γ gene expression. MAVS-deficient mice suffered significantly higher mortality rates as well as increased mucosal tissue inflammation and damage after C. difficile infection (P <0.05). MAVS−/− mice displayed a significantly greater increase in IL-6, IL-1β, TNF-α and IFN-β expression in colon tissues in contrast to WT mice challenged with C. difficile (P <0.05). RegIIIβ/γ gene expression was severely attenuated in the colons of MAVS−/− mice (P <0.05). These findings underscore MAVS as a vital innate immune system mediator in the intestinal mucosa and further suggests that MAVS-mediated maintenance of the intestinal epithelial barrier is an important defense against enteric pathogens.

IL-27/IL-27 Receptor Signaling Provides Protection in Clostridium difficile-Induced Colitis.

Clostridium difficile is a leading cause of nosocomial infection. The role of cytokine interleukin-27 (IL-27) in the immunopathology of C. difficile infection (CDI) remains unknown. The production of IL-27 was determined in human and murine CDI. Furthermore, wild-type (WT) and IL-27 receptor-deficient (WSX-1-/-) mice were treated with an antibiotic mixture and infected with C. difficile to investigate the effects of IL-27 on host response to CDI. IL-27 production was elevated during CDI in humans and mice. Infected WSX-1-/- mice experienced increased weight loss, enhanced colonic histology damage, less C. difficile clearance, and decreased survival compared to WT controls during CDI. IL-27 administration reduced CDI-associated mortality and tissue pathology with improved C. difficile clearance in WT mice after C. difficile challenge. Mechanistically, IL-27-mediated host defense against CDI was associated with downregulation of IL-17A and IL-23, but upregulation of IL-10 and interferon-gamma during CDI. Our data suggest a previously unrecognized role for IL-27 in the pathogenesis of CDI, potentially providing new insight for IL-27-mediated protection against C. difficile-induced pathology.

Clostridium difficile-induced colitis in mice is independent of leukotrienes

Clostridium difficile is the major cause of antibiotic-associated diarrhea and pseudomembranous colitis in healthcare settings. However, the host factors involved in the intestinal inflammatory response and pathogenesis of C. difficile infection (CDI) are largely unknown. Here we investigated the role of leukotrienes (LTs), a group of pro-inflammatory lipid mediators, in CDI. Notably, the neutrophil chemoattractant LTB4, but not cysteinyl (cys) LTs, was induced in the intestine of C57BL/6 mice infected with either C. difficile strain VPI 10463 or strain 630. Genetic or pharmacological ablation of LT production did not ameliorate C. difficile colitis or clinical signs of disease in infected mice. Histological analysis demonstrated that intestinal neutrophilic inflammation, edema and tissue damage in mice during acute and severe CDI were not modulated in the absence of LTs. In addition, CDI induced a burst of cytokines in the intestine of infected mice in a LT-independent manner. Serum levels of anti-toxin A immunoglobulin (Ig) G levels were also not modulated by endogenous LTs. Collectively, our results do not support a role for LTs in modulating host susceptibility to CDI in mice.

Potion or Poison? Probiotics

SUMMARY MESSAGE: Two types of probiotic (Lactobacillus rhamnosus and Saccharomyces boulardii) at high doses may prevent the onset of antibiotic-associated diarrhoea in children. Probiotics are generally well tolerated. Clinical benefit needs to be confirmed in larger studies across a greater range of probiotics. There is insufficient evidence to recommend probiotic therapy in adults as an adjunct to antibiotic therapy, specifically for Clostridium difficile-induced colitis.

Bacillus coagulans GBI-30, 6086 limits the recurrence of Clostridium difficile-Induced colitis following vancomycin withdrawal in mice

BackgroundRecently, we found that the probiotic strain Bacillus coagulans GBI-30, 6086 (GanedenBC30) improved indices of Clostridium difficile (C. difficile)-induced colitis in mice (Fitzpatrick et al., Gut Pathogens, 2011). Our goal was to determine if BC30 could also prevent the recurrence of C. difficile-induced colitis in mice, following initial treatment with vancomycin. During study days 0 through 5, mice were treated with antibiotics. On day 6, the C. difficile strain VPI 10463 was given by oro-gastric gavage at ≈ 5x104 CFU to induce colitis. Mice were treated on study days 6 to 10 with vancomycin (50 mg/kg) (vanco) or vehicle (saline) by gavage. On days 10 to16, mice were dosed by gavage with saline vehicle or BC30 (2 x 109 CFU per day). Mice were monitored for mortality, weight loss and diarrhea. On study days 14, 16 and 17, stools and colons were collected for analyzing other parameters of colitis.ResultsThe mean stool consistency score in Vehicle/C.difficile/Vanco mice increased from 0.4 (day 10) to a range of 1.1 to 1.4 (days 14 to 17), indicating the recurrence of colitis. On days 13 through 17, the stool consistency scores for the vancomycin/BC30 mice were significantly lower (p< 0.05) than for the vancomycin/vehicle cohort of animals. On day 17, 88.9% of mice treated with BC30 had normal stools, while this value was 0% with vehicle treatment (p value = 0.0004). Colonic myeloperoxidase (Units/2 cm colon) was significantly (p < 0.05) reduced from 4.3 ± 0.7 (Vehicle/C.difficile/Vanco) to 2.6 ± 0.2 (BC30/C. Difficle/Vanco). The colonic histology score and Keratinocyte derived-chemokine level in the colon were also lower in BC30 treated mice.SummaryIn BC30-treated mice, there was evidence of better stool consistency, as well as improved biochemical and histological indices of colitis, following initial treatment of animals with vancomycin.ConclusionBC30 limited the recurrence of CD-induced colitis following vancomycin withdrawal in mice.

Profound Alterations of Intestinal Microbiota following a Single Dose of Clindamycin Results in Sustained Susceptibility to Clostridium difficile-Induced Colitis

Antibiotic-induced changes in the intestinal microbiota predispose mammalian hosts to infection with antibiotic-resistant pathogens. Clostridium difficile is a Gram-positive intestinal pathogen that causes colitis and diarrhea in patients following antibiotic treatment. Clindamycin predisposes patients to C. difficile colitis. Here, we have used Roche-454 16S rRNA gene pyrosequencing to longitudinally characterize the intestinal microbiota of mice following clindamycin treatment in the presence or absence of C. difficile infection. We show that a single dose of clindamycin markedly reduces the diversity of the intestinal microbiota for at least 28 days, with an enduring loss of ca. 90% of normal microbial taxa from the cecum. Loss of microbial complexity results in dramatic sequential expansion and contraction of a subset of bacterial taxa that are minor contributors to the microbial consortium prior to antibiotic treatment. Inoculation of clindamycin-treated mice with C. difficile (VPI 10463) spores results in rapid development of diarrhea and colitis, with a 4- to 5-day period of profound weight loss and an associated 40 to 50% mortality rate. Recovering mice resolve diarrhea and regain weight but remain highly infected with toxin-producing vegetative C. difficile bacteria and, in comparison to the acute stage of infection, have persistent, albeit ameliorated cecal and colonic inflammation. The microbiota of "recovered" mice remains highly restricted, and mice remain susceptible to C. difficile infection at least 10 days following clindamycin, suggesting that resolution of diarrhea and weight gain may result from the activation of mucosal immune defenses.

Bacillus Coagulans (Bc 30) Improves Some Indices of Clostridium difficile-Induced Colitis in Mice

to be the prime players in the fermentation of the labeled starch. Similarly, a species closely related to Dorea from the Clostridium cluster XIVa was found to be the prime player in the fermentation of 13C-inulin, while Bifidobacterium adolescentis played an important role in the fermentation of 13C-lactose. In terms of metabolite production, propionate was found to be exclusively formed through the succinate pathway from starch, while a mixture of this pathway with the acrylate pathway was employed on inulin and lactose. This type of detailed information about the fermentation of substrates in the context of a complex microbiota can only be obtained through the use of stable isotope labeled substrates. It allows for the exact amount of kcal/g to be determined, and thus also the role of the microbiota in obesity can be assessed in detail. As an example, the caloric value of inulin (based on the metabolites that were produced from it) was found to be 2.05 kcal/g. In addition, the effect of microbial metabolites on gut health can be assessed. For this we have developed sophisticated gastroenterological tools to sample the colon in (healthy) human volunteers. The combination of these techniques holds great promise to unravel the processes occurring in the colon and linking them to health and disease.

Bacillus Coagulans GBI-30 (BC30) improves indices of Clostridium difficile-Induced colitis in mice

BackgroundProbiotics have beneficial effects in rodent models of Clostridium difficile (C. diffiicle)-induced colitis. The spore forming probiotic strain Bacillus Coagulans GBI-30, 6086 (BC30) has demonstrated anti-inflammatory and immune-modulating effects in vitro. Our goal was to determine if BC30 improved C. difficile-induced colitis in mice. Starting on study day 0, female C57BL/6 mice were dosed by oro-gastric gavage for 15 days with vehicle (saline) or BC30 (2 × 109 CFU per day). Mice in the C. difficile groups received an antibiotic mixture (study days 5 to 8 in the drinking water), and clindamycin (10 mg/kg, i.p., on study day 10). The C. difficile strain VPI 10463 was given by gavage at 104 CFU to induce colitis on day 11. On day 16, stools and colons were collected for further analyses.ResultsAll mice treated with BC30 survived on study day 13, while two mice treated with vehicle did not survive. On day 12, a significant difference (p = 0.0002) in the percentage of mice with normal stools (66.7%) was found in the BC30/C. difficile group, as compared to the vehicle/C. diffcile group (13.0%). On study day 16, 23.8% of mice treated with BC30 had normal stools, while this value was 0% with vehicle treatment (p value = 0.0187). On this day, the stool consistency score for the BC30/C. difficile group (1.1 ± 0.2) was significantly lower (p < 0.05) than for the vehicle/C. difficile cohort (1.9 ± 0.2). BC30 modestly attenuated the colonic pathology (crypt damage, edema, leukocyte influx) that was present following C. difficile infection. Colonic MIP-2 chemokine contents (pg/2 cm colon) were: 10.2 ± 0.5 (vehicle/no C. difficile), 24.6 ± 9.5 (vehicle/C. difficile) and 16.3 ± 4.3 (BC30/C. difficle).ConclusionThe probiotic BC30 improved some parameters of C. difficile-induced colitis in mice. BC30 prolonged the survival of C. diffiicle infected mice. Particularly, this probiotic improved the stool consistency of mice, in this infectious colitis model.

Clinical Indications for Probiotics: An Overview

Probiotic bacteria are used to treat or prevent a broad range of human diseases, conditions, and syndromes. In addition, there are areas of medical use that have been proposed for future probiotic applications. Randomized double-blind studies have provided evidence of probiotic effectiveness for the treatment and prevention of acute diarrhea and antibiotic-induced diarrhea, as well as for the prevention of cow milk-induced food allergy in infants and young children. Research studies have also provided evidence of effectiveness for the prevention of traveler's diarrhea, relapsing Clostridium difficile-induced colitis, and urinary tract infections. There are also studies indicating that probiotics may be useful for prevention of respiratory infections in children, dental caries, irritable bowel syndrome, and inflammatory bowel disease. Areas of future interest for the application of probiotics include colon and bladder cancers, diabetes, and rheumatoid arthritis. The probiotics with the greatest number of proven benefits are Lactobacillus rhamnosus strain GG and Saccharomyces boulardii.

Antibiotic administration in patients undergoing common surgical procedures in a community teaching hospital: the chaos continues.

The influence of recently published guidelines by the Surgical Infection Society (SIS) on current surgical practice are not well documented. The appropriateness of antibiotic administration in a cohort of surgical patients undergoing elective and emergency surgery in a department of surgery in an urban, community-based, private, 560-bed teaching hospital was retrospectively reviewed. The following were the criteria defining administration as appropriate as modified from SIS guidelines: Prophylactic use: (1) started prior to operation; (2) spectrum appropriate to the specific operation; (3) duration </= 24 hours. Therapeutic use: (1) started prior to operation; (2) spectrum appropriate to pathology; (3) Duration </= 24 hours for contamination or "resectable" infection and </= 5 days for established infection in the absence of clinical evidence of persisting infection. Any switchover from an appropriate agent to another appropriate or inappropriate agent in the same patient in the absence of microbiologic or clinical indication was considered inappropriate administration. We reviewed the charts of 211 randomly selected patients who underwent elective (n = 132) or emergency (n = 79) procedures during 1996. The operations included gastrectomy (n = 22), appendectomy (n = 27), open (n = 5) or laparoscopic (n = 27) cholecystectomy, colectomy (n = 28), hysterectomy (n = 8), laparotomy for intestinal obstruction (n = 11), mastectomy (n = 26), and ventral hernia repair (n = 37). A total of 17 antibiotics were used for prophylaxis and 21 for therapy. In 156 patients (74%) the administration was considered inappropriate. Eight patients in the inappropriate group developed diarrhea (two cases of Clostridium difficile-induced colitis) compared to two cases of diarrhea in the appropriate group (nonsignificant). The average duration of administration after elective and emergency operations was 3.3 and 5. 7 days, respectively. The total expense for excessive duration of administration was $18,533. Many surgeons are not familiar with the spectrum of antimicrobials and often do not distinguish between prophylactic and therapeutic administration. Antibiotic usage in current surgical practice is often inappropriate, excessive, and chaotic.

Update on Clostridium difficile-induced colitis

Update on Clostridium difficile-induced colitis

Update on Clostridium difficile-induced colitis, part 2

Clostridium difficile is a nosocomial pathogen able to survive unfavorable environments by sporulation; when conditions advantageous for rapid growth appear, the vegetative form is regenerated. Lack of conscientious hand washing and failure of health care providers to use disposable gloves facilitate transmission within institutions. Exposure to certain antimicrobials expedites C. difficile overgrowth within the colon by altering the composition of the normal gut microflora. Antineoplastic agents may also precipitate CDIC. The characteristics of the colonizing strain, the properties of the inciting drug, and individual host factors collectively seem to govern the expression of the disorder. Clinical presentations range from self-limiting diarrhea to severe diarrhea accompanied by abdominal pain, fever, and leukocytosis to potentially life-threatening PMC. A preponderance of data supports the interpretation that oral metronidazole and oral vancomycin are therapeutically equivalent for the treatment of all but the most severe cases of CDIC. Whether the two drugs are equivalent in severe CDIC is controversial and will probably remain so in the absence of a well-designed trial to expand on the findings of the study by Teasley et al. Because of the cost difference and therapeutic equivalence, oral metronidazole should be the preferred routine treatment for CDIC; oral vancomycin should be reserved for severe cases and cases that fail to respond to at least six days of oral metronidazole therapy. Another important argument, albeit a hypothetical one, for limiting institutional use of oral vancomycin is to minimize selective environmental pressure for the emergence and dissemination of vancomycin-resistant enterococci. An epidemic outbreak of CDIC caused by clindamycin-resistant C. difficile in an institution where clindamycin use was extremely high illustrates the possible consequences of such selective pressure. Oral metronidazole 250 mg four times daily will usually provide a satisfactory response, but clinicians may wish to consider increasing the total daily dose for some patients who have symptoms like fever and leukocytosis. For oral vancomycin, 125 mg four times daily is sufficient in virtually all circumstances. Ten days of therapy is usually adequate for either drug. CDIC in a patient unable to take medications orally presents a bit of a therapeutic dilemma. Two approaches that appear effective are rectal administration of vancomycin and intravenous administration of metronidazole, although intravenous metronidazole can fail to work, possibly because the colonic concentrations achieved are inadequate. Clinicians may wish to consider a total daily dose of intravenous metronidazole that is at the upper end of the adult dosage range, if this is feasible.(ABSTRACT TRUNCATED AT 400 WORDS)

Update on Clostridium difficile-induced colitis, Part 1

Recent findings on the epidemiology, pathogenesis, clinical manifestations, diagnosis, and treatment of Clostridium difficile-induced colitis (CDIC) are discussed. CDIC is a gastrointestinal disorder that results from colonization by and overgrowth of C. difficile. Among patients in the community who are treated with an oral antimicrobial, only 1 to 3 individuals per 100,000 develop CDIC, compared with as many as 1 per 100 hospitalized patients treated with an antimicrobial. The requirements for CDIC are (1) a readily available source of C. difficile; (2) exposure to drugs, most commonly certain antimicrobials, that disrupt the normal colonic microflora; (3) production of the requisite cytotoxins by the C. difficile strain colonizing the colon; and (4) the presence of individual risk factors, including advanced age, severe underlying illness, and a prolonged hospital stay. Among the varied clinical manifestations of CDIC, diarrhea is predominant and is often the sole symptom. In more severe cases, fever and leukocytosis are also present. The formation of pseudomembranous plaques is pathognomonic but relatively infrequent. Presumptive diagnosis is usually based on a positive cytotoxin assay result in the symptomatic patient. Patients who respond to discontinuation of the inciting drug or drugs should not be treated indiscriminately with antimicrobials. Asymptomatic carriers should not be treated, and a period of watchful waiting may be advisable in mild cases. When treatment is necessary, oral metronidazole is the agent of choice in all but the most severe cases. Whether oral metronidazole is therapeutically equivalent to oral vancomycin in severe CDIC is controversial. Regardless of the antimicrobial used, some patients suffer a recurrence of CDIC and a few have several relapses. There have been no comparative studies of treatment for relapsing CDIC. Of the investigational treatments, the tiacumicin macrolides and the yeast Saccharomyces boulardii appear most promising. Diagnostic assays based on the polymerase chain reaction should allow more timely intervention. Health care professionals who improve their understanding of CDIC will be better able to recognize the disorder, select the best treatment, and perhaps reduce the frequency of CDIC in hospitalized patients by working to alter patterns of antimicrobial use.