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Dysbiosis corresponds to the disruption of a formerly stable, functionally complete microbiota. In the gut, this imbalance can lead to adverse health outcomes in both the short and long terms, with a potential increase in the lifetime risks of various noncommunicable diseases and disorders such as atopy (like asthma), inflammatory bowel disease, neurological disorders, and even behavioural and psychological disorders. Although antibiotics are highly effective in reducing morbidity and mortality in infectious diseases, antibiotic-associated diarrhoea is a common, non-negligible clinical sign of gut dysbiosis (and the only visible one). Re-establishment of a normal (functional) gut microbiota is promoted by completion of the clinically indicated course of antibiotics, the removal of any other perturbing external factors, the passage of time (i.e. recovery through the microbiota's natural resilience), appropriate nutritional support, and—in selected cases—the addition of probiotics. Systematic reviews and meta-analyses of clinical trials have confirmed the strain-specific efficacy of some probiotics (notably the yeast Saccharomyces boulardii CNCM I-745 and the bacterium Lactobacillus rhamnosus GG) in the treatment and/or prevention of antibiotic-associated diarrhoea in children and in adults. Unusually for a probiotic, S. boulardii is a eukaryote and is not therefore directly affected by antibiotics—making it suitable for administration in cases of antibiotic-associated diarrhoea. A robust body of evidence from clinical trials and meta-analyses shows that the timely administration of an adequately dosed probiotic (upon initiation of antibiotic treatment or within 48 h) can help to prevent or resolve the consequences of antibiotic-associated dysbiosis (such as diarrhoea) and promote the resilience of the gut microbiota and a return to the pre-antibiotic state. A focus on the prescription of evidence-based, adequately dosed probiotics should help to limit unjustified and potentially ineffective self-medication. [ABSTRACT FROM AUTHOR]

Intestinal mucosal healing is the primary therapeutic goal of medical treatments for inflammatory bowel disease (IBD). Epithelial stem cells are key players in the healing process. Lgr5+ stem cells maintain cellular turnover during homeostasis in the colonic crypt. However, they are lost and dispensable for repair in a wide variety of injury models, including dextran sulfate sodium (DSS) colitis, radiation, helminth infection, and T-cell activation. The direct loss of Lgr5+ cells activates a plasticity response in the epithelium in which other cell types can serve as stem cells. Whether this paradigm applies to mouse models of IBD remains unknown. In contrast to previously tested models, IBD models involve an inflammatory response rooted in the loss of immunologic tolerance to intestinal luminal contents including the microbiome. Here, we show the persistence of Lgr5+ cells in oxazolone, 2,4,6-trinitrobenzene sulfonic acid (TNBS), and Il10-/-, and Il10-/- Tnfr1-/- IBD models. This contrasts with results obtained from DSS-induced injury. Through high-throughput expression profiling, we find that these colitis models were associated with distinct patterns of cytokine expression. Direct exposure of colonic epithelial organoids to DSS, oxazolone, or TNBS resulted in increased apoptosis and loss of Lgr5+ cells. Targeted ablation of Lgr5+ cells resulted in severe exacerbation of chronic, antibody-induced IL-10-deficient colitis, but had only modest effects in TNBS-induced colitis. These results show that distinct mouse models of IBD-like colitis induce different patterns of Lgr5+ stem cell retention and function. [ABSTRACT FROM AUTHOR]

Macrophages are critical mediators of intestinal defense and homeostasis. However, uncontrolled proinflammatory macrophage activity may contribute to chronic conditions such as inflammatory bowel disease. Currently, the regulatory feedback mechanisms restraining proinflammatory cytokine production in activated macrophages are not well understood. The ErbB4 receptor tyrosine kinase is induced on macrophages by proinflammatory stimulation, and chronic ErbB4 activation with its ligand NRG4 drives macrophage apoptosis after 2 days. However, the impact of endogenous NRG4/ErbB4 signaling on macrophage function remains untested. Using bone marrow-derived ErbB4-null or NRG4-null macrophages, we tested the hypothesis that NRG4/ ErbB4 signaling inhibits proinflammatory cytokine production. We found that deletion of either the receptor or its ligand resulted in elevated proinflammatory cytokine expression in classically (IFNc/LPS) activated cells, compared with activated cells generated from wild-type littermates. NRG4 was induced by IFNc/LPS activation in wild-type macrophages, and exogenous treatment with NRG4 led to a reduction in Tnf, Cxcl1, and Il1b expression within 24 h. RNA sequencing of ErbB4myeKO macrophages showed elevated expression of major regulators of inflammatory skewing (Sik2) and cytokine transport (Trim16). In vivo, ErbB4myeKO mice subjected to acute DSS colitis showed exaggerated disease, and ErbB4 myeloid knockout in the IL 10-KO chronic colitis model accelerated disease onset. Taken together, these findings demonstrate that NRG4/ErbB4 signaling in macrophages restrains the proinflammatory tone of these cells and is an important limiting regulator of colitis severity. These results highlight a previously unknown feedback mechanism by which growth factor signaling in immune cells prevents runaway inflammation and chronic disease. [ABSTRACT FROM AUTHOR]

We have demonstrated how management of key orchard pests including the insect invasive species Halyomorpha halys (Stål) (Hemiptera: Pentatomidae) can be accomplished using a systems-level approach termed IPM-CPR (Integrated Pest Management-Crop Perimeter Restructuring) in apple. We conducted on-farm comparisons of IPM-CPR to standard management program for managing H. halys , Cydia pomonella (L.) (Lepidoptera: Tortricidae), Grapholita molesta (Busck) (Lepidoptera: Tortricidae), and Lygus lineolaris Palisot de Beauvois (Hemiptera: Miridae) in commercial apple orchards in 2014, 2016, and 2017 in New Jersey, Maryland, and Virginia. The presence and abundance of key pests and fruit injury at harvest were used as a measure of success of the program. We compared the amount of insecticide applied for each management program. In majority of instances, there were no differences in the IPM-CPR and the standard management program in terms of H. halys numbers in baited pyramid traps and stink bug injury at harvest. Damage from C. pomonella and G. molesta in the IPM-CPR treatment was significantly lower than the standard management program in 2014 and 2017. Amount of active ingredient used was on average 62.1% lower in the IPM-CPR treatment compared with standard management program. Despite a reduction in insecticide use, there were minimal impacts on beneficial insects. Overall, IPM-CPR in apples successfully managed key orchard pests, including H. halys , and used significantly less insecticide than a standard insecticide-based management program and could be adopted as a systems-level approach for pest population reduction. [ABSTRACT FROM AUTHOR]

Advances in our understanding of the contribution of the gut microbiota to human health and the correlation of dysbiosis with diseases, including chronic intestinal conditions such as inflammatory bowel disease (IBD), have driven mechanistic investigations of probiotics in intestinal homeostasis and potential clinical applications. Probiotics have been shown to promote intestinal health by maintaining and restoring epithelial function, ensuring mucosal immune homeostasis, and inhibiting pathogenic bacteria. Recent findings reveal an approach for defining previously unrecognized probiotic-derived soluble factors as potential mechanisms of probiotic action. This review focuses on the impact of probiotics and probiotic-derived functional factors, including probiotic products and metabolites by probiotics, on the cellular responses and signaling pathways involved in maintaining intestinal homeostasis. Although there is limited information regarding the translation of probiotic treatment outcomes from in vitro and animal studies to clinical applications, potential approaches for increasing the clinical efficacy of probiotics for IBD, such as those based on probiotic-derived factors, are highlighted in this review. In this era of precision medicine and targeted therapies, more basic, preclinical, and clinical evidence is needed to clarify the efficacy of probiotics in maintaining intestinal health and preventing and treating disease. [ABSTRACT FROM AUTHOR]

The development of modern methods to induce optical transparency ("clearing") in biological tissues has enabled the three-dimensional (3D) reconstruction of intact organs at cellular resolution. New capabilities in visualization of rare cellular events, long-range interactions, and irregular structures will facilitate novel studies in the alimentary tract and gastrointestinal systems. The tubular geometry of the alimentary tract facilitates large-scale cellular reconstruction of cleared tissue without specialized microscopy setups. However, with the rapid pace of development of clearing agents and current relative paucity of research groups in the gastrointestinal field using these techniques, it can be daunting to incorporate tissue clearing into experimental workflows. Here, we give some advice and describe our own experience bringing tissue clearing and whole mount reconstruction into our laboratory's investigations. We present a brief overview of the chemical concepts that underpin tissue clearing, what sorts of questions whole mount imaging can answer, how to choose a clearing agent, an example of how to clear and image alimentary tissue, and what to do after obtaining the image. This short review will encourage other gastrointestinal researchers to consider how utilizing tissue clearing and creating 3D "maps" of tissue might deepen the impact of their studies. [ABSTRACT FROM AUTHOR]