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Non-alcoholic fatty liver disease (NAFLD) is the most common chronic liver disease in Western countries. There is growing evidence that dysbiosis of the intestinal microbiota and disruption of microbiota-host interactions contribute to the pathology of NAFLD. We previously demonstrated that gut microbiota-derived tryptophan metabolite indole-3-acetate (I3A) was decreased in both cecum and liver of high-fat diet-fed mice and attenuated the expression of inflammatory cytokines in macrophages and Tnfa and fatty acid-induced inflammatory responses in an aryl-hydrocarbon receptor (AhR)-dependent manner in hepatocytes. In this study, we investigated the effect of orally administered I3A in a mouse model of diet-induced NAFLD. Western diet (WD)-fed mice given sugar water (SW) with I3A showed dramatically decreased serum ALT, hepatic triglycerides (TG), liver steatosis, hepatocyte ballooning, lobular inflammation, and hepatic production of inflammatory cytokines, compared to WD-fed mice given only SW. Metagenomic analysis show that I3A administration did not significantly modify the intestinal microbiome, suggesting that I3A's beneficial effects likely reflect the metabolite's direct actions on the liver. Administration of I3A partially reversed WD-induced alterations of liver metabolome and proteome, notably, decreasing expression of several enzymes in hepatic lipogenesis and ß-oxidation. Mechanistically, we also show that AMP-activated protein kinase (AMPK) mediates the anti-inflammatory effects of I3A in macrophages. The potency of I3A in alleviating liver steatosis and inflammation clearly demonstrates its potential as a therapeutic modality for preventing the progression of steatosis to non-alcoholic steatohepatitis (NASH). [ABSTRACT FROM AUTHOR]

It was recently reported that the hydroxyflavones quercetin and kaempferol bind the orphan nuclear receptor 4A1 (NR4A1, Nur77) and act as antagonists in cancer cells and tumors, and they inhibit pro-oncogenic NR4A1-regulated genes and pathways. In this study, we investigated the interactions of flavone, six hydroxyflavones, seven dihydroxyflavones, three trihydroxyflavones, two tetrahydroxyflavones, and one pentahydroxyflavone with the ligand-binding domain (LBD) of NR4A1 using direct-binding fluorescence and an isothermal titration calorimetry (ITC) assays. Flavone and the hydroxyflavones bound NR4A1, and their KD values ranged from 0.36 µM for 3,5,7-trihydroxyflavone (galangin) to 45.8 µM for 3′-hydroxyflavone. KD values determined using ITC and KD values for most (15/20) of the hydroxyflavones were decreased compared to those obtained using the fluorescence assay. The results of binding, transactivation and receptor–ligand modeling assays showed that KD values, transactivation data and docking scores for these compounds are highly variable with respect to the number and position of the hydroxyl groups on the flavone backbone structure, suggesting that hydroxyflavones are selective NR4A1 modulators. Nevertheless, the data show that hydroxyflavone-based neutraceuticals are NR4A1 ligands and that some of these compounds can now be repurposed and used to target sub-populations of patients that overexpress NR4A1. [ABSTRACT FROM AUTHOR]

Background: Our recent study demonstrated that selective aryl hydrocarbon receptor modulators (SAhRMs), such as 1,4-dihydroxy-2-napthoic acid (DHNA) act as antidepressants in female mice. Given that some effects of certain SAhRMs are known to also be mediated via estrogen receptor signaling, this study examined whether the effects of SAhRMs on mood, emotional state, and cognition are sex-dependent.Methods: C57BL/6N mice were fed with vehicle or 20 mg/kg DHNA for three weeks prior to four weeks of unpredictable chronic mild stress (UCMS). Mice were examined for depression-like behaviors (sucrose preference, forced swim test (FST), splash test, tape groom test), emotional state (open-field test, light/dark test, marble burying, novelty-induced hypophagia, elevated-plus maze), and cognition (object location recognition, novel object recognition, Morris water maze).Results: In females, UCMS decreased sucrose preference and increased FST immobility time; both effects were prevented by DHNA. In males, UCMS increased FST immobility time, and increased the latency to groom in the splash test. These effects were not mitigated by DHNA. However, in males, UCMS induced an increase in novelty-induced locomotion, an increase in the time spent in the light compartment in the L/D test, and an increase in the time spent with an object in a novel location. These effects were prevented by DHNA.Conclusions: Our findings indicate that DHNA has high potential to act as antidepressants in females. However, given classical interpretation, DHNA did not appear to act as an antidepressant in males. Nonetheless, our findings indicate that DHNA can mitigate stress effects and reactivity in males. [ABSTRACT FROM AUTHOR]

Supplemental digital content is available in the text. Purpose: Chronic overfeeding via a high-fat/high-sugar (HFHS) diet decreases wheel running and substantially alters the gut metabolome of C57BL/6J mice. In this study, we tested the hypothesis that fecal microbial transplants can modulate the effect of diet on wheel running. Methods: Singly housed, 6-wk-old male C57BL/6J mice were fed either a grain-based diet (CHOW) or HFHS diet and provided a running wheel for 13 wk. Low-active, HFHS-exposed mice were then either switched to a CHOW diet and given an oral fecal microbial transplant from mice fed the CHOW diet, switched to a CHOW diet and given a sham transplant, or remained on the HFHS diet and given a fecal microbial transplant from mice fed the CHOW diet. Total wheel running, nutrient intake, body composition, fecal microbial composition, fecal metabolite composition, and liver steatosis were measured at various times throughout the study. Results: We found that an HFHS diet decreases wheel running activity, increases body fat, and decreases microbial alpha diversity compared with a CHOW diet. Improvements in wheel running, body composition, and microbial alpha diversity were accomplished within 2 wk for mice switched from an HFHS diet to a CHOW diet with no clear evidence of an added benefit from fecal transplants. A fecal transplant from mice fed a CHOW diet without altering diet did not improve wheel running or body composition. Wheel running, body composition, fecal microbial composition, fecal metabolite composition, and liver steatosis percentage were primarily determined by diet. Conclusions: Our results suggest that diet is a primary mediator of wheel running with no clear effect from fecal microbial transplants. [ABSTRACT FROM AUTHOR]

Background: Current pharmaceutical treatments for depression are sometimes ineffective and may have unwanted side effects that interfere with patient compliance. This study examined the potential antidepressant-like effects of dietary- and microbial-derived aryl hydrocarbon receptor (AhR) ligands, 3,3'-diindolylmethane (DIM) and 1,4-dihydroxy-2-naphthoic acid (1,4-DHNA).Methods: Female C57BL/6 mice were subjected to unpredictable chronic mild stress (UCMS) or were unstressed. For three weeks prior to UCMS mice were fed daily with vehicle or 20 mg/kg DIM, 1,4-DHNA or AhR-inactive isomer 3,7-DHNA; another group was subjected to two weeks UCMS before ligand administration began. Mice were examined for anhedonia-like behavior as measured by the sucrose preference test. Additionally, anxiety levels of the mice were examined before UCMS and ligand administration began and at the end in the open field, light/dark, elevated plus maze, novelty-induced hypophagia, and marble burying tests. At the end of the experiment they were also examined in the Morris water maze (MWM) task.Results: Both DIM and 1,4-DHNA, but not 3,7-DHNA, successfully prevented and reversed UCMS-induced anhedonia-like behavior. Furthermore, both DIM and DHNA had little to no effect on anxiety levels and did not induce spatial learning deficits.Limitations: Additional studies are required to determine to what degree the antidepressant-like effects of DIM and 1,4-DHNA can be attributed to their activities as AhR ligands.Conclusions: Our findings indicate that dietary and microbial-derived AhR ligands may have clinical applications as potential antidepressants. Future studies are necessary to elucidate the role of AhR in depression-like states and the underlying mechanisms of action. [ABSTRACT FROM AUTHOR]

IL22 signaling plays an important role in maintaining gastrointestinal epithelial barrier function, cell proliferation, and protection of intestinal stem cells from genotoxicants. Emerging studies indicate that the aryl hydrocarbon receptor (AhR), a ligand-activated transcription factor, promotes production of IL22 in gut immune cells. However, it remains to be determined if AhR signaling can also affect the responsiveness of colonic epithelial cells to IL22. Here, we show that IL22 treatment induces the phosphorylation of STAT3, inhibits colonic organoid growth, and promotes colonic cell proliferation in vivo. Notably, intestinal cell-specific AhR knockout (KO) reduces responsiveness to IL22 and compromises DNA damage response after exposure to carcinogen, in part due to the enhancement of suppressor of cytokine signaling 3 (SOCS3) expression. Deletion of SOCS3 increases levels of pSTAT3 in AhR KO organoids, and phenocopies the effects of IL22 treatment on wild-type (WT) organoid growth. In addition, pSTAT3 levels are inversely associated with increased azoxymethane/dextran sulfate sodium (AOM/DSS)-induced colon tumorigenesis in AhR KO mice. These findings indicate that AhR function is required for optimal IL22 signaling in colonic epithelial cells and provide rationale for targeting AhR as a means of reducing colon cancer risk. NEW & NOTEWORTHY AhR is a key transcription factor controlling expression of IL22 in gut immune cells. In this study, we show for the first time that AhR signaling also regulates IL22 response in colonic epithelial cells by modulating SOCS3 expression. [ABSTRACT FROM AUTHOR]

Hydroxylated chalcones are phytochemicals which are biosynthetic precursors of flavonoids and their 1,3-diaryl-prop-2-en-1-one structure is used as a scaffold for drug development. In this study, the structure-dependent activation of aryl hydrocarbon receptor (AhR)-responsive CYP1A1, CYP1B1, and UGT1A1 genes was investigated in Caco2 colon cancer cells and in non-transformed young adult mouse colonocytes (YAMC) cells. The effects of a series of di- and trihydroxychalcones as AhR agonists was structure dependent with maximal induction of CYP1A1, CYP1B1, and UGT1A1 in Caco2 cells observed for compounds containing 2,2′-dihydroxy substituents and this included 2,2′-dihydroxy-, 2,2′,4′-trihydroxy-, and 2,2′,5′-trihydroxychalcones. In contrast, 2′,4,5′-, 2′3′,4′-, 2′,4,4′-trihydroxy, and 2′,3-, 2′,4-, 2′,4′-, and 2′,5-dihydroxychalcones exhibited low to non-detectable AhR activity in Caco2 cells. In addition, all of the hydroxychalcones exhibited minimal to non-detectable activity in YAMC cells, whereas 2,3,7,8-tetrachlorodibenzo-p-dioxin (TCDD) induced CYP1A1, CYP1B1, and UGT1A1 in Caco2 and YAMC cells. The activity of AhR-active chalcones was confirmed by determining their effects in AhR-deficient Caco2 cells. In addition, 2,2′-dihydroxychalcone induced CYP1A1 protein and formation of an AhR-DNA complex in an in vitro assay. Simulation and modeling studies of hydroxylated chalcones confirmed their interactions with the AhR ligand-binding domain and were consistent with their structure-dependent activity as AhR ligands. Thus, this study identifies hydroxylated chalcones as AhR agonists with potential for these phytochemicals to impact AhR-mediated colonic pathways. [ABSTRACT FROM AUTHOR]

• Longitudinal approach offers insights unavailable from cross-sectional approach. • Analyzing sparse and unevenly sampled time-series data brings unique challenges. • Current methods and tools for analyzing multi-omics time-series data are critically reviewed. The gut microbiota and its metabolites play critical roles in human health and disease. Advances in high-throughput sequencing, mass spectrometry, and other omics assay platforms have improved our ability to generate large volumes of data exploring the temporal variations in the compositions and functions of microbial communities. To elucidate mechanisms, methods and tools are needed that can rigorously model the dependencies within time-series data. Longitudinal data are often sparse and unevenly sampled, and nontrivial challenges remain in determining statistical significance, normalization across different data types, and model validation. In this review, we highlight recent developments in models and software tools for the analysis of time series microbiome and metabolome data, as well as integration of these data. [ABSTRACT FROM AUTHOR]

Tryptophan metabolites exhibit aryl hydrocarbon receptor (AhR) agonist activity and recent studies show that the phenylalanine metabolites serotonin and carbidopa, a drug used in treating Parkinson's disease, activated the AhR. In this study, we identified the neuroactive hormone dopamine as an inducer of drug-metabolizing enzymes CYP1A1, CYP1B1, and UGT1A1 in colon and glioblastoma cells and similar results were observed for carbidopa. In contrast, carbidopa but not dopamine exhibited AhR activity in BxPC3 pancreatic cancer cells whereas minimal activity was observed for both compounds in Panc1 pancreatic cancer cells. In contrast with a previous report, the induction responses and cytotoxicity of carbidopa was observed only at high concentrations (100 mM) in BxPC3 cells. Our results show that similar to serotonin and several tryptophan metabolites, dopamine is also an AhR-active compound. [ABSTRACT FROM AUTHOR]

The aryl hydrocarbon receptor (AhR), a ligand‐activated transcription factor that senses xenobiotics, diet, and gut microbial‐derived metabolites, is increasingly recognized as a key regulator of intestinal biology. However, its effects on the function of colonic stem and progenitor cells remain largely unexplored. Here, we observed that inducible deletion of AhR in Lgr5+ stem cells increases the percentage of colonic stem cells and enhances organoid initiating capacity and growth of sorted stem and progenitor cells, while AhR activation has the opposite effect. Moreover, intestinal‐specific AhR knockout increases basal stem cell and crypt injury‐induced cell proliferation and promotes colon tumorigenesis in a preclinical colitis‐associated tumor model by upregulating FoxM1 signaling. Mechanistically, AhR transcriptionally suppresses FoxM1 expression. Activation of AhR in human organoids recapitulates phenotypes observed in mice, such as reduction in the percentage of colonic stem cells, promotion of stem cell differentiation, and attenuation of FoxM1 signaling. These findings indicate that the AhR‐FoxM1 axis, at least in part, mediates colonic stem/progenitor cell behavior. Synopsis: The aryl hydrocarbon receptor (AhR), a ligand‐activated transcription factor, senses cues from environmental toxicants and dietary/microbiota‐derived tryptophan metabolites. Here, AhR signaling is implicated in the maintenance and functionality of colonic stem/progenitor cells via regulation of FoxM1 expression, subsequently affecting colon tumorigenesis. AhR knockout expands the intestinal stem cell population.AhR activation decreases the clonogenic capacity of colonic stem/progenitor cells both in mice and human organoids.AhR acts as a transcriptional suppressor of FoxM1 to control cell proliferation.Loss of AhR in intestinal epithelial cells promotes colitis‐associated colon tumorigenesis. [ABSTRACT FROM AUTHOR]

Bacterial chemotaxis to prominent microbiota metabolites such as indole is important in the formation of microbial communities in the gastrointestinal (GI) tract. However, the basis of chemotaxis to indole is poorly understood. Here, we exposed Escherichia coli to a range of indole concentrations and measured the dynamic responses of individual flagellar motors to determine the chemotaxis response. Below 1 mM indole, a repellent-only response was observed. At 1 mM indole and higher, a time-dependent inversion from a repellent to an attractant response was observed. The repellent and attractant responses were mediated by the Tsr and Tar chemoreceptors, respectively. Also, the flagellar motor itself mediated a repellent response independent of the receptors. Chemotaxis assays revealed that receptor-mediated adaptation to indole caused a bipartite response-wild-type cells were attracted to regions of high indole concentration if they had previously adapted to indole but were otherwise repelled. We propose that indole spatially segregates cells based on their state of adaptation to repel invaders while recruiting beneficial resident bacteria to growing microbial communities within the GI tract. [ABSTRACT FROM AUTHOR]

Consumption of a high-fat diet has been associated with an increased risk of developing colorectal cancer (CRC). However, the effects of the interaction between dietary fat content and the aryl hydrocarbon receptor (AhR) on colorectal carcinogenesis remain unclear. Mainly known for its role in xenobiotic metabolism, AhR has been identified as an important regulator for maintaining intestinal epithelial homeostasis. Although previous research using whole body AhR knockout mice has revealed an increased incidence of colon and cecal tumors, the unique role of AhR activity in intestinal epithelial cells (IECs) and modifying effects of fat content in the diet at different stages of sporadic CRC development are yet to be elucidated. In the present study, we have examined the effects of a high-fat diet on IEC-specific AhR knockout mice in a model of sporadic CRC. Although loss of AhR activity in IECs significantly induced the development of premalignant lesions, in a separate experiment, no significant changes in colon mass incidence were observed. Moreover, consumption of a high-fat diet promoted cell proliferation in crypts at the premalignant colon cancer lesion stage and colon mass multiplicity as well as -catenin expression and nuclear localization in actively proliferating cells in colon masses. Our data demonstrate the modifying effects of high-fat diet and AhR deletion in IECs on tumor initiation and progression. NEW & NOTEWORTHY Through the use of an intestinal-specific aryl hydrocarbon receptor (AhR) knockout mouse model, this study demonstrates that the expression of AhR in intestinal epithelial cells is required to reduce the formation of premalignant colon cancer lesions. Furthermore, consumption of a high-fat diet and the loss of AhR in intestinal epithelial cells influences the development of colorectal cancer at various stages. [ABSTRACT FROM AUTHOR]

Microbiologically influenced corrosion (MIC) accounts for approximately 20–50% of total corrosion costs in the United States. Microorganisms causing MIC in various field locations such as oil pipelines and cooling water systems have been historically studied using either culture- or DNA hybridization- or polymerase chain reaction (PCR)-based methods to estimate levels of the microorganisms (e.g., sulfate reducing bacteria) present in the community and obtain an accurate microbial fingerprint of the community. While these approaches provide information on the community composition at each MIC-impacted field location, the composition of microbial communities is distinct at different MIC impacted field locations and equipment. Moreover, all the microorganisms identified at a specific MIC impacted location need not contribute to the observed corrosion at that location. Since metabolism gives a direct readout of microbial activity, an emerging hypothesis is that correlating the metabolic footprint of the community to the microbial community composition can provide information on the key microbial species involved in MIC. This review discusses advances in molecular methods for investigating microbial community composition and metabolic footprint that are needed, along with information on electrochemical mechanisms, to develop a comprehensive understanding of MIC mechanisms. • Investigating microbial communities is vital for systems-level understanding of MIC. • Use of metabolomics methods for investigating microbial communities is recently emerging. • Metabolomics methods provide insights to the formation of microbial communities and initiation of MIC. • Composition and function are equally important to characterize a microbial community. • Integrating –omics data with current knowledge on MIC mechanisms is critical for comprehensive knowledge of MIC. [ABSTRACT FROM AUTHOR]

Graphical abstract Abstract There is increasing evidence that the intestinal microbiota plays a mechanistic role in the etiology of non-alcoholic fatty liver disease (NAFLD). Animal and human studies have linked small molecule metabolites produced by commensal bacteria in the gut contribute to not only intestinal inflammation, but also to hepatic inflammation. These immunomodulatory metabolites are capable of engaging host cellular receptors, and may mediate the observed association between gut dysbiosis and NAFLD. This review focuses on the effects and potential mechanisms of three specific classes of metabolites that synthesized or modified by gut bacteria: short chain fatty acids, amino acid catabolites, and bile acids. In particular, we discuss their role as ligands for cell surface and nuclear receptors regulating metabolic and inflammatory pathways in the intestine and liver. Studies reveal that the metabolites can both agonize and antagonize their cognate receptors to reduce or exacerbate liver steatosis and inflammation, and that the effects are metabolite- and context-specific. Further studies are warranted to more comprehensively understand bacterial metabolite-mediated gut-liver in NAFLD. This understanding could help identify novel therapeutics and therapeutic targets to intervene in the disease through the gut microbiota. [ABSTRACT FROM AUTHOR]

Unsubstituted flavone induced CYP1A1, CYP1B1 and UGT1A1 gene expression in Caco2 cells and was characterized as an aryl hydrocarbon receptor (AhR) agonist. The structure-activity relationships among 15 mono- and dihydroxyflavones showed that addition of one or two hydroxyl groups resulted in active (e.g.: 5- and 6- mono- and 5,6-dihydroxyflavones) and inactive (e.g.: 7-mono, 7,4′ and 6,4′-dihydroxyflavones) AhR ligands. Ligand docking studies of flavone, mono- and dihydroxyflavones to the human AhR resulted in similar docking scores that varied from −3.48 to −4.58 kcal/mol and these values did not distinguish between AhR-active and AhR-inactive mono- and dihydroxyflavones. The AhR-inactive flavones were subsequently investigated as AhR antagonists by determining their activities as inhibitors of TCDD-induced expression of CYP1A1, CYP1AA2 and UGT 1A1 gene expression in Caco2 cells. Initial studies with 7,4′-dihydroxyflavone showed that this compound was an AhR antagonist in Caco2 cells and resembled the activity of the classical AhR antagonist CH223191. With few exceptions most of the remaining AhR-inactive compounds in terms of inducing AhR responsive genes were also AhR antagonists. Thus, based on modeling studies, mono- and dihydroxyflavones bind with similar affinities to the AhR and exhibit AhR agonist or antagonist activities, however, the structural requirements (substitution patterns) for predicting these opposing activities were not apparent and could only be determined using bioassays. • Flavone activates the aryl hydrocarbon receptor (AhR). • Lower hychoxyflavones also activate the AhR. • Some hychoxyflavones are AhR antagonists. • SARs for AhR agonist/antagonist activities not apparent. [ABSTRACT FROM AUTHOR]

This work deals with adhesion of Escherichia coli O157:H7 and Salmonella enterica subsp. enterica serovar Typhimurium LT2 (S. Typhimurium LT2) on polyethylene glycol (PEG) coated tomato surfaces. PEG coating was characterized by water contact angle technique, scanning electron microscopy, and secondary ion mass spectrometry. It was shown that PEG films could physisorb on the tomato surfaces after the oxygen plasma treatment, which made some outermost layers of the surfaces hydrophilic. Bacterial adhesion on PEG coated tomato surface was studied by standard plate count, fluorescence microscopy, and scanning electron microscopy techniques. Fully covered PEG film reduced the bacterial attachment 90% or more in comparison to the bare tomato surface. The degree of bacterial attachment decreased exponentially with increasing PEG coverage. When desired, PEG film could be removed by rinsing with water. Overall, this work demonstrates the proof-of-concept that an ultrathin film of polyethylene glycol may be used to effectively inhibit the attachment of pathogenic bacteria on tomato surfaces. [ABSTRACT FROM AUTHOR]

There is growing interest in the crosstalk between the gut microbiome, host metabolomic features, and disease pathogenesis. The current investigation compared long–term (26 week) and acute (3 day) dietary spinach intake in a genetic model of colorectal cancer. Metabolomic analyses in the polyposis in rat colon (Pirc) model and in wild–type animals corroborated key contributions to anticancer outcomes by spinach–derived linoleate bioactives and a butanoate metabolite linked to increased α–diversity of the gut microbiome. Combining linoleate and butanoate metabolites in human colon cancer cells revealed enhanced apoptosis and reduced cell viability, paralleling the apoptosis induction in colon tumors from rats given long–term spinach treatment. Mechanistic studies in cell–based assays and in vivo implicated the linoleate and butanoate metabolites in targeting histone deacetylase (HDAC) activity and the interferon–γ (IFN–γ) signaling axis. Clinical translation of these findings to at–risk patients might provide valuable quality–of–life benefits by delaying surgical interventions and drug therapies with adverse side effects. [ABSTRACT FROM AUTHOR]

Chronic low-grade inflammation is a hallmark of aging, which is now coined as inflamm-aging. Inflamm-aging contributes to many age-associated diseases such as obesity, type 2 diabetes, cardiovascular disease, and inflammatory bowel disease (IBD). We have shown that gut hormone ghrelin, via its receptor growth hormone secretagogue receptor (GHS-R), regulates energy metabolism and inflammation in aging. Emerging evidence suggests that gut microbiome has a critical role in intestinal immunity of the host. To determine whether microbiome is an integral driving force of GHS-R mediated immune-metabolic homeostasis in aging, we assessed the gut microbiome profiles of young and old GHS-R global knockout (KO) mice. While young GHS-R KO mice showed marginal changes in Bacteroidetes and Firmicutes, aged GHS-R KO mice exhibited reduced Bacteroidetes and increased Firmicutes, featuring a disease-susceptible microbiome profile. To further study the role of GHS-R in intestinal inflammation in aging, we induced acute colitis in young and aged GHS-R KO mice using dextran sulfate sodium (DSS). The GHS-R KO mice showed more severe disease activity scores, higher proinflammatory cytokine expression, and decreased expression of tight junction markers. These results suggest that GHS-R plays an important role in microbiome homeostasis and gut inflammation during aging; GHS-R suppression exacerbates intestinal inflammation in aging and increases vulnerability to colitis. Collectively, our finding reveals for the first time that GHS-R is an important regulator of intestinal health in aging; targeting GHS-R may present a novel therapeutic strategy for prevention/treatment of aging leaky gut and inflammatory bowel disease. [ABSTRACT FROM AUTHOR]

Ni2+ and Co2+ are sensed as repellents by the Escherichia coli Tar chemoreceptor. The periplasmic Ni2+ binding protein, NikA, has been suggested to sense Ni2+. We show here that neither NikA nor the membrane-bound NikB and NikC proteins of the Ni2+ transport system are required for repellent taxis in response to Ni2+. [ABSTRACT FROM AUTHOR]

Biocompatible antibacterial coatings are highly desirable to prevent bacterial colonization on a wide range of medical devices from hip implants to skin grafts. Traditional polyelectrolytes are unable to directly form coatings with cationic antibiotics at neutral pH and suffer from high degrees of antibiotic release upon exposure to physiological concentrations of salt. Here, novel inorganic-organic hybrid polymer coatings based on direct layer-by-layer assembly of anionic polyphosphazenes (PPzs) of various degrees of fluorination with cationic antibiotics (polymyxin B, colistin, gentamicin, and neomycin) are reported. The coatings displayed low levels of antibiotic release upon exposure to salt and pH-triggered response of controlled doses of antibiotics. Importantly, coatings remained highly surface active against Escherichia coli and Staphylococcus aureus , even after 30 days of pre-exposure to physiological conditions (bacteria-free) or after repeated bacterial challenge. Moreover, coatings displayed low (<1%) hemolytic activity for both rabbit and porcine blood. Coatings deposited on either hard (Si wafers) or soft (electrospun fiber matrices) materials were non-toxic towards fibroblasts (NIH/3T3) and displayed controllable fibroblast adhesion via PPz fluorination degree. Finally, coatings showed excellent antibacterial activity in ex vivo pig skin studies. Taken together, these results suggest a new avenue to form highly tunable, biocompatible polymer coatings for medical device surfaces. Image 1 [ABSTRACT FROM AUTHOR]

• Indole modulates pro-inflammatory signaling. • HTC-8 human colon-cancer cells were pre-treated with indole. • Pre-treatment of indole reduced phosphorylation of NF-κB and IL-8 secretion. • Computational model simulation results reflected experimental data. The human gastrointestinal (GI) tract is colonized by a highly diverse and complex microbial community (i.e., microbiota). The microbiota plays an important role in the development of the immune system, specifically mediating inflammatory responses, however the exact mechanisms are poorly understood. We have developed a mathematical model describing the effect of indole on host inflammatory signaling in HCT-8 human intestinal epithelial cells. In this model, indole modulates transcription factor nuclear factor κ B (NF-κB) and produces the chemokine interleukin-8 (IL-8) through the activation of the aryl hydrocarbon receptor (AhR). Phosphorylated NF-κB exhibits dose and time-dependent responses to indole concentrations and IL-8 production shows a significant down-regulation for 0.1 ng/mL TNF-α stimulation. The model shows agreeable simulation results with the experimental data for IL-8 secretion and normalized NF-κB values. Our results suggest that microbial metabolites such as indole can modulate inflammatory signaling in HTC-8 cells through receptor-mediated processes. [ABSTRACT FROM AUTHOR]