Microbial hydrogen economy alleviates colitis by reprogramming colonocyte metabolism and reinforcing intestinal barrier.

With the rapid development and high therapeutic efficiency and biosafety of gas-involving theranostics, hydrogen medicine has been particularly outstanding because hydrogen gas (H2), a microbial-derived gas, has potent anti-oxidative, anti-apoptotic, and anti-inflammatory activities in many disease models. Studies have suggested that H2-enriched saline/water alleviates colitis in murine models; however, the underlying mechanism remains poorly understood. Despite evidence demonstrating the importance of the microbial hydrogen economy, which reflects the balance between H2-producing (hydrogenogenic) and H2-utilizing (hydrogenotrophic) microbes in maintaining colonic mucosal ecosystems, minimal efforts have been exerted to manipulate relevant H2-microbe interactions for colonic health. Consistent with previous studies, we found that administration of hydrogen-rich saline (HS) ameliorated dextran sulfate sodium-induced acute colitis in a mouse model. Furthermore, we demonstrated that HS administration can increase the abundance of intestinal-specific short-chain fatty acid (SCFA)-producing bacteria and SCFA production, thereby activating the intracellular butyrate sensor peroxisome proliferator-activated receptor γ signaling and decreasing the epithelial expression of Nos2, consequently promoting the recovery of the colonic anaerobic environment. Our results also indicated that HS administration ameliorated disrupted intestinal barrier functions by modulating specific mucosa-associated mucolytic bacteria, leading to substantial inhibition of opportunistic pathogenic Escherichia coli expansion as well as a significant increase in the expression of interepithelial tight junction proteins and a decrease in intestinal barrier permeability in mice with colitis. Exogenous H2 reprograms colonocyte metabolism by regulating the H2-gut microbiota-SCFAs axis and strengthens the intestinal barrier by modulating specific mucosa-associated mucolytic bacteria, wherein improved microbial hydrogen economy alleviates colitis.

Immunomodulatory assessment of Portulaca oleracea L. extract in a mouse model of colitis.

Ulcerative colitis (UC) is a gastrointestinal inflammatory disease with a multifactorial pathophysiology. This study aims to investigate the immunomodulatory effect of Portulaca oleracea leaf ethanolic extract (POE) on acetic acid (AA)-induced UC in mice. Experimental animals received oral doses of POE (200 mg/kg for 7 days) after an induction of colitis by intrarectal AA administration. In mice with AA-induced UC treated with POE, the results revealed a significant modulation in body weight and colon length. Moreover, treatment with POE downregulated the interleukin 1, 6, and 17, tumor necrosis factor-alpha, gamma interferon, and nuclear factor-kappa B levels compared with the colitis group. Furthermore, POE markedly inhibited histological damage, decreased myeloperoxidase activity and reduced fecal calprotectin level compared with the colitis group. These data are consistent with the reduction in total bacterial content in the colon. Taken together, treatment with POE may reduce colonic inflammation by alleviating the immune response and inhibiting the severity of colitis. The HPLC analysis of POE resulted in the identification of seven medicinal compounds comprising two phenolic acids (ferulic and caffeic acids) and five flavonoids (kaempferol, quercetin, rutin, narenginin and hesperidin). Subsequent analysis of POE by GC-MS revealed ten phytocomponents; the major percentages were hexadecenoic acid, methyl ester (29.8119%), α-linolenic acid (25.8431%), 16-octadecenoic acid, methyl ester (15.1578%) and α-tocopherol (10.7848%). Delta-lactams and alkanes were the minor components. Such natural plant-derived substances and their probable synergistic action appear to contribute to a promising therapeutic protocol for colitis.

Worm-Based Alternate Assessment of Probiotic Intervention against Gut Barrier Infection.

The epithelial barrier is the frontline defense against enteropathogenic bacteria and nutrition-linked xenobiotic stressors in the alimentary tract. In particular, enteropathogenic Escherichia coli (EPEC) insults the gut barrier and is increasingly implicated in chronic intestinal diseases such as inflammatory bowel disease. For the efficient development of intervention against barrier-linked distress, the present study provided a Caenorhabditis elegans-based assessment instead of extensive preclinical evaluations using mammalian models. In particular, EPEC infected the gut and shortened the lifespan of C. elegans, which was counteracted by colonization of E. coli strain Nissle 1917 (EcN). In addition to the competitive actions of EcN against EPEC, EcN improved the gut barrier integrity of worms via the Zonula occludens ortholog (Zoo-1) induction, which was verified in the murine infection and colitis model. The worm-based assessment provided a crucial methodology and important insights into the potent chronic events in the human gut barrier after the ingestion of probiotic candidates as a mucoactive dietary or therapeutic agent.

Evaluation of fixed and variable hospital costs due to Clostridium difficile infection: institutional incentives and directions for future research.

BACKGROUND: Economic analysis of Clostridium difficile infection (CDI) should consider the incentives facing institutional decision-makers. To avoid overstating the financial benefits of infection prevention, fixed and variable costs should be distinguished. AIM: To quantify CDI fixed and variable costs in a tertiary referral hospital during August 2015. METHODS: A micro-costing analysis estimated CDI costs per patient, including the additional costs of a CDI outbreak. Resource use was quantified after review of patient charts, pharmacy data, administrative resource input, and records of salary and cleaning/decontamination expenditure. FINDINGS: The incremental cost of CDI was €75,680 (mean: €5,820 per patient) with key cost drivers being cleaning, pharmaceuticals, and length of stay (LOS). Additional LOS ranged from 1.75 to 22.55 days. For seven patients involved in a CDI outbreak, excluding the value of the 58 lost bed-days (€34,585); costs were 30% higher (€7,589 per patient). Therefore, total spending on CDI was €88,062 (mean: €6,773 across all patients). Potential savings from variable costs were €1,026 (17%) or €1,768 (26%) if outbreak costs were included. Investment in an antimicrobial pharmacist would require 47 CDI cases to be prevented annually. Prevention of 5%, 10% and 20% CDI would reduce attributable costs by €4,403, €8,806 and €17,612. Increasing the incremental LOS attributable to CDI to seven days per patient would have increased costs to €7,478 or €8,431 (if outbreak costs were included). CONCLUSION: As much CDI costs are fixed, potential savings from infection prevention are limited. Future analysis must consider more effectively this distinction and its impact on institutional decision-making.

The burden of healthcare-associated Clostridium difficile infection in a non-metropolitan setting.

OBJECTIVE: Healthcare-associated Clostridium difficile infection (HCA-CDI) remains a major cause of morbidity and mortality in industrialized countries. However, few data exist on the burden of HCA-CDI in multi-site non-metropolitan settings. This study examined the introduction of an antimicrobial stewardship programme (ASP) in relation to HCA-CDI rates, and the effect of HCA-CDI on length of stay (LOS) and hospital costs. METHODS: A comparative before-and-after intervention study of patients aged ≥16 years with HCA-CDI from December 2010 to April 2016 across the nine hospitals of a non-metropolitan health district in New South Wales, Australia was undertaken. The intervention comprised a multi-site ASP supported by a clinical decision support system, with subsequent introduction of email feedback of HCA-CDI cases to admitting medical officers. MAIN OUTCOME MEASURES: HCA-CDI rates, comparative LOS and hospital costs, prior use of antimicrobials and proton pump inhibitors, and appropriateness of CDI treatment. RESULTS: HCA-CDI rates rose from 3.07 to 4.60 cases per 10,000 occupied bed-days pre-intervention, and remained stable at 4 cases per 10,000 occupied bed-days post-intervention (P=0.24). Median LOS (17 vs six days; P<0.01) and hospital costs (AU$19,222 vs $7861; P<0.01) were significantly greater for HCA-CDI cases (N=91) than for matched controls (N=172). Half of the patients with severe HCA-CDI (4/8) did not receive initial appropriate treatment (oral vancomycin). CONCLUSIONS: HCA-CDI placed a significant burden on the regional and rural health service through increased LOS and hospital costs. Interventions targeting HCA-CDI could be employed to consolidate the effects of ASPs.

High morbidity and mortality of Clostridium difficile infection and its associations with ribotype 002 in Hong Kong.

OBJECTIVES: We aim to study the disease burden, risk factors and severity of Clostridium difficile infection (CDI) in Hong Kong. METHODS: We conducted a prospective, case-control study in three acute-care hospitals in Hong Kong. Adult inpatients who developed CDI diarrhoea confirmed by PCR (n = 139) were compared with the non-CDI controls (n = 114). Ribotyping of isolates and antimicrobial susceptibility testing were performed. RESULTS: The estimated crude annual incidence of CDI was 23-33/100,000 population, and 133-207/100,000 population among those aged ≥65 years. The mean age of CDI patients was 71.5. Nursing home care, recent hospitalization, antibiotics exposure (adjusted OR 3.0, 95% CI 1.3-7.1) and proton-pump inhibitors use (adjusted OR 2.2, 95% CI 1.2-3.9) were risk factors. Severe CDI occurred in 41.7%. Overall mortality was 16.5% (among severe CDI, 26.5%). The commonest ribotypes were 002 (22.8%), 014 (14.1%), 012 and 046; ribotype 027 was absent. Ribotype 002 was associated with fluoroquinolone resistance and higher mortality (47.6% vs. 12.7%; adjusted HR 2.8, 95% CI 1.1-7.0). CONCLUSIONS: Our findings show high morbidity and mortality of CDI in the older adults, and identify ribotype 002 as a possible virulent strain causing serious infections in this cohort.

Physiological relevance of food grade microcapsules: Impact of milk protein based microcapsules on inflammation in mouse models for inflammatory bowel diseases.

In order to increase beneficial effects of bioactive compounds in functional food and dietary supplements, enormous efforts are put in the technological development of microcapsules. Although these products are often tailor-made for disease susceptible consumer, the physiological impact of microcapsule uptake on the respective target consumer has never been addressed. The present study aimed to assess the relevance of this aspect by analyzing the impact of milk protein based microcapsules on experimental inflammatory bowel disease. Long-term feeding of sodium caseinate or rennet gel microcapsules resulted in significant alterations in the intestinal microbiota of healthy mice. In TNFΔARE/wt mice, a model for chronic ileal inflammation, rennet gel microcapsules resulted in further increased splenomegaly, whereas ileal inflammation was unchanged. In IL10(-/-) mice, a model for chronic colitis, both types of microcapsules induced a local increase of the intestinal inflammation. The present study is the first to demonstrate that, independent of their cargo, microcapsules have the potential to affect the intestinal microbiota and to exert unprecedented detrimental effects on disease-susceptible individuals. In conclusion, the impact of microcapsule uptake on the respective target consumer groups should be thoroughly investigated in advance to their commercial use in functional food or dietary supplements.

Clostridium difficile colitis in patients undergoing lumbar spine surgery.

STUDY DESIGN: Retrospective database analysis. OBJECTIVE: To investigate incidence, comorbidities, and impact on health care resources of Clostridium difficile infection after lumbar spine surgery. SUMMARY OF BACKGROUND DATA: C. difficile colitis is reportedly increasing in hospitalized patients and can have a negative impact on patient outcomes. No data exist on estimates of C. difficile infection rates and its consequences on patient outcomes and health care resources among patients undergoing lumbar spine surgery. METHODS: The Nationwide Inpatient Sample was examined from 2002 to 2011. Patients were included for study based on International Classification of Diseases, Ninth Revision, Clinical Modification, procedural codes for lumbar spine surgery for degenerative diagnoses. Baseline patient characteristics were determined and multivariable analyses assessed factors associated with increased incidence of C. difficile and risk of mortality. RESULTS: The incidence of C. difficile infection in patients undergoing lumbar spine surgery is 0.11%. At baseline, patients infected with C. difficile were significantly older (65.4 yr vs. 58.9 yr, P<0.0001) and more likely to have diabetes with chronic complications, neurological complications, congestive heart failure, pulmonary disorders, coagulopathy, and renal failure. Lumbar fusion (P=0.0001) and lumbar fusion revision (P=0.0003) were associated with increased odds of postoperative infection. Small hospital size was associated with decreased odds (odds ratio [OR], 0.5; P<0.001), whereas urban hospitals were associated with increased odds (OR, 2.14; P<0.14) of acquiring infection. Uninsured (OR, 1.62; P<0.0001) and patients with Medicaid (OR, 1.33; P<0.0001) were associated with higher odds of acquiring postoperative infection. C. difficile increased hospital length of stay by 8 days (P<0.0001), hospital charges by 2-fold (P<0.0001), and inpatient mortality to 4% from 0.11% (P<0.0001). CONCLUSION: C. difficile infection after lumbar spine surgery carries a 36.4-fold increase in mortality and costs approximately $10,658,646 per year to manage. These data suggest that great care should be taken to avoid C. difficile colitis in patients undergoing lumbar spine surgery because it is associated with longer hospital stays, greater overall costs, and increased inpatient mortality. LEVEL OF EVIDENCE: 3.

The morbidity of Clostridium difficile infection after elective colonic resection-results from a national population database.

BACKGROUND: Clostridium difficile (CD), a gram-positive rod bacterium, resides normally within the human colon. Antibiotic treatment alters normal colonic flora, potentiating abnormal overgrowth of CD. METHODS: This study examined the 2004 to 2006 Nationwide Inpatient Sample to determine outcomes of CD colitis after 695,010 elective colonic resections. RESULTS: CD infection, occurring in 1.4% of patients, was associated with higher pulmonary (12.1% vs 6.4%) and gastrointestinal (12.8% vs 10.5%) complications as well as an increased length of stay (22.6 vs 10.9 days) and mortality (16.2% vs 4.9%; all P < .001). CD colitis patients more frequently held Medicare insurance (68% vs 51%) and underwent small segmental colonic resection as opposed to a defined anatomic resection (20.0% vs 9.9%; P < .001). An underlying diagnosis of colon cancer was associated with a lower incidence of CD colitis (odds ratio, .71; 95% confidence interval, .59-.84; P < .001). CONCLUSIONS: CD colitis is associated with worse outcomes after elective colonic resection.

1H NMR-based metabonomic assessment of probiotic effects in a colitis mouse model.

Metabolic profiling of the fecal extracts of male mice was carried out to assess the effects of probiotics on colonic inflammation using (1)H NMR spectroscopy coupled with multivariate data analysis. The control group (n = 5) was administered phosphate buffered saline for 14 days. Acute colitis was induced with dextran sulfate sodium (DSS) for 7 days following administration of phosphate buffered saline for 7 days (DSS-treated group, n = 5). LAB + DSS-treated group (n = 5) was administered lactic acid bacteria (LAB) daily for 7 days followed by treatment with DSS for 7 days to investigate protective effect of LAB against DSS-inducible colitis. Histological damage, myeloperoxidase activity, and malondialdehyde content of colon tissue were reduced, whereas colon length increased in LAB + DSS-treated mice compared to those in DSS-treated mice. DSS treatment was associated with fecal excretion of amino acids, short chain fatty acids, and nucleotides, revealing significant decreases of threonine, alanine, glutamate, glutamine, aspartate, lysine, glycine, butyrate, uracil, and hypoxanthine together with increases of monosaccharides, glucose, and trimethylamine in the feces of mice with DSS-induced colitis. Increased levels of acetate, butyrate, and glutamine and decreased levels of trimethylamine were found in the feces of LAB + DSS-treated mice compared to DSS-treated mice alone. The increased short chain fatty acids levels in the feces of mice fed with LAB indicate that the probiotics have protective effects against DSS-induced colitis via modulation of the gut microbiota. This work highlights the possibility for alternative approach of metabonomics in feces for assessing the probiotic effect in an animal model of inflammatory bowel disease.

The burden of Clostridium difficile in surgical patients in the United States.

BACKGROUND: Clostridium difficile colitis is the predominant hospital-acquired gastrointestinal infection in the United States and has emerged as an important nosocomial cause of morbidity and death. Although several institutional studies have examined the effects of C. difficile on hospitalized patients, its nationwide impact on surgical patients has yet to be defined. METHODS: To provide a national estimate of the burden of C. difficile, we performed a five-year retrospective analysis of the Agency for Healthcare Research and Quality's National Inpatient Sample Database, which represents a stratified 20% sample of hospitals in the United States, from 1999 to 2003. All surgical inpatient discharge data from 997 hospitals in 37 states were analyzed to determine the association of C. difficile infections with patient demographics, hospital characteristics, surgical procedure, length of stay (LOS), total charges, and in-hospital mortality rate. Univariate analysis was performed to identify any association between the presence of C. difficile infection and the outcome variables using chi-square contingency table analysis or the Student t-test following the exclusion of patients with other medical complications. Multivariate regression analysis was used to determine whether the presence of C. difficile infection was an independent predictor of increased LOS, total charges, and in-hospital mortality rate when controlling for surgery type, age, sex, payor, and hospital characteristics. RESULTS: Clostridium difficile infection was reported as a discharge diagnosis for 8,113 (0.52%) of all 1,553,597 inpatients who had undergone a general surgical procedure. The incidence increased significantly in 2002 (34% higher than in 2001; p < 0.0001). The following patient and hospital characteristics were associated with the highest incidence of C. difficile infection (all p < 0.0001): Age > 64 years (0.95%); Medicare beneficiary status (0.94%); north-eastern hospital location (0.73%); and large (0.55%), urban (0.56%), or teaching hospital (0.61%). Patients undergoing an emergency operation were at higher risk than those having operations performed electively (0.8% vs. 0.3%; p < 0.0001). Colectomy, small-bowel resection, and gastric resection were associated with the highest risk of C. difficile infection (incidence after colectomy 1.11%; odds ratio [OR] 2.77, 95% confidence interval [CI] 2.65, 2.89, p < 0.0001; small-bowel resection 1.17%, OR 2.40, 95% CI 2.26, 2.54, p < 0.0001; gastric resection 1.02%, OR 2.26, 95% CI 2.03, 2.52, p < 0.0001). Patients undergoing cholecystectomy and appendectomy had the lowest risk of C. difficile infection (cholecystectomy 0.41%, OR 0.37, 95% CI 0.35, 0.39, p < 0.0001; appendectomy 0.20%, OR 0.45, 95% CI 0.42, 0.49, p < 0.0001). Multivariable analysis demonstrated that C. difficile was an independent predictor of LOS, which increased by 16.0 days (95% CI 15.6, 16.4 days; p < 0.0001) in the presence of infection. Total charges increased by $77,483 (95% CI $75,174, $79,793; p < 0.0001), and there was a 3.4-fold increase in the mortality rate (95% CI 3.02, 3.77; p < 0.0001) compared with patients who did not acquire C. difficile. CONCLUSIONS: Epidemiologic data suggest that the incidence of C. difficile infection is increasing in U.S. surgical patients and that the infection is most prevalent after emergency operations and among patients having intestinal tract resections. Infection with C. difficile is an independent predictor of increased LOS, total charges, and mortality rate after surgery and represents a considerable burden to both patients and hospitals. Preventing C. difficile infection offers a potentially significant improvement in patient outcomes, as well as a reduction in hospital costs and resource expenditures.

[Effect of bificol on the intestinal microflora of chronic colitis patients working in antiboitic prodiction]. / Vliianie bifikola na mikrofloru kishechnika bol'nykh knronicheskim kolitom u usloviiakh proizvodstva antibiotikov

Data on the use of bificol, a new Soviet preparation, and its effect on the intestine microflora of patients with chronic colitis occupied in production of penicillin are presented. It was shown that by the 28th day of the preparation use the level of the intestine bacteria in the patients' intestine reliably increased. The number of immobile strains decreased from 67.6 to 36.6 per cent. Bifidoflora normalized by the 14th day of the treatment. Some clinical inprovement, i.e. stool normalization, lessening of the stomach pain, increased appetite were observed by the 4th--5th day of the treatment with bificol. On the basis of the microbiological and clinical data it was shown that treatment of the patients with chronic colitis in antibiotic production should continue for at least 28 days and in individual cases for longer periods of time. It is recommended to use the preparation in 10 doses a day divided into 2 parts.