Gut microbiota mediates diurnal variation of acetaminophen induced acute liver injury in mice. Gong Shenhai,Lan Tian,Zeng Liyan,Luo Haihua,Yang Xiaoyu,Li Na,Chen Xiaojiao,Liu Zhanguo,Li Rui,Win Sanda,Liu Shuwen,Zhou Hongwei,Schnabl Bernd,Jiang Yong,Kaplowitz Neil,Chen Peng Journal of hepatology BACKGROUND & AIMS:Acetaminophen (APAP) induced hepatotoxicity is a leading cause of acute liver failure worldwide. It is well established that the liver damage induced by acetaminophen exhibits diurnal variation. However, the detailed mechanism for the hepatotoxic variation is not clear. Herein, we aimed to determine the relative contributions of gut microbiota in modulating the diurnal variation of hepatotoxicity induced by APAP. METHODS:Male Balb/C mice were treated with or without antibiotics and a single dose of orally administered APAP (300 mg/kg) at ZT0 (when the light is on-start of resting period) and ZT12 (when the light is off-start of active period). RESULTS:In agreement with previous findings, hepatic injury was markedly enhanced at ZT12 compared with ZT0. Interestingly, upon antibiotic treatment, ZT12 displayed a protective effect against APAP hepatotoxicity similar to ZT0. Moreover, mice that received the cecal content from ZT12 showed more severe liver damage than mice that received the cecal content from ZT0. 16S sequencing data revealed significant differences in the cecal content between ZT0 and ZT12 in the compositional level. Furthermore, metabolomic analysis showed that the gut microbial metabolites were also different between ZT0 and ZT12. Specifically, the level of 1-phenyl-1,2-propanedione (PPD) was significantly higher at ZT12 than ZT0. Treatment with PPD alone did not cause obvious liver damage. However, PPD synergistically enhanced APAP-induced hepatic injury in vivo and in vitro. Finally, we found Saccharomyces cerevisiae, which could reduce intestinal PPD levels, was able to markedly alleviate APAP-induced liver damage at ZT12. CONCLUSIONS:The gut microbial metabolite PPD was responsible, at least in part, for the diurnal variation of hepatotoxicity induced by APAP by decreasing glutathione levels. LAY SUMMARY:Acetaminophen (APAP) induced acute liver failure because of over dose is a leading public health problem. APAP-induced liver injury exhibits diurnal variation, specifically APAP causes more severe liver damage when taken at night compared with in the morning. Herein, we showed that gut microbial metabolite, 1-phenyl-1,2-propanedione is involved in the rhythmic hepatotoxicity induced by APAP, by depleting hepatic glutathione (an important antioxidant) levels. Our data suggest gut microbiota may be a potential target for reducing APAP-induced acute liver injury. 10.1016/j.jhep.2018.02.024
    Prebiotics Reduce Body Fat and Alter Intestinal Microbiota in Children Who Are Overweight or With Obesity. Nicolucci Alissa C,Hume Megan P,Martínez Inés,Mayengbam Shyamchand,Walter Jens,Reimer Raylene A Gastroenterology BACKGROUND & AIMS:It might be possible to manipulate the intestinal microbiota with prebiotics or other agents to prevent or treat obesity. However, little is known about the ability of prebiotics to specifically modify gut microbiota in children with overweight/obesity or reduce body weight. We performed a randomized controlled trial to study the effects of prebiotics on body composition, markers of inflammation, bile acids in fecal samples, and composition of the intestinal microbiota in children with overweight or obesity. METHODS:We performed a single-center, double-blind, placebo-controlled trial of 2 separate cohorts (March 2014 and August 2014) at the University of Calgary in Canada. Participants included children, 7-12 years old, with overweight or obesity (>85th percentile of body mass index) but otherwise healthy. Participants were randomly assigned to groups given either oligofructose-enriched inulin (OI; 8 g/day; n=22) or maltodextrin placebo (isocaloric dose, controls; n=20) once daily for 16 weeks. Fat mass and lean mass were measured using dual-energy-x-ray absorptiometry. Height, weight, and waist circumference were measured at baseline and every 4 weeks thereafter. Blood samples were collected at baseline and 16 weeks, and analyzed for lipids, cytokines, lipopolysaccharide, and insulin. Fecal samples were collected at baseline and 16 weeks; bile acids were profiled using high-performance liquid chromatography and the composition of the microbiota was analyzed by 16S rRNA sequencing and quantitative polymerase chain reaction. The primary outcome was change in percent body fat from baseline to 16 weeks. RESULTS:After 16 weeks, children who consumed OI had significant decreases in body weight z-score (decrease of 3.1%), percent body fat (decrease of 2.4%), and percent trunk fat (decrease of 3.8%) compared with children given placebo (increase of 0.5%, increase of 0.05%, and decrease of 0.3%, respectively). Children who consumed OI also had a significant reduction in level of interleukin 6 from baseline (decrease of 15%) compared with the placebo group (increase of 25%). There was a significant decrease in serum triglycerides (decrease of 19%) in the OI group. Quantitative polymerase chain reaction showed a significant increase in Bifidobacterium spp. in the OI group compared with controls. 16S rRNA sequencing revealed significant increases in species of the genus Bifidobacterium and decreases in Bacteroides vulgatus within the group who consumed OI. In fecal samples, levels of primary bile acids increased in the placebo group but not in the OI group over the 16-week study period. CONCLUSIONS:In a placebo-controlled, randomized trial, we found a prebiotic (OI) to selectively alter the intestinal microbiota and significantly reduce body weight z-score, percent body fat, percent trunk fat, and serum level of interleukin 6 in children with overweight or obesity (Clinicaltrials.gov no: NCT02125955). 10.1053/j.gastro.2017.05.055
    Microbiome Signatures Associated With Steatohepatitis and Moderate to Severe Fibrosis in Children With Nonalcoholic Fatty Liver Disease. Schwimmer Jeffrey B,Johnson Jethro S,Angeles Jorge E,Behling Cynthia,Belt Patricia H,Borecki Ingrid,Bross Craig,Durelle Janis,Goyal Nidhi P,Hamilton Gavin,Holtz Mary L,Lavine Joel E,Mitreva Makedonka,Newton Kimberly P,Pan Amy,Simpson Pippa M,Sirlin Claude B,Sodergren Erica,Tyagi Rahul,Yates Katherine P,Weinstock George M,Salzman Nita H Gastroenterology BACKGROUND & AIMS:The intestinal microbiome might affect the development and severity of nonalcoholic fatty liver disease (NAFLD). We analyzed microbiomes of children with and without NAFLD. METHODS:We performed a prospective, observational, cross-sectional study of 87 children (age range, 8-17 years) with biopsy-proven NAFLD and 37 children with obesity without NAFLD (controls). Fecal samples were collected and microbiome composition and functions were assessed using 16S ribosomal RNA amplicon sequencing and metagenomic shotgun sequencing. Microbial taxa were identified using zero-inflated negative binomial modeling. Genes contributing to bacterial pathways were identified using gene set enrichment analysis. RESULTS:Fecal microbiomes of children with NAFLD had lower α-diversity than those of control children (3.32 vs 3.52, P = .016). Fecal microbiomes from children with nonalcoholic steatohepatitis (NASH) had the lowest α-diversity (control, 3.52; NAFLD, 3.36; borderline NASH, 3.37; NASH, 2.97; P = .001). High abundance of Prevotella copri was associated with more severe fibrosis (P = .036). Genes for lipopolysaccharide biosynthesis were enriched in microbiomes from children with NASH (P < .001). Classification and regression tree model with level of alanine aminotransferase and relative abundance of the lipopolysaccharide pathway gene encoding 3-deoxy-d-manno-octulosonate 8-phosphate-phosphatase identified patients with NASH with an area under the receiver operating characteristic curve value of 0.92. Genes involved in flagellar assembly were enriched in the fecal microbiomes of patients with moderate to severe fibrosis (P < .001). Classification and regression tree models based on level of alanine aminotransferase and abundance of genes encoding flagellar biosynthesis protein had good accuracy for identifying case children with moderate to severe fibrosis (area under the receiver operating characteristic curve, 0.87). CONCLUSIONS:In an analysis of fecal microbiomes of children with NAFLD, we associated NAFLD and NASH with intestinal dysbiosis. NAFLD and its severity were associated with greater abundance of genes encoding inflammatory bacterial products. Alterations to the intestinal microbiome might contribute to the pathogenesis of NAFLD and be used as markers of disease or severity. 10.1053/j.gastro.2019.06.028
    Obesity: ANGPTL4 - the link binding obesity and glucose intolerance. Morris Alan Nature reviews. Endocrinology 10.1038/nrendo.2018.35
    Gut microbiota confers host resistance to obesity by metabolizing dietary polyunsaturated fatty acids. Miyamoto Junki,Igarashi Miki,Watanabe Keita,Karaki Shin-Ichiro,Mukouyama Hiromi,Kishino Shigenobu,Li Xuan,Ichimura Atsuhiko,Irie Junichiro,Sugimoto Yukihiko,Mizutani Tetsuya,Sugawara Tatsuya,Miki Takashi,Ogawa Jun,Drucker Daniel J,Arita Makoto,Itoh Hiroshi,Kimura Ikuo Nature communications Gut microbiota mediates the effects of diet, thereby modifying host metabolism and the incidence of metabolic disorders. Increased consumption of omega-6 polyunsaturated fatty acid (PUFA) that is abundant in Western diet contributes to obesity and related diseases. Although gut-microbiota-related metabolic pathways of dietary PUFAs were recently elucidated, the effects on host physiological function remain unclear. Here, we demonstrate that gut microbiota confers host resistance to high-fat diet (HFD)-induced obesity by modulating dietary PUFAs metabolism. Supplementation of 10-hydroxy-cis-12-octadecenoic acid (HYA), an initial linoleic acid-related gut-microbial metabolite, attenuates HFD-induced obesity in mice without eliciting arachidonic acid-mediated adipose inflammation and by improving metabolic condition via free fatty acid receptors. Moreover, Lactobacillus-colonized mice show similar effects with elevated HYA levels. Our findings illustrate the interplay between gut microbiota and host energy metabolism via the metabolites of dietary omega-6-FAs thereby shedding light on the prevention and treatment of metabolic disorders by targeting gut microbial metabolites. 10.1038/s41467-019-11978-0
    Gut Microbiota Promotes Obesity-Associated Liver Cancer through PGE-Mediated Suppression of Antitumor Immunity. Loo Tze Mun,Kamachi Fumitaka,Watanabe Yoshihiro,Yoshimoto Shin,Kanda Hiroaki,Arai Yuriko,Nakajima-Takagi Yaeko,Iwama Atsushi,Koga Tomoaki,Sugimoto Yukihiko,Ozawa Takayuki,Nakamura Masaru,Kumagai Miho,Watashi Koichi,Taketo Makoto M,Aoki Tomohiro,Narumiya Shuh,Oshima Masanobu,Arita Makoto,Hara Eiji,Ohtani Naoko Cancer discovery Obesity increases the risk of cancers, including hepatocellular carcinomas (HCC). However, the precise molecular mechanisms through which obesity promotes HCC development are still unclear. Recent studies have shown that gut microbiota may influence liver diseases by transferring its metabolites and components. Here, we show that the hepatic translocation of obesity-induced lipoteichoic acid (LTA), a Gram-positive gut microbial component, promotes HCC development by creating a tumor-promoting microenvironment. LTA enhances the senescence-associated secretory phenotype (SASP) of hepatic stellate cells (HSC) collaboratively with an obesity-induced gut microbial metabolite, deoxycholic acid, to upregulate the expression of SASP factors and COX2 through Toll-like receptor 2. Interestingly, COX2-mediated prostaglandin E (PGE) production suppresses the antitumor immunity through a PTGER4 receptor, thereby contributing to HCC progression. Moreover, COX2 overexpression and excess PGE production were detected in HSCs in human HCCs with noncirrhotic, nonalcoholic steatohepatitis (NASH), indicating that a similar mechanism could function in humans. We showed the importance of the gut-liver axis in obesity-associated HCC. The gut microbiota-driven COX2 pathway produced the lipid mediator PGE in senescent HSCs in the tumor microenvironment, which plays a pivotal role in suppressing antitumor immunity, suggesting that PGE and its receptor may be novel therapeutic targets for noncirrhotic NASH-associated HCC. . 10.1158/2159-8290.CD-16-0932
    Sex-specific association between gut microbiome and fat distribution. Min Yan,Ma Xiaoguang,Sankaran Kris,Ru Yuan,Chen Lijin,Baiocchi Mike,Zhu Shankuan Nature communications The gut microbiome has been linked to host obesity; however, sex-specific associations between microbiome and fat distribution are not well understood. Here we show sex-specific microbiome signatures contributing to obesity despite both sexes having similar gut microbiome characteristics, including overall abundance and diversity. Our comparisons of the taxa associated with the android fat ratio in men and women found that there is no widespread species-level overlap. We did observe overlap between the sexes at the genus and family levels in the gut microbiome, such as Holdemanella and Gemmiger; however, they had opposite correlations with fat distribution in men and women. Our findings support a role for fat distribution in sex-specific relationships with the composition of the microbiome. Our results suggest that studies of the gut microbiome and abdominal obesity-related disease outcomes should account for sex-specific differences. 10.1038/s41467-019-10440-5
    Interleukin-36 cytokines alter the intestinal microbiome and can protect against obesity and metabolic dysfunction. Giannoudaki Eirini,Hernandez-Santana Yasmina E,Mulfaul Kelly,Doyle Sarah L,Hams Emily,Fallon Padraic G,Mat Arimin,O'Shea Donal,Kopf Manfred,Hogan Andrew E,Walsh Patrick T Nature communications Members of the interleukin-1 (IL-1) family are important mediators of obesity and metabolic disease and have been described to often play opposing roles. Here we report that the interleukin-36 (IL-36) subfamily can play a protective role against the development of disease. Elevated IL-36 cytokine expression is found in the serum of obese patients and negatively correlates with blood glucose levels among those presenting with type 2 diabetes. Mice lacking IL-36Ra, an IL-36 family signalling antagonist, develop less diet-induced weight gain, hyperglycemia and insulin resistance. These protective effects correlate with increased abundance of the metabolically protective bacteria Akkermansia muciniphila in the intestinal microbiome. IL-36 cytokines promote its outgrowth as well as increased colonic mucus secretion. These findings identify a protective role for IL-36 cytokines in obesity and metabolic disease, adding to the current understanding of the role the broader IL-1 family plays in regulating disease pathogenesis. 10.1038/s41467-019-11944-w
    An obesity-associated gut microbiome reprograms the intestinal epigenome and leads to altered colonic gene expression. Qin Yufeng,Roberts John D,Grimm Sara A,Lih Fred B,Deterding Leesa J,Li Ruifang,Chrysovergis Kaliopi,Wade Paul A Genome biology BACKGROUND:The gut microbiome, a key constituent of the colonic environment, has been implicated as an important modulator of human health. The eukaryotic epigenome is postulated to respond to environmental stimuli through alterations in chromatin features and, ultimately, gene expression. How the host mediates epigenomic responses to gut microbiota is an emerging area of interest. Here, we profile the gut microbiome and chromatin characteristics in colon epithelium from mice fed either an obesogenic or control diet, followed by an analysis of the resultant changes in gene expression. RESULTS:The obesogenic diet shapes the microbiome prior to the development of obesity, leading to altered bacterial metabolite production which predisposes the host to obesity. This microbiota-diet interaction leads to changes in histone modification at active enhancers that are enriched for binding sites for signal responsive transcription factors. These alterations of histone methylation and acetylation are associated with signaling pathways integral to the development of colon cancer. The transplantation of obesogenic diet-conditioned microbiota into germ free mice, combined with an obesogenic diet, recapitulates the features of the long-term diet regimen. The diet/microbiome-dependent changes are reflected in both the composition of the recipient animals' microbiome as well as in the set of transcription factor motifs identified at diet-influenced enhancers. CONCLUSIONS:These findings suggest that the gut microbiome, under specific dietary exposures, stimulates a reprogramming of the enhancer landscape in the colon, with downstream effects on transcription factors. These chromatin changes may be associated with those seen during colon cancer development. 10.1186/s13059-018-1389-1
    Obese Individuals with and without Type 2 Diabetes Show Different Gut Microbial Functional Capacity and Composition. Thingholm Louise B,Rühlemann Malte C,Koch Manja,Fuqua Brie,Laucke Guido,Boehm Ruwen,Bang Corinna,Franzosa Eric A,Hübenthal Matthias,Rahnavard Ali,Frost Fabian,Lloyd-Price Jason,Schirmer Melanie,Lusis Aldons J,Vulpe Chris D,Lerch Markus M,Homuth Georg,Kacprowski Tim,Schmidt Carsten O,Nöthlings Ute,Karlsen Tom H,Lieb Wolfgang,Laudes Matthias,Franke Andre,Huttenhower Curtis Cell host & microbe Obesity and type 2 diabetes (T2D) are metabolic disorders that are linked to microbiome alterations. However, their co-occurrence poses challenges in disentangling microbial features unique to each condition. We analyzed gut microbiomes of lean non-diabetic (n = 633), obese non-diabetic (n = 494), and obese individuals with T2D (n = 153) from German population and metabolic disease cohorts. Microbial taxonomic and functional profiles were analyzed along with medical histories, serum metabolomics, biometrics, and dietary data. Obesity was associated with alterations in microbiome composition, individual taxa, and functions with notable changes in Akkermansia, Faecalibacterium, Oscillibacter, and Alistipes, as well as in serum metabolites that correlated with gut microbial patterns. However, microbiome associations were modest for T2D, with nominal increases in Escherichia/Shigella. Medications, including antihypertensives and antidiabetics, along with dietary supplements including iron, were significantly associated with microbiome variation. These results differentiate microbial components of these interrelated metabolic diseases and identify dietary and medication exposures to consider in future studies. 10.1016/j.chom.2019.07.004
    Gut microbiome-mediated bile acid metabolism regulates liver cancer via NKT cells. Ma Chi,Han Miaojun,Heinrich Bernd,Fu Qiong,Zhang Qianfei,Sandhu Milan,Agdashian David,Terabe Masaki,Berzofsky Jay A,Fako Valerie,Ritz Thomas,Longerich Thomas,Theriot Casey M,McCulloch John A,Roy Soumen,Yuan Wuxing,Thovarai Vishal,Sen Shurjo K,Ruchirawat Mathuros,Korangy Firouzeh,Wang Xin Wei,Trinchieri Giorgio,Greten Tim F Science (New York, N.Y.) Primary liver tumors and liver metastasis currently represent the leading cause of cancer-related death. Commensal bacteria are important regulators of antitumor immunity, and although the liver is exposed to gut bacteria, their role in antitumor surveillance of liver tumors is poorly understood. We found that altering commensal gut bacteria in mice induced a liver-selective antitumor effect, with an increase of hepatic CXCR6 natural killer T (NKT) cells and heightened interferon-γ production upon antigen stimulation. In vivo functional studies showed that NKT cells mediated liver-selective tumor inhibition. NKT cell accumulation was regulated by CXCL16 expression of liver sinusoidal endothelial cells, which was controlled by gut microbiome-mediated primary-to-secondary bile acid conversion. Our study suggests a link between gut bacteria-controlled bile acid metabolism and liver antitumor immunosurveillance. 10.1126/science.aan5931
    Gold Nanoparticles Cure Bacterial Infection with Benefit to Intestinal Microflora. Li Juanjuan,Cha Ruitao,Zhao Xiaohui,Guo Hongbo,Luo Huize,Wang Mingzheng,Zhou Fengshan,Jiang Xingyu ACS nano Antibiotics that are most used to cure bacterial infections in the clinic result in the imbalance of intestinal microflora, destroy the intestinal barrier, and induce bacterial resistance. There is an urgent need for antibacterial agent therapy for bacterial infections that does not destroy intestinal microflora. Herein, we applied 4,6-diamino-2-pyrimidinethiol (DAPT)-coated Au nanoparticles (D-Au NPs) for therapy of bacterial infection induced by Escherichia coli ( E. coli) in the gut. We cultured D-Au NPs and E. coli in an anaerobic atmosphere to evaluate their bactericidal effect. We studied the microflora, distribution of Au, and biomarkers in mice after a 28-day oral administration to analyze the effect of Au NPs on mice. D-Au NPs cured bacterial infections more effectively than levofloxacin without harming intestinal microflora. D-Au NPs showed great potential as alternatives to oral antibiotics. 10.1021/acsnano.9b01002
    Risks of Saccharomyces boulardii-Containing Probiotics for the Prevention of Clostridium difficile Infection in the Elderly. Dauby Nicolas Gastroenterology 10.1053/j.gastro.2017.04.054
    Use of Probiotics in Hospitalized Adults to Prevent Clostridium difficile Infection: DownGRADE the Quality of Evidence? Viggars Andrew P,Gracie David J,Ford Alexander C Gastroenterology 10.1053/j.gastro.2017.05.067
    Genotypes and virulence in serotype K2 Klebsiella pneumoniae from liver abscess and non-infectious carriers in Hong Kong, Singapore and Taiwan. Lin Jung-Chung,Koh Tse Hsien,Lee Nelson,Fung Chang-Phone,Chang Feng-Yee,Tsai Yu-Kuo,Ip Margaret,Siu L Kristopher Gut pathogens In Klebsiella pneumoniae liver abscess (KP-LA), K. pneumoniae K2 is the most frequently isolated serotype after K1, but this serotype has been much less studied. In the present study, the molecular types sequences type (MLST) of serotype K2 isolates from three different regions in Asia were identified and the virulence of these isolates was investigated. Eight different MLSTs were found among 26 isolates (ST 65, 66, 86, 373, 374, 375, 380, and 434). There were two major MLST groups, ST-65-like (42%) and ST86-like (46%). No isolates contained allS while all isolates contained rmpA. The prevalence of aerobactin gene and kfu were 25/26 (96%) and 3/26 (11.5%) respectively. Although liver abscess isolates were generally more resistant (11/15 isolates) to serum killing, there was no specific distribution of serum killing resistant or susceptible ST types between stool carriage and liver abscess isolates. Neutrophil phagocytosis showed that the liver abscess and carriage isolates varied in their susceptibility to phagocytosis. Strains with resistance to both neutrophil phagocytosis and serum killing were generally hypervirulent with lethality at LD50 < 10(3) colony forming units by intraperitoneal injection. In conclusion, Anti-phagocytosis and resistance to serum killing are two parameters that most predict hyperviurlence in serotype K2 isolates. Unlike serotype K1 KP-LA that mainly belong to ST-23, ST-65-like and -86-like are the two major MLST types among serotype K2 isolates from Singapore, Hong Kong and Taiwan. 10.1186/1757-4749-6-21
    The use of predictive scores in the management of patients with carbapenem-resistant Klebsiella pneumoniae infection. Giannella Maddalena,Pascale Renato,Gutiérrez-Gutiérrez Belén,Cano Angela,Viale Pierluigi Expert review of anti-infective therapy INTRODUCTION:Carbapenem-resistant Klebsiella pneumoniae (CR-KP) infections are associated with high morbidity and mortality rates. A therapeutic approach based on the patient risk stratification could improve outcome and avoid antibiotic misuse. Areas covered: English literature search, from 2008 to 2018, was done using PubMed database. Risk factors for developing CR-KP infection in several settings were reviewed. Since, rectal carriage was a main risk factor for developing infection, we revised in deep clinical score to predict infection among colonized patients. Furthermore, we investigated overall and treatment-related risk factors for poor outcome in patients with CR-KP infection, in particular the carbapenem producing Enterobacteriacieae (CPE)-INCREMENT score. Finally, an algorithm, based on such scores, for the therapeutic management of patients with CR-KP colonization was commented. Expert opinion: The therapeutic approach analyzed in this review could help physicians to avoid antibiotic overuse as well as to start promptly with the most appropriate antibiotic regimen. However, it has to be validated in further studies, mainly among special population such as immunocompromised patients. The availability of new drugs, fast microbiology, and analysis of gut microbiome could significantly improve the management of CR-KP colonized and/or infected patients. 10.1080/14787210.2019.1595590
    KPC-producing Klebsiella pneumoniae rectal colonization is a risk factor for mortality in patients with diabetic foot infections. Tascini C,Lipsky B A,Iacopi E,Ripoli A,Sbrana F,Coppelli A,Goretti C,Piaggesi A,Menichetti F Clinical microbiology and infection : the official publication of the European Society of Clinical Microbiology and Infectious Diseases To evaluate the relationship between carbapenemase-producing Klebsiella pneumoniae (KPC-Kp) gut colonization and mortality in diabetic patients with a foot infection (DFI) we performed a single-centre, retrospective, matched case-control study. In the study period, we identified 21 patients with DFI who had KPC-Kp gut colonization and 21 controls. The 90-day mortality rate was significantly higher in patients with colonized guts (47%) than the controls (4%) (p 0.013). A multivariate analysis demonstrated that gut colonization with KPC-Kp was the only independent predictor of mortality: odds ratio 13.33, 95% CI 1.90-272.80, p 0.024. In patients with DFI, KPC-Kp gut colonization appears to be an important risk factor for mortality. 10.1016/j.cmi.2015.04.010
    The Klebsiella pneumoniae citrate synthase gene, gltA, influences site specific fitness during infection. Vornhagen Jay,Sun Yuang,Breen Paul,Forsyth Valerie,Zhao Lili,Mobley Harry L T,Bachman Michael A PLoS pathogens Klebsiella pneumoniae (Kp), one of the most common causes of healthcare-associated infections, increases patient morbidity, mortality, and hospitalization costs. Kp must acquire nutrients from the host for successful infection; however, the host is able to prevent bacterial nutrient acquisition through multiple systems. This includes the innate immune protein lipocalin 2 (Lcn2), which prevents Kp iron acquisition. To identify novel Lcn2-dependent Kp factors that mediate evasion of nutritional immunity during lung infection, we undertook an InSeq study using a pool of >20,000 transposon mutants administered to Lcn2+/+ and Lcn2-/- mice. Comparing transposon mutant frequencies between mouse genotypes, we identified the Kp citrate synthase, GltA, as potentially interacting with Lcn2, and this novel finding was independently validated. Interestingly, in vitro studies suggest that this interaction is not direct. Given that GltA is involved in oxidative metabolism, we screened the ability of this mutant to use a variety of carbon and nitrogen sources. The results indicated that the gltA mutant has a distinct amino acid auxotrophy rendering it reliant upon glutamate family amino acids for growth. Deletion of Lcn2 from the host leads to increased amino acid levels in bronchioloalveolar lavage fluid, corresponding to increased fitness of the gltA mutant in vivo and ex vivo. Accordingly, addition of glutamate family amino acids to Lcn2+/+ bronchioloalveolar lavage fluid rescued growth of the gltA mutant. Using a variety of mouse models of infection, we show that GltA is an organ-specific fitness factor required for complete fitness in the spleen, liver, and gut, but dispensable in the bloodstream. Similar to bronchioloalveolar lavage fluid, addition of glutamate family amino acids to Lcn2+/+ organ lysates was sufficient to rescue the loss of gltA. Together, this study describes a critical role for GltA in Kp infection and provides unique insight into how metabolic flexibility impacts bacterial fitness during infection. 10.1371/journal.ppat.1008010
    Fermented ginseng improved alcohol liver injury in association with changes in the gut microbiota of mice. Fan Jingjing,Wang Yushan,You Ying,Ai Zhiyi,Dai Weichang,Piao Chunhong,Liu Junmei,Wang Yuhua Food & function The interactions among the liver, intestine and immune system play an important role in alcoholic liver injury. In this study, C57BL/6N mice with alcoholic injury were treated with unfermented and Lactobacillus fermentum KP-3-fermented ginseng. The indicators of hepatic steatosis, inflammation and injury were evaluated. The number of beneficial and harmful bacteria in the mice ileum and colon was counted by a traditional method; moreover, the diversity analysis of the cecum flora was performed. The alcohol exposure increased the levels of ALT, AST, TNF-α and IL-6 inflammatory factors and liver steatosis. In addition, the alcohol-fed miceexhibited a lower number of Lactobacilli and Bifidobacteria in the ileum and colon; the cecum flora diversity in the mice showed that alcohol obviously enhanced the abundance of the unclassified S24-7 of the Bacteroidetes phylum and the Proteobacteria genus of the Sutterella phylum and reduced the abundance of short-chain fatty acid-producing bacteria such as Akkermansia in the Verrucomicrobia phylum and those belonging to the Allobaculum genus, the Ruminococcus genus, and the Adlercreutzia genus in the Actinobacteria phylum. All these changes were improved by fermented ginseng. Conclusively, fermented ginseng could alleviate the alcoholic liver injury and disorder of the intestine by adjusting the intestinal flora. 10.1039/c9fo01415b
    Treatment of a Klebsiella pneumoniae KPC cellulitis and gut decolonization with ceftazidime/avibactam in a migrant from Libya. Carannante Novella,Pallotto Carlo,Bernardo Mariano,Di Caprio Giovanni,Tascini Carlo Journal of chemotherapy (Florence, Italy) KPC-producing Klebsiella pneumoniae (KPC-Kp) is nowadays a global concern. Ceftazidime/avibactam is the most promising novel antibiotic combination available at the moment. We describe the case of a migrant with no risk factors for an infection due to multidrug resistant bacteria. He suffered from a KPC-Kp cellulitis and was treated with a ceftazidime/avibactam-meropenem-fosfomycin combination that not only eradicated the infection but also decontaminated his gut. Ceftazidime/avibactam-based treatment can be useful also in decontamination procedures. 10.1080/1120009X.2018.1424504
    Urinary TMAO Levels Are Associated with the Taxonomic Composition of the Gut Microbiota and with the Choline TMA-Lyase Gene () Harbored by Enterobacteriaceae. Dalla Via Alessandro,Gargari Giorgio,Taverniti Valentina,Rondini Greta,Velardi Ilaria,Gambaro Veniero,Visconti Giacomo Luca,De Vitis Valerio,Gardana Claudio,Ragg Enzio,Pinto Andrea,Riso Patrizia,Guglielmetti Simone Nutrients Gut microbiota metabolization of dietary choline may promote atherosclerosis through trimethylamine (TMA), which is rapidly absorbed and converted in the liver to proatherogenic trimethylamine-N-oxide (TMAO). The aim of this study was to verify whether TMAO urinary levels may be associated with the fecal relative abundance of specific bacterial taxa and the bacterial choline TMA-lyase gene . The analysis of sequences available in GenBank grouped the gene into two main clusters, cut-Dd and cut-Kp. A quantitative real-time polymerase chain reaction (qPCR) protocol was developed to quantify and was used with DNA isolated from three fecal samples collected weekly over the course of three consecutive weeks from 16 healthy adults. The same DNA was used for 16S rRNA gene profiling. Concomitantly, urine was used to quantify TMAO by ultra-performance liquid chromatography coupled with tandem mass spectrometry (UPLC-MS/MS). All samples were positive for and TMAO. Correlation analysis showed that the cut-Kp gene cluster was significantly associated with . Linear mixed models revealed that urinary TMAO levels may be predicted by fecal cut-Kp and by 23 operational taxonomic units (OTUs). Most of the OTUs significantly associated with TMAO were also significantly associated with cut-Kp, confirming the possible relationship between these two factors. In conclusion, this preliminary method-development study suggests the existence of a relationship between TMAO excreted in urine, specific fecal bacterial OTUs, and a subgroup ascribable to the choline-TMA conversion enzymes of . 10.3390/nu12010062
    Genome-Wide Screening for Enteric Colonization Factors in Carbapenem-Resistant ST258 Klebsiella pneumoniae. Jung Hea-Jin,Littmann Eric R,Seok Ruth,Leiner Ingrid M,Taur Ying,Peled Jonathan,van den Brink Marcel,Ling Lilan,Chen Liang,Kreiswirth Barry N,Goodman Andrew L,Pamer Eric G mBio A diverse, antibiotic-naive microbiota prevents highly antibiotic-resistant microbes, including carbapenem-resistant (CR), from achieving dense colonization of the intestinal lumen. Antibiotic-mediated destruction of the microbiota leads to expansion of CR in the gut, markedly increasing the risk of bacteremia in vulnerable patients. While preventing dense colonization represents a rational approach to reduce intra- and interpatient dissemination of CR, little is known about pathogen-associated factors that enable dense growth and persistence in the intestinal lumen. To identify genetic factors essential for dense colonization of the gut by CR, we constructed a highly saturated transposon mutant library with >150,000 unique mutations in an ST258 strain of CR and screened for growth and intestinal colonization in antibiotic-treated mice. Stochastic and partially reversible fluctuations in the representation of different mutations during dense colonization revealed the dynamic nature of intestinal microbial populations. We identified genes that are crucial for early and late stages of dense gut colonization and confirmed their role by testing isogenic mutants in competition assays with wild-type CR- Screening of the transposon library also identified mutations that enhanced CR growth. These newly identified colonization factors may provide novel therapeutic opportunities to reduce intestinal colonization by CR- is a common cause of bloodstream infections in immunocompromised and hospitalized patients, and over the last 2 decades, some strains have acquired resistance to nearly all available antibiotics, including broad-spectrum carbapenems. The U.S. Centers for Disease Control and Prevention has listed carbapenem-resistant (CR) as an urgent public health threat. Dense colonization of the intestine by CR and other antibiotic-resistant bacteria is associated with an increased risk of bacteremia. Reducing the density of gut colonization by CR is likely to reduce their transmission from patient to patient in health care facilities as well as systemic infections. How CR expands and persists in the gut lumen, however, is poorly understood. Herein, we generated a highly saturated mutant library in a multidrug-resistant strain and identified genetic factors that are associated with dense gut colonization by This study sheds light on host colonization by and identifies potential colonization factors that contribute to high-density persistence of in the intestine. 10.1128/mBio.02663-18
    Increased Relative Abundance of Klebsiella pneumoniae Carbapenemase-producing Klebsiella pneumoniae Within the Gut Microbiota Is Associated With Risk of Bloodstream Infection in Long-term Acute Care Hospital Patients. Shimasaki Teppei,Seekatz Anna,Bassis Christine,Rhee Yoona,Yelin Rachel D,Fogg Louis,Dangana Thelma,Cisneros Enrique Cornejo,Weinstein Robert A,Okamoto Koh,Lolans Karen,Schoeny Michael,Lin Michael Y,Moore Nicholas M,Young Vincent B,Hayden Mary K, Clinical infectious diseases : an official publication of the Infectious Diseases Society of America BACKGROUND:An association between increased relative abundance of specific bacterial taxa in the intestinal microbiota and bacteremia has been reported in some high-risk patient populations. METHODS:We collected weekly rectal swab samples from patients at 1 long-term acute care hospital (LTACH) in Chicago from May 2015 to May 2016. Samples positive for Klebsiella pneumoniae carbapenemase-producing Klebsiella pneumoniae (KPC-Kp) by polymerase chain reaction and culture underwent 16S rRNA gene sequence analysis; relative abundance of the operational taxonomic unit containing KPC-Kp was determined. Receiver operator characteristic (ROC) curves were constructed using results from the sample with highest relative abundance of KPC-Kp from each patient admission, excluding samples collected after KPC-Kp bacteremia. Cox regression analysis was performed to evaluate risk factors associated with time to achieve KPC-Kp relative abundance thresholds calculated by ROC curve analysis. RESULTS:We collected 2319 samples from 562 admissions (506 patients); KPC-Kp colonization was detected in 255 (45.4%) admissions and KPC-Kp bacteremia in 11 (4.3%). A relative abundance cutoff of 22% predicted KPC-Kp bacteremia with sensitivity 73%, specificity 72%, and relative risk 4.2 (P = .01). In a multivariable Cox regression model adjusted for age, Charlson comorbidity index, and medical devices, carbapenem receipt was associated with achieving the 22% relative abundance threshold (P = .044). CONCLUSION:Carbapenem receipt was associated with increased hazard for high relative abundance of KPC-Kp in the gut microbiota. Increased relative abundance of KPC-Kp was associated with KPC-Kp bacteremia. Whether bacteremia arose directly from bacterial translocation or indirectly from skin contamination followed by bloodstream invasion remains to be determined. 10.1093/cid/ciy796
    Identification and management of Shigella infection in children with diarrhoea: a systematic review and meta-analysis. Tickell Kirkby D,Brander Rebecca L,Atlas Hannah E,Pernica Jeffrey M,Walson Judd L,Pavlinac Patricia B The Lancet. Global health BACKGROUND:Shigella infections are a leading cause of diarrhoeal death among children in low-income and middle-income countries. WHO guidelines reserve antibiotics for treating children with dysentery. Reliance on dysentery for identification and management of Shigella infection might miss an opportunity to reduce Shigella-associated morbidity and mortality. We aimed to systematically review and evaluate Shigella-associated and dysentery-associated mortality, the diagnostic value of dysentery for the identification of Shigella infection, and the efficacy of antibiotics for children with Shigella or dysentery, or both. METHODS:We did three systematic reviews (for mortality, diagnostic value, and antibiotic treatment of Shigella and dysentery), and meta-analyses where appropriate, of studies in resource-limited settings. We searched MEDLINE, Embase, and LILACS database for studies published before Jan 1, 2017, in English, French, and Spanish. We included studies of human beings with diarrhoea and accepted all study-specific definitions of dysentery. For the mortality and diagnostic value searches, we excluded studies that did not include an effect estimate or data necessary to calculate this estimate. The search for treatment included only randomised controlled trials that were done after Jan 1, 1980, and assessed antibiotics in children (aged <18 years) with dysentery or laboratory-confirmed Shigella. We extracted or calculated odds ratios (ORs) and 95% CIs for relative mortality and did random-effects meta-analysis to arrive at pooled ORs. We calculated 95% CIs assuming a binomial distribution and did random-effects meta-regression of log-transformed sensitivity and specificity estimates for diagnostic value. We assessed the heterogeneity of papers included in these meta-analyses using the I statistic and evaluated publication bias using funnel plots. This review is registered with PROSPERO (CRD42017063896). FINDINGS:3649 papers were identified and 60 studies were included for analyses: 13 for mortality, 27 for diagnostic value, and 20 for treatment. Shigella infection was associated with mortality (pooled OR 2·8, 95% CI 1·6-4·8; p=0·000) whereas dysentery was not associated with mortality (1·3, 0·7-2·3; p=0·37). Between 1977 and 2016, dysentery identified 1·9-85·9% of confirmed Shigella infections, with sensitivity decreasing over time (p=0·04). Ten (50%) of 20 included antibiotic trials were among children with dysentery, none were placebo-controlled, and two (10%) evaluated antibiotics no longer recommended for acute infectious diarrhoea. Ciprofloxacin showed superior microbiological, but not clinical, effectiveness compared with pivmecillinam, and no superior microbiological and clinical effectiveness compared with gatifloxacin. Substantial heterogeneity was reported for meta-analyses of the Shigella-associated mortality studies (I=78·3%) and dysentery-associated mortality studies (I=73·2%). Too few mortality studies were identified to meaningfully test for publication bias. No evidence of publication bias was found in this analysis of studies of diagnostic value. INTERPRETATION:Current WHO guidelines appear to manage dysentery effectively, but might miss opportunities to reduce mortality among children infected with Shigella who present without bloody stool. Further studies should quantify potential decreases in mortality and morbidity associated with antibiotic therapy for children with non-dysenteric Shigella infection. FUNDING:Bill & Melinda Gates Foundation and the Center for AIDS Research International Core. 10.1016/S2214-109X(17)30392-3
    Comparative efficacy of treatments for Clostridium difficile infection: a systematic review and network meta-analysis. Beinortas Tumas,Burr Nicholas E,Wilcox Mark H,Subramanian Venkataraman The Lancet. Infectious diseases BACKGROUND:Several new treatments for Clostridium difficile infections have been investigated. We aimed to compare and rank treatments for non-multiply recurrent infections with C difficile in adults. METHODS:We did a random effects network meta-analysis within a frequentist setting to obtain direct and indirect comparisons of trials. We searched MEDLINE, Embase, Web of Science, Cochrane Central Register of Controlled Trials, and ClinicalTrials.gov for published and unpublished trials from the creation of these databases until June 30, 2017. We included randomised controlled trials of treatments for non-multiply recurrent infections with confirmed C difficile in adults (at least 18 years) that reported both primary cure and recurrence rates, and we used the Cochrane Risk of Bias tool to appraise trial methods. For our analysis, we extracted the total numbers of patients with primary cure and recurrence from published and unpublished reports. The primary outcome was sustained symptomatic cure, defined as the number of patients with resolution of diarrhoea minus the number with recurrence or death. FINDINGS:Of 23 004 studies screened, 24 trials, which comprised 5361 patients and 13 different treatments, were included in the analysis. The overall quality of evidence was rated as moderate to low. For sustained symptomatic cure, fidaxomicin (odds ratio 0·67, 95% CI 0·55-0·82) and teicoplanin (0·37, 0·14-0·94) were significantly better than vancomycin. Teicoplanin (0·27, 0·10-0·70), ridinilazole (0·41, 0·19-0·88), fidaxomicin (0·49, 0·35-0·68), surotomycin (0·66, 0·45-0·97), and vancomycin (0·73, 0·56-0·95) were better than metronidazole. Bacitracin was inferior to teicoplanin (0·22, 0·06-0·77) and fidaxomicin (0·40, 0·17-0·94), and tolevamer was inferior to all drugs except for LFF571 (0·50, 0·18-1·39) and bacitracin (0·67, 0·28-1·58). Global heterogeneity of the entire network was low (Cochran's Q=15·70; p=0·47). INTERPRETATION:Among the treatments for non-multiply recurrent infections by C difficile, the highest quality evidence indicates that fidaxomicin provides a sustained symptomatic cure most frequently. Fidaxomicin is a better treatment option than vancomycin for all patients except those with severe infections with C difficile and could be considered as a first-line therapy. Metronidazole should not be recommended for treatment of C difficile. FUNDING:None. 10.1016/S1473-3099(18)30285-8
    Evidence-based nutritional and pharmacological interventions targeting chronic low-grade inflammation in middle-age and older adults: A systematic review and meta-analysis. Custodero C,Mankowski R T,Lee S A,Chen Z,Wu S,Manini T M,Hincapie Echeverri J,Sabbà C,Beavers D P,Cauley J A,Espeland M A,Fielding R A,Kritchevsky S B,Liu C K,McDermott M M,Miller M E,Tracy R P,Newman A B,Ambrosius W T,Pahor M,Anton S D Ageing research reviews Growing evidence suggests chronic low-grade inflammation (LGI) as a possible mechanism underlying the aging process. Some biological and pharmaceutical compounds may reduce systemic inflammation and potentially avert functional decline occurring with aging. The aim of the present meta-analysis was to examine the association of pre-selected interventions on two established biomarkers of inflammation, interleukin-6 (IL-6), and C-reactive protein (CRP) in middle-age and older adults with chronic LGI. We reviewed the literature on potential anti-inflammatory compounds, selecting them based on safety, tolerability, acceptability, innovation, affordability, and evidence from randomized controlled trials. Six compounds met all five inclusion criteria for our systematic review and meta-analysis: angiotensin II receptor blockers (ARBs), metformin, omega-3, probiotics, resveratrol and vitamin D. We searched in MEDLINE, PubMed and EMBASE database until January 2017. A total of 49 articles fulfilled the selection criteria. Effect size of each study and pooled effect size for each compound were measured by the standardized mean difference. I was computed to measure heterogeneity of effects across studies. The following compounds showed a significant small to large effect in reducing IL-6 levels: probiotics (-0.68 pg/ml), ARBs (-0.37 pg/ml) and omega-3 (-0.19 pg/ml). For CRP, a significant small to medium effect was observed with probiotics (-0.43 mg/L), ARBs (-0.2 mg/L), omega-3 (-0.17 mg/L) and metformin (-0.16 mg/L). Resveratrol and vitamin D were not associated with any significant reductions in either biomarker. These results suggest that nutritional and pharmaceutical compounds can significantly reduce established biomarkers of systemic inflammation in middle-age and older adults. The findings should be interpreted with caution, however, due to the evidence of heterogeneity across the studies. 10.1016/j.arr.2018.05.004
    Perioperative Probiotics or Synbiotics in Adults Undergoing Elective Abdominal Surgery: A Systematic Review and Meta-analysis of Randomized Controlled Trials. Chowdhury Abeed H,Adiamah Alfred,Kushairi Anisa,Varadhan Krishna K,Krznaric Zeljko,Kulkarni Anil D,Neal Keith R,Lobo Dileep N Annals of surgery OBJECTIVE:To define the impact of perioperative treatment with probiotics or synbiotics on postoperative outcome in patients undergoing abdominal surgery. BACKGROUND:Postoperative surgical infection accounts for a third of all cases of sepsis, and is a leading cause of morbidity and mortality. Probiotics, prebiotics, and synbiotics (preparations that combine probiotics and prebiotics) are nutritional adjuncts that are emerging as novel therapeutic modalities for preventing surgical infections. However, current evidence on their effects is conflicting. METHODS:A comprehensive search of the PubMed, Embase, and WHO Global Index Medicus electronic databases was performed to identify randomized controlled trials evaluating probiotics or synbiotics in adult patients undergoing elective colorectal, upper gastrointestinal, transplant, or hepatopancreaticobiliary surgery. Bibliographies of studies were also searched. The primary outcome measure was incidence of postoperative infectious complications. Secondary outcomes included incidence of noninfectious complications, mortality, length of hospital stay, and any treatment-related adverse events. Quantitative pooling of the data was undertaken using a random effects model. RESULTS:A total of 34 randomized controlled trials reporting on 2723 participants were included. In the intervention arm, 1354 patients received prebiotic or symbiotic preparations, whereas 1369 patients in the control arm received placebo or standard care. Perioperative administration of either probiotics or synbiotics significantly reduced the risk of infectious complications following abdominal surgery [relative risk (RR) 0.56; 95% confidence interval (CI) 0.46-0.69; P < 0.00001, n = 2723, I = 42%]. Synbiotics showed greater effect on postoperative infections compared with probiotics alone (synbiotics RR: 0.46; 95% CI: 0.33-0.66; P < 0.0001, n = 1399, I = 53% probiotics RR: 0.65; 95% CI: 0.53-0.80; P < 0.0001, n = 1324, I = 18%). Synbiotics but not probiotics also led to a reduction in total length of stay (synbiotics weighted mean difference: -3.89; 95% CI: -6.60 to -1.18 days; P = 0.005, n = 535, I = 91% probiotics RR: -0.65; 95% CI: -2.03-0.72; P = 0.35, n = 294, I = 65%). There were no significant differences in mortality (RR: 0.98; 95% CI: 0.54-1.80; P = 0.96, n = 1729, I = 0%) or noninfectious complications between the intervention and control groups. The preparations were well tolerated with no significant adverse events reported. CONCLUSIONS:Probiotics and synbiotics are safe and effective nutritional adjuncts in reducing postoperative infective complications in elective abdominal surgery. The treatment effects are greatest with synbiotics. 10.1097/SLA.0000000000003581
    Prevention of Clostridium difficile Infection With Probiotics. Evans Charlesnika T,Johnson Stuart Clinical infectious diseases : an official publication of the Infectious Diseases Society of America Despite advances in the diagnosis and treatment of Clostridium difficile infection (CDI) and prevention efforts to reduce the spread of C. difficile, CDI remains a significant challenge to healthcare systems worldwide. Further advances in prevention of CDI may need to focus on those who continue to be exposed to the organism and who are susceptible. Interventions directed toward this susceptible population, particularly hospitalized patients who receive antibiotics, may be effective. There is moderate evidence on the effectiveness of probiotics to prevent primary CDI, but there are few data to support use in secondary prevention of recurrent CDI. This review discusses the literature available on the use of probiotics to prevent primary and secondary CDI. 10.1093/cid/civ138
    In response to 'Effects of probiotics on body weight, body mass index, fat mass and fat percentage in subjects with overweight or obesity: a systematic review and meta-analysis of randomized controlled trials'. Fuller N R Obesity reviews : an official journal of the International Association for the Study of Obesity 10.1111/obr.12687
    Effectiveness of Probiotic, Prebiotic, and Synbiotic Therapies in Reducing Postoperative Complications: A Systematic Review and Network Meta-analysis. Kasatpibal Nongyao,Whitney JoAnne D,Saokaew Surasak,Kengkla Kirati,Heitkemper Margaret M,Apisarnthanarak Anucha Clinical infectious diseases : an official publication of the Infectious Diseases Society of America Background:Microbiome-directed therapies are increasingly used preoperatively and postoperatively to improve postoperative outcomes. Recently, the effectiveness of probiotics, prebiotics, and synbiotics in reducing postoperative complications (POCs) has been questioned. This systematic review aimed to examine and rank the effectiveness of these therapies on POCs in adult surgical patients. Methods:We searched for articles from PubMed, Embase, Cochrane, Web of Science, Scopus, and CINAHL plus. From 2002 to 2015, 31 articles meeting the inclusion criteria were identified in the literature. Risk of bias and heterogeneity were assessed. Network meta-analyses (NMA) were performed using random-effects modeling to obtain estimates for study outcomes. Risk ratios (RRs) and 95% confidence intervals (CIs) were estimated. We then ranked the comparative effects of all regimens with the surface under the cumulative ranking (SUCRA) probabilities. Results:A total of 2,952 patients were included. We found that synbiotic therapy was the best regimen in reducing surgical site infection (SSI) (RR = 0.28; 95% CI, 0.12-0.64) in adult surgical patients. Synbiotic therapy was also the best intervention to reduce pneumonia (RR = 0.28; 95% CI, 0.09-0.90), sepsis (RR = 0.09; 95% CI, 0.01-0.94), hospital stay (mean = 9.66 days, 95% CI, 7.60-11.72), and duration of antibiotic administration (mean = 5.61 days, 95% CI, 3.19-8.02). No regimen significantly reduced mortality. Conclusions:This network meta-analysis suggests that synbiotic therapy is the first rank to reduce SSI, pneumonia, sepsis, hospital stay, and antibiotic use. Surgeons should consider the use of synbiotics as an adjunctive therapy to prevent POCs among adult surgical patients. Increasing use of synbiotics may help to reduce the use of antibiotics and multidrug resistance. 10.1093/cid/cix114
    Patients Receiving Prebiotics and Probiotics Before Liver Transplantation Develop Fewer Infections Than Controls: A Systematic Review and Meta-Analysis. Sawas Tarek,Al Halabi Shadi,Hernaez Ruben,Carey William D,Cho Won Kyoo Clinical gastroenterology and hepatology : the official clinical practice journal of the American Gastroenterological Association BACKGROUND & AIMS:Among patients who have received liver transplants, infections increase morbidity and mortality and prolong hospital stays. Administration of antibiotics and surgical trauma create intestinal barrier dysfunction and microbial imbalances that allow enteric bacteria to translocate to the blood. Probiotics are believed to prevent bacterial translocation by stabilizing the intestinal barrier and stimulating proliferation of the intestinal epithelium, mucus secretion, and motility. We performed a meta-analysis to determine the effects of probiotics on infections in patients receiving liver transplants. METHODS:We searched PubMed and EMBASE for controlled trials that evaluated the effects of prebiotics and probiotics on infections in patients who underwent liver transplantation. Heterogeneity was analyzed by the Cochran Q statistic. Pooled Mantel-Haenszel relative risks were calculated with a fixed-effects model. RESULTS:We identified 4 controlled studies, comprising 246 participants (123 received probiotics, 123 served as controls), for inclusion in the meta-analysis. In these studies, the intervention groups received enteric nutrition and fiber (prebiotics) with probiotics, and the control groups received only enteric nutrition and fiber without probiotics. The infection rate was 7% in groups that received probiotics vs 35% in control groups (relative risk [RR], 0.21; 95% confidence interval [CI], 0.11-0.41; P = .001). The number needed to treat to prevent 1 infection was 3.6. In subgroup analyses, only 2% of subjects in the probiotic groups developed urinary tract infections, compared with 16% of controls (RR, 0.14; 95% CI, 0.04-0.47; P < .001); only 2% of subjects in the probiotic groups developed intra-abdominal infections, compared with 11% of controls (RR, 0.27; 95% CI, 0.09-0.78; P = .02). Subjects receiving probiotics also had shorter stays in the hospital than controls (mean difference, 1.41 d; P < .001), as well as in the intensive care unit (mean difference, 1.41 d; P < .001), and duration of antibiotic use (mean difference, 3.89 d; P < .001). There was no difference in mortality between groups (RR, 0.97; 95% CI, 0.21-4.47). There was no significant heterogeneity among studies. CONCLUSIONS:Based on the meta-analysis, giving patients a combination of probiotics and prebiotics before, or on the day of, liver transplantation reduces the rate of infection after surgery. These agents also reduced the amount of time spent in the hospital or intensive care unit and the duration of antibiotic use. 10.1016/j.cgh.2015.05.027
    Effects of probiotics on body weight, body mass index, fat mass and fat percentage in subjects with overweight or obesity: a systematic review and meta-analysis of randomized controlled trials. Borgeraas H,Johnson L K,Skattebu J,Hertel J K,Hjelmesaeth J Obesity reviews : an official journal of the International Association for the Study of Obesity A systematic review and meta-analysis of randomized controlled trials was conducted to examine the effects of probiotic supplementation on body weight, body mass index (BMI), fat mass and fat percentage in subjects with overweight (BMI 25-29.9 kg m ) or obesity (BMI ≥30 kg m ). MEDLINE, EMBASE and the Cochrane Central Register of Controlled Trials were searched for studies published between 1946 and September 2016. A meta-analysis, using a random effects model, was performed to calculate the weighted mean difference between the intervention and control groups. Of 800 studies identified through the literature search, 15 were finally included. The studies comprised a total of 957 subjects (63% women), with the mean BMI being 27.6 kg m and the duration of the interventions ranging from 3 to 12 weeks. Administration of probiotics resulted in a significantly larger reduction in body weight (weighted mean difference [95% confidence interval]; -0.60 [-1.19, -0.01] kg, I  = 49%), BMI (-0.27 [-0.45, -0.08] kg m , I  = 57%) and fat percentage (-0.60 [-1.20, -0.01] %, I  = 19%), compared with placebo; however, the effect sizes were small. The effect of probiotics on fat mass was non-significant (-0.42 [-1.08, 0.23] kg, I  = 84%). 10.1111/obr.12626
    The efficacy and safety of probiotics in people with cancer: a systematic review. Redman M G,Ward E J,Phillips R S Annals of oncology : official journal of the European Society for Medical Oncology BACKGROUND:Probiotics are living microorganisms that are generally thought of as being beneficial to the recipient. They have been shown to be effective in people with acute infectious diarrhoea, and cost-effective in antibiotic-associated diarrhoea. Probiotics may have a role in people with cancer, as various cancer treatments often lead to diarrhoea. However, as people with cancer are often immunocompromised, it is important to assess for adverse events (AEs) such as infection, which could potentially be a consequence of deliberate ingestion of living microorganisms. DESIGN:A systematic review was carried out to collect, analyse and synthesise all available data on the efficacy and safety of probiotics in people with cancer (PROSPERO registration: CRD42012003454). Randomised, controlled trials, identified through screening multiple databases and grey literature, were included for analysing efficacy, while all studies were included for the analysis of safety of probiotics. Primary outcomes were the reduction in duration, severity and incidence of antibiotic-associated diarrhoea and chemotherapy-associated diarrhoea, and AEs, especially probiotic-associated infection. Where possible, data were combined for meta-analysis by a random-effects model, assessing causes of heterogeneity, including differences in strains, dosage and patient characteristics. RESULTS:Eleven studies (N = 1557 participants) were included for assessing efficacy. Results show that probiotics may reduce the severity and frequency of diarrhoea in patients with cancer and may reduce the requirement for anti-diarrhoeal medication, but more studies are needed to assess the true effect. For example comparing probiotic use to control 25 groups on effect on Common Toxicity Criteria ≥2 grade diarrhoea, odds ratio (OR) = 0.32 [95% confidence interval (CI) of 0.13-0.79; P = 0.01]. Seventeen studies (N = 1530) were included in the safety analysis. Five case reports showed probiotic-related bacteraemia/fungaemia/positive blood cultures. CONCLUSIONS:Probiotics may be a rare cause of sepsis. Further evidence needs to be collated to determine whether probiotics provide a significant overall benefit for people with cancer. 10.1093/annonc/mdu106
    Probiotics for the prevention of allergy: A systematic review and meta-analysis of randomized controlled trials. Cuello-Garcia Carlos A,Brożek Jan L,Fiocchi Alessandro,Pawankar Ruby,Yepes-Nuñez Juan José,Terracciano Luigi,Gandhi Shreyas,Agarwal Arnav,Zhang Yuan,Schünemann Holger J The Journal of allergy and clinical immunology BACKGROUND:Allergic diseases are considered a health burden because of their high and constantly increasing prevalence, high direct and indirect costs, and undesirable effects on quality of life. Probiotics have been suggested as an intervention to prevent allergic diseases. OBJECTIVE:We sought to synthesize the evidence supporting use of probiotics for the prevention of allergies and inform World Allergy Organization guidelines on probiotic use. METHODS:We performed a systematic review of randomized trials assessing the effects of any probiotic administered to pregnant women, breast-feeding mothers, and/or infants. RESULTS:Of 2403 articles published until December 2014 identified in Cochrane Central Register of Controlled Trials, MEDLINE, and Embase, 29 studies fulfilled a priori specified inclusion criteria for the analyses. Probiotics reduced the risk of eczema when used by women during the last trimester of pregnancy (relative risk [RR], 0.71; 95% CI, 0.60-0.84), when used by breast-feeding mothers (RR, 0.57; 95% CI, 0.47-0.69), or when given to infants (RR, 0.80; 95% CI, 0.68-0.94). Evidence did not support an effect on other allergies, nutrition status, or incidence of adverse effects. The certainty in the evidence according to the Grading of Recommendation Assessment Development and Evaluation approach is low or very low because of the risk of bias, inconsistency and imprecision of results, and indirectness of available research. CONCLUSION:Probiotics used by pregnant women or breast-feeding mothers and/or given to infants reduced the risk of eczema in infants; however, the certainty in the evidence is low. No effect was observed for the prevention of other allergic conditions. 10.1016/j.jaci.2015.04.031