Acidic chitinase primes the protective immune response to gastrointestinal nematodes.

Acidic mammalian chitinase (AMCase) is known to be induced by allergens and helminths, yet its role in immunity is unclear. Using AMCase-deficient mice, we show that AMCase deficiency reduced the number of group 2 innate lymphoid cells during allergen challenge but was not required for establishment of type 2 inflammation in the lung in response to allergens or helminths. In contrast, AMCase-deficient mice showed a profound defect in type 2 immunity following infection with the chitin-containing gastrointestinal nematodes Nippostrongylus brasiliensis and Heligmosomoides polygyrus bakeri. The impaired immunity was associated with reduced mucus production and decreased intestinal expression of the signature type 2 response genes Il13, Chil3, Retnlb, and Clca1. CD103(+) dendritic cells, which regulate T cell homing, were also reduced in mesenteric lymph nodes of infected AMCase-deficient mice. Thus, AMCase functions as a critical initiator of protective type 2 responses to intestinal nematodes but is largely dispensable for allergic responses in the lung.

Evaluating the temporal association between the recency of prescribed controlled substance acquisition and fatal and non-fatal opioid overdose.

BACKGROUND: Previous studies have explored psychosocial effects as possible triggers of opioid overdose (OOD). However, little is known about the temporal association between OOD and prescribed controlled substance (CS) acquisition. OBJECTIVE: The objective of this study was to evaluate the temporal relationship between OOD and acquiring prescribed CSs prior to OOD. METHODS: This study is an exploratory descriptive analysis using Arkansas Prescription Drug Monitoring Program (AR-PDMP) data linked to death certificate and statewide inpatient discharge records. All persons with ≥1 AR-PDMP prescription fill(s) between 1 January 2014 and 31 December 2017 were included (n = 1,946,686). For persons that experienced OOD and had ≥1 PDMP record(s), the difference in days between OOD and the most recent AR-PDMP prescription filled prior to an OOD was recorded. To account for censoring, a sensitivity analysis was conducted restricting the study group to "New AR-PDMP Entrants" that had at least a 180-day gap between consecutive AR-PDMP fill dates. RESULTS: 28,998,307 AR-PDMP records were analyzed for 1,946,686 individuals. 7195 persons experienced 9223 OODs and 414 (4.49%) of those were fatal. Of these, 6236 experienced ≥1 OOD and acquired prescribed CSs prior to or on the day of the first OOD. Of those that experienced ≥1 OOD(s), 2201 (30.59%) had an AR-PDMP record in the 0- to 5-day period prior to their overdose and 497 (6.91%) had an AR-PDMP record the day prior to their overdose. Among New AR-PDMP Entrants that experienced ≥1 OOD(s), 408 (27.38%) had an AR-PDMP record in the 0- to 5-day period prior to their overdose. CONCLUSION: Though the vast majority of persons accessing CSs in Arkansas did not experience an OOD, a sizable proportion of persons that experience an OOD(s) obtained prescribed CSs immediately prior.

Bidirectional brain-gut interactions and chronic pathological changes after traumatic brain injury in mice.

OBJECTIVES: Traumatic brain injury (TBI) has complex effects on the gastrointestinal tract that are associated with TBI-related morbidity and mortality. We examined changes in mucosal barrier properties and enteric glial cell response in the gut after experimental TBI in mice, as well as effects of the enteric pathogen Citrobacter rodentium (Cr) on both gut and brain after injury. METHODS: Moderate-level TBI was induced in C57BL/6mice by controlled cortical impact (CCI). Mucosal barrier function was assessed by transepithelial resistance, fluorescent-labelled dextran flux, and quantification of tight junction proteins. Enteric glial cell number and activation were measured by Sox10 expression and GFAP reactivity, respectively. Separate groups of mice were challenged with Cr infection during the chronic phase of TBI, and host immune response, barrier integrity, enteric glial cell reactivity, and progression of brain injury and inflammation were assessed. RESULTS: Chronic CCI induced changes in colon morphology, including increased mucosal depth and smooth muscle thickening. At day 28 post-CCI, increased paracellular permeability and decreased claudin-1 mRNA and protein expression were observed in the absence of inflammation in the colon. Colonic glial cell GFAP and Sox10 expression were significantly increased 28days after brain injury. Clearance of Cr and upregulation of Th1/Th17 cytokines in the colon were unaffected by CCI; however, colonic paracellular flux and enteric glial cell GFAP expression were significantly increased. Importantly, Cr infection in chronically-injured mice worsened the brain lesion injury and increased astrocyte- and microglial-mediated inflammation. CONCLUSION: These experimental studies demonstrate chronic and bidirectional brain-gut interactions after TBI, which may negatively impact late outcomes after brain injury.

IL-25 or IL-17E Protects against High-Fat Diet-Induced Hepatic Steatosis in Mice Dependent upon IL-13 Activation of STAT6.

IL-25 or IL-17E is a member of IL-17 cytokine family and has immune-modulating activities. The role of IL-25 in maintaining lipid metabolic homeostasis remains unknown. We investigated the effects of exogenous IL-25 or deficiency of IL-25 on hepatic lipid accumulation. IL-25 expression was examined in paraffin-embedded tissue sections of liver from patients or in the livers from mice. Mouse model of steatosis was induced by feeding a high-fat diet (HFD). Extent of steatosis as well as expression of cytokines, key enzymes for lipid metabolic pathways, markers for Kupffer cells/macrophages, and lipid droplet (LD) proteins, were analyzed. Our results show that hepatic steatosis in mice was accompanied by increased LD proteins, but decreased IL-25 in the liver. Decreased hepatic IL-25 was also observed in patients with fatty liver. Administration of IL-25 to HFD-fed wild-type mice led to a significant improvement in hepatic steatosis. This effect was associated with increased expression of IL-13, development of alternatively activated Kupffer cells/macrophages, and decreased expression of LD proteins in the liver. In contrast, administration of IL-25 to HFD-fed mice deficient in STAT6 or IL-13 had no effects. In addition, stimulation of primary hepatocytes with IL-13, but not IL-25, resulted in downregulation of LD proteins. Finally, mice deficient in IL-25 had exacerbated hepatic lipid accumulation when fed the HFD. These data demonstrate that dysregulated IL-25 expression contributes to lipid accumulation, whereas exogenous IL-25 protects against hepatic steatosis through IL-13 activation of STAT6. IL-25 and IL-13 are potential therapeutic agents for hepatic steatosis and associated pathologies.

Transcriptomic Analysis of the Swarm Motility Phenotype of Salmonella enterica Serovar Typhimurium Mutant Defective in Periplasmic Glucan Synthesis.

Movement of food-borne pathogens on moist surfaces enables them to migrate towards more favorable niches and facilitate their survival for extended periods of time. Salmonella enterica serovar Typhimurium mutants defective in Osmoregulated periplasmic glucans (OPG) synthesis are unable to exhibit motility on moist surfaces (swarming); however, their mobility in liquid (swim motility) remains unaffected. In order to understand the role of OPG in swarm motility, transcriptomic analysis was performed using cells growing on a moist agar surface. In opgGH deletion mutant, lack of OPG significantly altered transcription of 1039 genes out of total 4712 genes (22%). Introduction of a plasmid-borne copy of opgGH into opgGH deletion mutant restored normal expression of all but 30 genes, indicating a wide-range influence of OPG on gene expression under swarm motility condition. Major pathways that were differentially expressed in opgGH mutants were motility, virulence and invasion, and genes related to the secondary messenger molecule, cyclic di-GMP. These observations provide insights and help explain the pleiotropic nature of OPG mutants such as sub-optimal virulence and competitive organ colonization in mice, biofilm formation, and sensitivity towards detergent stress.

Prooxidant and antioxidant properties of salicylaldehyde isonicotinoyl hydrazone iron chelators in HepG2 cells.

BACKGROUND: Salicylaldehyde isonicotinoyl hydrazone (SIH) is an iron chelator of the aroylhydrazone class that displays antioxidant or prooxidant effects in different mammalian cell lines. Because the liver is the major site of iron storage, elucidating the effect of SIH on hepatic oxidative metabolism is critical for designing effective hepatic antioxidant therapies. METHODS: Hepatocyte-like HepG2 cells were exposed to SIH or to analogs showing greater stability, such as N'-[1-(2-Hydroxyphenyl)ethyliden]isonicotinoyl hydrazide (HAPI), or devoid of iron chelating properties, such as benzaldehyde isonicotinoyl hydrazone (BIH), and toxicity, oxidative stress and antioxidant (glutathione) metabolism were evaluated. RESULTS: Autoxidation of Fe(2+)in vitro increased in the presence of SIH or HAPI (but not BIH), an effect partially blocked by Fe(2+) chelation. Incubation of HepG2 cells with SIH or HAPI (but not BIH) was non-toxic and increased reactive oxygen species (ROS) levels, activated the transcription factor Nrf2, induced the catalytic subunit of γ-glutamate cysteine ligase (Gclc), and increased glutathione concentration. Fe(2+) chelation decreased ROS and inhibited Nrf2 activation, and Nrf2 knock-down inhibited the induction of Gclc in the presence of HAPI. Inhibition of γ-glutamate cysteine ligase enzymatic activity inhibited the increase in glutathione caused by HAPI, and increased oxidative stress. CONCLUSIONS: SIH iron chelators display both prooxidant (increasing the autoxidation rate of Fe(2+)) and antioxidant (activating Nrf2 signaling) effects. GENERAL SIGNIFICANCE: Activation by SIH iron chelators of a hormetic antioxidant response contributes to their antioxidant properties and modulates the anti- and pro-oxidant balance.

Critical Role for Interleukin-25 in Host Protective Th2 Memory Response against Heligmosomoides polygyrus bakeri.

Infection with parasitic nematodes, especially gastrointestinal geohelminths, affects hundreds of millions of people worldwide and thus poses a major risk to global health. The host mechanism of defense against enteric nematode infection remains to be fully understood, but it involves a polarized type 2 immunity leading to alterations in intestinal function that facilitate worm expulsion. We investigated the role of interleukin-25 (IL-25) in host protection against Heligmosomoides polygyrus bakeri infection in mice. Our results showed that Il25 and its receptor subunit, Il17rb, were upregulated during a primary infection and a secondary challenge infection with H. polygyrus bakeri Genetic deletion of IL-25 (IL-25-/-) led to an attenuated type 2 cytokine response and increased worm fecundity in mice with a primary H. polygyrus bakeri infection. In addition, the full spectrum of the host memory response against a secondary infection with H. polygyrus bakeri was severely impaired in IL-25-/- mice, including delayed type 2 cytokine responses, an attenuated functional response of the intestinal smooth muscle and epithelium, diminished intestinal smooth muscle hypertrophy/hyperplasia, and impaired worm expulsion. Furthermore, exogenous administration of IL-25 restored the host protective memory response against H. polygyrus bakeri infection in IL-25-/- mice. These data demonstrate that IL-25 is critical for host protective immunity against H. polygyrus bakeri infection, highlighting its potential application as a therapeutic agent against parasitic nematode infection worldwide.

Type 3 muscarinic receptors contribute to intestinal mucosal homeostasis and clearance of Nippostrongylus brasiliensis through induction of TH2 cytokines.

Despite increased appreciation for the role of nicotinic receptors in the modulation of and response to inflammation, the contribution of muscarinic receptors to mucosal homeostasis, clearance of enteric pathogens, and modulation of immune cell function remains relatively undefined. Uninfected and Nippostrongylus brasiliensis-infected wild-type and type 3 muscarinic receptor (M3R)-deficient (Chrm3(-/-)) mice were studied to determine the contribution of M3R to mucosal homeostasis as well as host defense against the TH2-eliciting enteric nematode N. brasiliensis Intestinal permeability and expression of TH1/TH17 cytokines were increased in uninfected Chrm3(-/-) small intestine. Notably, in Chrm3(-/-) mice infected with N. brasiliensis, small intestinal upregulation of TH2 cytokines was attenuated and nematode clearance was delayed. In Chrm3(-/-) mice, TH2-dependent changes in small intestinal function including smooth muscle hypercontractility, increased epithelial permeability, decreased epithelial secretion and absorption, and goblet cell expansion were absent despite N. brasiliensis infection. These findings identify an important role for M3R in host defense and clearance of N. brasiliensis, and support the expanding role of cholinergic muscarinic receptors in maintaining mucosal homeostasis.

Understanding the host-adapted state of Citrobacter rodentium by transcriptomic analysis.

Citrobacter rodentium (Cr) is a mouse pathogen that mimics many aspects of enteropathogenic Escherichia coli infections including producing attaching and effacing (A/E) lesions. Host-adapted (HA) Cr cells that are shed at the peak of infection have been reported to be hyper-infective. The exact mechanism underlying this phenomenon has remained elusive since the pathogen loses its HA 'status' immediately upon subculturing in laboratory media. We sequenced the entire transcriptome of Cr directly from the feces of infected mice and analyzed the gene expression pattern. We observed that the entire transcriptional machinery as well as several transcriptional regulators to be differentially expressed when compared with the transcriptome of cells grown on laboratory media. Major adhesion and effector genes, tir and eae, were highly expressed in HA along with many genes located on all five loci of enterocyte effacement regions (LEE 1-5). Notable absent among the HA expressed genes were 19 fimbrial operons and non-fimbrial adhesions and several non-LEE encoded effectors. These results demonstrate that host-adapted Cr has a unique transcriptome that is associated with increased host transmission.

A type 4 resistant potato starch alters the cecal microbiome and gene expression in mice fed a western diet based on NHANES data.

Four major types of resistant starch (RS1-4) are present in foods, all of which can alter the microbiome and are fermented in the cecum and colon to produce short-chain fatty acids (SCFAs). Type 4 RSs are chemically modified starches, not normally found in foods, but have become a popular food additive as their addition increases fiber content. Multiple studies, in humans and rodents, have explored how different RS4 affect post-prandial glucose metabolism, but fewer studies have examined the effects of RS4 consumption on the microbiome. In addition, many RS studies conducted in rodents use high-fat diets that do not approximate what is typically consumed by humans. To address this, mice were fed a Total Western Diet (TWD), based on National Health and Nutrition Examination Survey (NHANES) data that mimics the macro and micronutrient composition of a typical American diet, for six weeks, and then supplemented with 0, 2, 5, or 10% of the RS4, Versafibe 1490™ (VF), a phosphorylated and cross-linked potato starch, for an additional three weeks. The cecal contents were analyzed for SCFA content and microbiota composition. Butyrate production was increased while branched chain SCFA production decreased. The alpha-diversity of the microbiome decreased in mice fed the TWD with 10% VF 1490 added while the beta-diversity plot showed that the 5% and 10% VF groups were distinct from mice fed the TWD. Similarly, the largest changes in relative abundance of various genera were greatest in mice fed the 10% VF diet. To examine the effect of VF consumption on tissue gene expression, cecal and distal colon tissue mRNA abundance were analyzed by RNASeq. Gene expression changes were more prevalent in the cecum than the colon and in mice fed the 10% VF diet, but the number of changes was substantially lower than we previously observed in mice fed the TWD supplemented with native potato starch (RPS). These results provide additional evidence that the structure of the RS is a major factor determining its effects on the microbiome and gene expression in the cecum and colon.

Phospholipid-rich krill oil promotes intestinal health by strengthening beneficial gut microbial interactions in an infectious colitis model.

Krill oil (KO) is rich in bioactive ingredients including phospholipids, omega-3 fatty acids, and astaxanthin. While health benefits and roles of KO in modulating lipid metabolism are well documented, its ability to alleviate symptoms related to infectious colitis and modulate gut microbial interactions is still largely unknown. Here we used a multi-omics approach, including transcriptome, microbiome, and metabolome analyses, to understand how KO mediates gut microbial interactions and promotes epithelial healing in an infectious colitis model. KO reversed the infection-induced intestinal hyperplasia to baseline. KO dampened intestinal inflammation via multiple targets, mediating several proinflammatory pathways, including IL17 signaling, and reducing luminal histamine levels. KO supplementation enriched butyrate-producing bacteria, including Roseburia and Clostridium, and strengthened beneficial microbial interactions in the gut microbial community. Supplementation with phospholipid-rich KO also increased microbial phylogenetic diversity. KO enhanced mucosal barrier function by increasing the production of Muc6 and the antimicrobial peptide, Leap2. KO played an active role during epithelial healing by inhibiting the expression of granzyme K while increasing the expression of a colitis protective factor, Dclk1. Together, our findings demonstrate that KO rich in omega-3 phospholipids can play a protective role in infectious colitis and should be considered a dietary option for promoting gut health.

ILC2s navigate tissue redistribution during infection using stage-specific S1P receptors.

Lymphocytes can circulate as well as take residence within tissues. While the mechanisms by which circulating populations are recruited to infection sites have been extensively characterized, the molecular basis for the recirculation of tissue-resident cells is less understood. Here, we show that helminth infection- or IL-25-induced redistribution of intestinal group 2 innate lymphoid cells (ILC2s) requires access to the lymphatic vessel network. Although the secondary lymphoid structure is an essential signal hub for adaptive lymphocyte differentiation and dispatch, it is redundant for ILC2 migration and effector function. Upon IL-25 stimulation, a dramatic change in epigenetic landscape occurs in intestinal ILC2s, leading to the expression of sphingosine-1-phosphate receptors (S1PRs). Among the various S1PRs, we found that S1PR5 is critical for ILC2 exit from intestinal tissue to lymph. By contrast, S1PR1 plays a dominant role in ILC2 egress from mesenteric lymph nodes to blood circulation and then to distal tissues including the lung where the redistributed ILC2s contribute to tissue repair. The requirement of two S1PRs for ILC2 migration is largely due to the dynamic expression of the tissue-retention marker CD69, which mediates S1PR1 internalization. Thus, our study demonstrates a stage-specific requirement of different S1P receptors for ILC2 redistribution during infection. We therefore propose a fundamental paradigm that innate and adaptive lymphocytes utilize a shared vascular network frame and specialized navigation cues for migration.

Selenium status alters the immune response and expulsion of adult Heligmosomoides bakeri worms in mice.

Heligmosomoides bakeri is a nematode with parasitic development exclusively in the small intestine of infected mice that induces a potent STAT6-dependent Th2 immune response. We previously demonstrated that host protective expulsion of adult H. bakeri worms from a challenge infection was delayed in selenium (Se)-deficient mice. In order to explore mechanisms associated with the delayed expulsion, 3-week-old female BALB/c mice were placed on a torula yeast-based diet with or without 0.2 ppm Se, and after 5 weeks, they were inoculated with H. bakeri infective third-stage larvae (L3s). Two weeks after inoculation, the mice were treated with an anthelmintic and then rested, reinoculated with L3s, and evaluated at various times after reinoculation. Analysis of gene expression in parasite-induced cysts and surrounding tissue isolated from the intestine of infected mice showed that the local-tissue Th2 response was decreased in Se-deficient mice compared to that in Se-adequate mice. In addition, adult worms recovered from Se-deficient mice had higher ATP levels than worms from Se-adequate mice, indicating greater metabolic activity in the face of a suboptimal Se-dependent local immune response. Notably, the process of worm expulsion was restored within 2 to 4 days after feeding a Se-adequate diet to Se-deficient mice. Expulsion was associated with an increased local expression of Th2-associated genes in the small intestine, intestinal glutathione peroxidase activity, secreted Relm-ß protein, anti-H. bakeri IgG1 production, and reduced worm fecundity and ATP-dependent metabolic activity.

Parasitic nematode-induced modulation of body weight and associated metabolic dysfunction in mouse models of obesity.

Obesity is associated with a chronic low-grade inflammation characterized by increased levels of proinflammatory cytokines that are implicated in disrupted metabolic homeostasis. Parasitic nematode infection induces a polarized Th2 cytokine response and has been explored to treat autoimmune diseases. We investigated the effects of nematode infection against obesity and the associated metabolic dysfunction. Infection of RIP2-Opa1KO mice or C57BL/6 mice fed a high-fat diet (HFD) with Nippostrongylus brasiliensis decreased weight gain and was associated with improved glucose metabolism. Infection of obese mice fed the HFD reduced body weight and adipose tissue mass, ameliorated hepatic steatosis associated with a decreased expression of key lipogenic enzymes/mediators, and improved glucose metabolism, accompanied by changes in the profile of metabolic hormones. The infection resulted in a phenotypic change in adipose tissue macrophages that was characterized by upregulation of alternative activation markers. Interleukin-13 (IL-13) activation of the STAT6 signaling pathway was required for the infection-induced attenuation of steatosis but not for improved glucose metabolism, whereas weight loss was attributed to both IL-13/STAT6-dependent and -independent mechanisms. Parasitic nematode infection has both preventive and therapeutic effects against the development of obesity and associated features of metabolic dysfunction in mice.

Hypervirulent-host-associated Citrobacter rodentium cells have poor acid tolerance.

Enhanced virulence or infectivity after passage through a mammalian host has been reported for a number of enteric food-borne pathogens. Citrobacter rodentium is a mouse pathogen that mimics many aspects of enterohemorrhagic Escherichia coli infection of humans and serves as a useful model for studying virulence mechanisms. Emergence of a hyperinfectious state after passage through mouse gastrointestinal tract was reported for C. rodentium. We wanted to investigate if increased acid tolerance could explain hypervirulence status of C. rodentium. Although we were able to observe hyperinfectious state of C. rodentium upon host passage, the cells were extremely acid sensitive. Growth under mildly acidic conditions (LB-MES, pH 5.5) induced acid tolerance of C. rodentium, but did not improve the organism's ability to establish infection. Growth under anaerobic environment on fecal components also did not induce hyperinfectious state. Thus, contrary to conventional anticipation, hypervirulent C. rodentium cells were found to be acid sensitive thereby revealing limitations of the role of mouse gastric acidity by itself in elucidating the hypervirulent phenotype.

Ellagitannin Punicalagin Disrupts the Pathways Related to Bacterial Growth and Affects Multiple Pattern Recognition Receptor Signaling by Acting as a Selective Histone Deacetylase Inhibitor.

Punicalagin (PA) is a key ellagitannin abundant in pomegranate with wide-ranging biological activities. In this study, we examined the biological processes by which PA regulates bacterial growth and inflammation in human cells using multiomics and molecular docking approaches. PA promoted macrophage-mediated bacterial killing and inhibited the growth of Citrobacter rodentium by inducing a distinct metabolome pattern. PA acted as a selective regulator of histone deacetylases (HDACs) and affected 37 pathways in macrophages, including signaling mediated by pattern recognition receptors, such as Toll-like and NOD-like receptors. In silico simulation showed that PA can bind with high affinity to HDAC7. PA downregulated HDAC7 at both mRNA and protein levels and resulted in a decrease in the level of histone 3 lysine 27 acetylation. Our findings provide evidence that PA exerts its biological effects via multiple pathways, which can be exploited in the development of this bioactive food ingredient for disease management.

Multi-omics analysis detected multiple pathways by which pomegranate punicalagin exerts its biological effects in modulating host-microbiota interactions in murine colitis models.

As one of the key bioactive food ingredients in pomegranate, punicalagin (PA) possesses wide-ranging functional activities. However, the knowledge on PA-modulated microbial interactions and their physiological relevance in the gastrointestinal tract is limited. In this study, the modulating effects of PA on host-microbiota interactions were examined using multi-omics approaches in two colitis models. In a chemical colitis model, PA ingestion dampened intestinal inflammation and repressed gut microbial diversity. PA significantly reversed multiple lipids and γ-glutamyl amino acids from elevated levels in colitis mice to the baseline. Anti-inflammatory and microbiota-modulating effects of PA were further validated in an infectious colitis model induced by Citrobacter rodentium, in which PA also restored the microbial dysbiosis index to the baseline and promoted microbial interactions. Multiple microbial signatures with high predictive accuracy for key colitis pathophysiological parameters were identified, which can be developed as biomarkers for monitoring the efficacy of PA-containing functional foods in promoting gut health. Our findings should facilitate the exploitation of dual applications of PA as a bioactive food ingredient and a therapeutic agent.

Urethral Slings for Irradiated Patients With Male Stress Urinary Incontinence: A Meta-analysis.

OBJECTIVE: To systematically compare success, cure and complication rates of urethral sling surgeries in stress urinary incontinence patients with and without a history of pelvic radiotherapy (RT). MATERIALS AND METHODS: We searched PUBMED, EMBASE, and Web of Science to identify relevant articles. The primary outcomes were the success and cure rates. The secondary outcomes included the rates of infection, urethral erosion, total complications, explantation, and satisfaction. Outcomes were analyzed using a random-effects model to calculate the unadjusted odds ratio (OR) in patients with a history of RT compared with those without prior RT. RESULTS: On pooled analysis, we found significantly lower odds of success (OR 0.68; 95% confidence interval [CI] 0.53-0.87, P < .001) and cure (OR 0.67; 95% CI 0.55-0.82, P < .001) in radiated patients than in nonirradiated patients. Subgroup analysis by type of sling showed significantly lower odds of success in Advance subgroup (OR 0.66; 95% CI 0.45-0.95, P < .001) and significantly lower odds of cure in Advance (OR 0.59; 95% CI 0.36-0.95, P < .001) and Atoms subgroups (OR 0.70; 95% CI 0.54-0.93, P < .001). We also found significantly greater odds of sling explantation (OR 2.93; 95% CI 1.62-5.29, P < .001) and infection (OR 3.06, 95% CI 1.03-9.07, P < .001) in radiated patients than in nonradiated patients. CONCLUSION: Patients with a history of pelvic RT have lower odds of success and cure and higher odds of infection and sling explantation than those without a history of pelvic RT.

Biological pathways via which the anthocyanin malvidin alleviated the murine colitis induced by Citrobacter rodentium.

Enteropathogenic E. coli (EPEC) is a causal agent for diarrheal diseases and contributes to morbidity and mortality in children under the age of five years. The emergence and rapid spread of antibiotic resistant EPEC strains necessitate the search for novel alternatives to antibiotics. In this study, we used Citrobacter rodentium, a natural mouse pathogen that mimics many aspects of human EPEC infections, to investigate the antimicrobial properties of the blueberry anthocyanin malvidin 3-glucoside (MG) using a multi-omics approach. MG supplementation reversed the bodyweight loss induced by C. rodentium infection and improved colonic hyperplasia and histopathological scores. In the colon tissue, MG supplementation significantly increased the expression of Hace1, a key regulator of TNFα-driven signaling, and impacted multiple pathways, such as TGFß signaling. MG partially restored C. rodentium-induced microbial dysbiosis and significantly enhanced the abundance of the probiotic Bifidobacterium animalis. Moreover, MG disrupted the interactions of E. coli with other gut microbes. MG significantly mediated several host- and microbiota-derived metabolites, such as cytosine, ureidopropionic acid, and glutaric acid. MG normalized the bioactive lipid oleoylethanolamine, a member of the endocannabinoid system, from the dysregulated level in infected mice, directly contributing to its overall beneficial effects. Our findings provided novel insights into molecular processes via which the flavonoid malvidin exerts its biological effects in the gastrointestinal tract.

Role of anionic charges of osmoregulated periplasmic glucans of Salmonella enterica serovar Typhimurium SL1344 in mice virulence.

opgB gene of Salmonella enterica serovar Typhimurium was identified earlier in a genome-wide screen for mice virulence (Valentine et al. in Infect Immun 66:3378-3383, 1998). Although mutation in opgB resulted in avirulent Salmonella strain, how this gene contributes to pathogenesis remains unclear. Based on DNA homology, opgB is predicted to be responsible for adding phosphoglycerate residues to osmoregulated periplasmic glucans (OPGs) giving them anionic characteristics. In Escherichia coli, yet another gene, opgC, is also reported to contribute to anionic characteristics of OPGs by adding succinic acid residues. We constructed opgB, opgC, and opgBC double mutants of S. enterica serovar Typhimurium strain SL1344. As predicted opgBC mutant synthesized neutral OPGs that were devoid of any anionic substituents. However, opgB, opgC, and opgBC mutations had no significant impact on mice virulence as well as on competitive organ colonization. In low osmotic conditions, opgB, opgC, and opgBC mutants exhibited delay in growth initiation in the presence of sodium deoxycholate. Anionic substituents of OPGs from Salmonella although appear to be needed to overcome resistance of deoxycholate in hypoosmotic growth media, no evidence was found for their role in mice virulence.