Streptomycin-induced inflammation enhances Escherichia coli gut colonization through nitrate respiration.

UnlabelledTreatment with streptomycin enhances the growth of human commensal Escherichia coli isolates in the mouse intestine, suggesting that the resident microbial community (microbiota) can inhibit the growth of invading microbes, a phenomenon known as "colonization resistance." However, the precise mechanisms by which streptomycin treatment lowers colonization resistance remain obscure. Here we show that streptomycin treatment rendered mice more susceptible to the development of chemically induced colitis, raising the possibility that the antibiotic might lower colonization resistance by changing mucosal immune responses rather than by preventing microbe-microbe interactions. Investigation of the underlying mechanism revealed a mild inflammatory infiltrate in the cecal mucosa of streptomycin-treated mice, which was accompanied by elevated expression of Nos2, the gene that encodes inducible nitric oxide synthase. In turn, this inflammatory response enhanced the luminal growth of E. coli by nitrate respiration in a Nos2-dependent fashion. These data identify low-level intestinal inflammation as one of the factors responsible for the loss of resistance to E. coli colonization after streptomycin treatment.ImportanceOur intestine is host to a complex microbial community that confers benefits by educating the immune system and providing niche protection. Perturbation of intestinal communities by streptomycin treatment lowers "colonization resistance" through unknown mechanisms. Here we show that streptomycin increases the inflammatory tone of the intestinal mucosa, thereby making the bowel more susceptible to dextran sulfate sodium treatment and boosting the Nos2-dependent growth of commensal Escherichia coli by nitrate respiration. These data point to the generation of alternative electron acceptors as a by-product of the inflammatory host response as an important factor responsible for lowering resistance to colonization by facultative anaerobic bacteria such as E. coli

Intestinal Stem Cells to Advance Drug Development, Precision, and Regenerative Medicine: A Paradigm Shift in Translational Research

Recent advances in our understanding of the intestinal stem cell niche and the role of key signaling pathways on cell growth and maintenance have allowed the development of fully differentiated epithelial cells in 3D organoids. Stem cell-derived organoids carry significant levels of proteins that are natively expressed in the gut and have important roles in drug transport and metabolism. They are, therefore, particularly relevant to study the gastrointestinal (GI) absorption of oral medications. In addition, organoids have the potential to serve as a robust preclinical model for demonstrating the effectiveness of new drugs more rapidly, with more certainty, and at lower costs compared with live animal studies. Importantly, because they are derived from individuals with different genotypes, environmental risk factors and drug sensitivity profiles, organoids are a highly relevant screening system for personalized therapy in both human and veterinary medicine. Lastly, and in the context of patient-specific congenital diseases, orthotopic transplantation of engineered organoids could repair and/or replace damaged epithelial tissues reported in various GI diseases, such as inflammatory bowel disease, cystic fibrosis, and tuft enteropathy. Ongoing translational research on organoids derived from dogs with naturally occurring digestive disorders has the potential to improve the predictability of preclinical models used for optimizing the therapeutic management of severe chronic enteropathies in human patients

Best Practices for Microbiome Study Design in Companion Animal Research.

The gut microbiome is a community of microorganisms that inhabits an animal host's gastrointestinal tract, with important effects on animal health that are shaped by multiple environmental, dietary, and host-associated factors. Clinical and dietary trials in companion animals are increasingly including assessment of the microbiome, but interpretation of these results is often hampered by suboptimal choices in study design. Here, we review best practices for conducting feeding trials or clinical trials that intend to study the effects of an intervention on the microbiota. Choices for experimental design, including a review of basic designs, controls, and comparison groups, are discussed in the context of special considerations necessary for microbiome studies. Diet is one of the strongest influences on the composition of gut microbiota, so applications specific to nutritional interventions are discussed in detail. Lastly, we provide specific advice for successful recruitment of colony animals and household pets into an intervention study. This review is intended to serve as a resource to academic and industry researchers, clinicians, and veterinarians alike, for studies that test many different types of interventions

Collateral Damage: Microbiota-Derived Metabolites and Immune Function in the Antibiotic Era

Our long-standing evolutionary association with gut-associated microbial communities has given rise to an intimate relationship, which affects many aspects of human health. Recent studies on the mechanisms that link these microbial communities to immune education, nutrition, and protection against pathogens point to microbiota-derived metabolites as key players during these microbe-host interactions. A disruption of gut-associated microbial communities by antibiotic treatment can result in a depletion of microbiota-derived metabolites, thereby enhancing pathogen susceptibility, impairing immune homeostasis, and contributing to the rise of certain chronic inflammatory diseases. Here, we highlight some of the recently elucidated mechanisms that showcase the impacts of microbiota-derived metabolites on human health

Best Practices for Microbiome Study Design in Companion Animal Research.

The gut microbiome is a community of microorganisms that inhabits an animal host's gastrointestinal tract, with important effects on animal health that are shaped by multiple environmental, dietary, and host-associated factors. Clinical and dietary trials in companion animals are increasingly including assessment of the microbiome, but interpretation of these results is often hampered by suboptimal choices in study design. Here, we review best practices for conducting feeding trials or clinical trials that intend to study the effects of an intervention on the microbiota. Choices for experimental design, including a review of basic designs, controls, and comparison groups, are discussed in the context of special considerations necessary for microbiome studies. Diet is one of the strongest influences on the composition of gut microbiota, so applications specific to nutritional interventions are discussed in detail. Lastly, we provide specific advice for successful recruitment of colony animals and household pets into an intervention study. This review is intended to serve as a resource to academic and industry researchers, clinicians, and veterinarians alike, for studies that test many different types of interventions

Intestinal Stem Cells to Advance Drug Development, Precision, and Regenerative Medicine: A Paradigm Shift in Translational Research

Recent advances in our understanding of the intestinal stem cell niche and the role of key signaling pathways on cell growth and maintenance have allowed the development of fully differentiated epithelial cells in 3D organoids. Stem cell-derived organoids carry significant levels of proteins that are natively expressed in the gut and have important roles in drug transport and metabolism. They are, therefore, particularly relevant to study the gastrointestinal (GI) absorption of oral medications. In addition, organoids have the potential to serve as a robust preclinical model for demonstrating the effectiveness of new drugs more rapidly, with more certainty, and at lower costs compared with live animal studies. Importantly, because they are derived from individuals with different genotypes, environmental risk factors and drug sensitivity profiles, organoids are a highly relevant screening system for personalized therapy in both human and veterinary medicine. Lastly, and in the context of patient-specific congenital diseases, orthotopic transplantation of engineered organoids could repair and/or replace damaged epithelial tissues reported in various GI diseases, such as inflammatory bowel disease, cystic fibrosis, and tuft enteropathy. Ongoing translational research on organoids derived from dogs with naturally occurring digestive disorders has the potential to improve the predictability of preclinical models used for optimizing the therapeutic management of severe chronic enteropathies in human patients.This article is published as Mochel, Jonathan P., Albert E. Jergens, Dawn Kingsbury, Hyun Jung Kim, Martín G. Martín, and Karin Allenspach. "Intestinal Stem Cells to Advance Drug Development, Precision, and Regenerative Medicine: A Paradigm Shift in Translational Research." The AAPS journal 20, no. 1 (2018): 17. doi: 10.1208/s12248-017-0178-1. Posted with permission.</p

Microbiome Responses to Fecal Microbiota Transplantation in Cats with Chronic Digestive Issues.

There is growing interest in the application of fecal microbiota transplants (FMTs) in small animal medicine, but there are few published studies that have tested their effects in the domestic cat (Felis catus). Here we use 16S rRNA gene sequencing to examine fecal microbiome changes in 46 domestic cats with chronic digestive issues that received FMTs using lyophilized stool that was delivered in oral capsules. Fecal samples were collected from FMT recipients before and two weeks after the end of the full course of 50 capsules, as well as from their stool donors (N = 10), and other healthy cats (N = 113). The fecal microbiomes of FMT recipients varied with host clinical signs and dry kibble consumption, and shifts in the relative abundances of Clostridium, Collinsella, Megamonas, Desulfovibrio and Escherichia were observed after FMT. Overall, donors shared 13% of their bacterial amplicon sequence variants (ASVs) with FMT recipients and the most commonly shared ASVs were classified as Prevotella 9, Peptoclostridium, Bacteroides, and Collinsella. Lastly, the fecal microbiomes of cats with diarrhea became more similar to the microbiomes of age-matched and diet-matched healthy cats compared to cats with constipation. Overall, our results suggest that microbiome responses to FMT may be modulated by the FMT recipients initial presenting clinical signs, diet, and their donors microbiome

Neutrophils are a source of gamma interferon during acute Salmonella enterica serovar Typhimurium colitis.

Gamma interferon (IFN-γ) is an important driver of intestinal inflammation during colitis caused by Salmonella enterica serovar Typhimurium. Here we used the mouse colitis model to investigate the cellular sources of IFN-γ in the cecal mucosa during the acute phase of an S. Typhimurium infection. While IFN-γ staining was detected in T cells, NK cells, and inflammatory monocytes at 2 days after infection, the majority of IFN-γ-positive cells in the cecal mucosa were neutrophils. Furthermore, neutrophil depletion blunted mucosal Ifng expression and reduced the severity of intestinal lesions during S. Typhimurium infection. We conclude that neutrophils are a prominent cellular source of IFN-γ during the innate phase of S. Typhimurium-induced colitis