New opportunities in mechanistic and functional microbiome studies.

The field of microbiome research has experienced remarkable growth, leading to unprecedented discoveries of the molecular mechanisms that dictate host-microbiota interactions and their crucial roles in human health. In this "chemical biology of the microbiome" focus issue from Cell Chemical Biology, this Voices piece asks researchers from a range of backgrounds to share their insights on the most exciting recent developments in the microbiome field.

PgtE protease enables virulent to evade C3-mediated serum and neutrophil killing.

Non-typhoidal serovars, such as serovar Typhimurium (STm), are a leading cause of inflammatory diarrhea in otherwise healthy individuals. Among children, the elderly, and immunocompromised individuals, STm can spread to systemic sites and cause potentially lethal bacteremia. Phagocytic cells and the immune complement system are pivotal to preventing the dissemination of STm.

Amino acid competition shapes gut carriage.

Antimicrobial resistance is an urgent threat to human health. Asymptomatic colonization is often critical for persistence of antimicrobial-resistant pathogens. Gut colonization by the antimicrobial-resistant priority pathogen is associated with increased risk of clinical infection.

Commensal Yeast Promotes Typhimurium Virulence.

Enteric pathogens engage in complex interactions with the host and the resident microbiota to establish gut colonization. Although mechanistic interactions between enteric pathogens and bacterial commensals have been extensively studied, whether and how commensal fungi affect pathogenesis of enteric infections remains largely unknown. Here we show that colonization with the common human gut commensal fungus worsened infections with the enteric pathogen serovar Typhimurium.

Pangenome Analysis Reveals Novel Contact-Dependent Growth Inhibition System and Phenazine Biosynthesis Operons in BL95 That Are Located in An Integrative and Conjugative Element.

is a leading cause of urinary tract infections and a common commensal of the gastrointestinal tract. Our recent study (JB) showed that strain BL95 employs a novel contact-dependent killing system against enteric bacteria in the mouse gut and in vitro. To uncover the genetic determinants of this system, we performed whole-genome sequencing of BL95 and compared it with 98 complete genomes of .

Robbing the thief.

Salmonella employs an arsenal of different tools to obtain iron. In this issue of Cell Host & Microbe, Spiga et al. add to these mechanisms, revealing that commensal Bacteroides species use a specialized lipoprotein to acquire catecholate siderophores from Enterobacteriaceae, only to have them reacquired by Salmonella.

Neglected gut microbiome: interactions of the non-bacterial gut microbiota with enteric pathogens.

A diverse array of commensal microorganisms inhabits the human intestinal tract. The most abundant and most studied members of this microbial community are undoubtedly bacteria. Their important role in gut physiology, defense against pathogens, and immune system education has been well documented over the last decades.

Bacterial Chitinases and Their Role in Human Infection.

It has been widely appreciated that numerous bacterial species express chitinases for the purpose of degrading environmental chitin. However, chitinases and chitin-binding proteins are also expressed by pathogenic bacterial species during infection even though mammals do not produce chitin. Alternative molecular targets are therefore likely present within the host.

Salmonella enterica serovar Typhimurium chitinases modulate the intestinal glycome and promote small intestinal invasion.

Salmonella enterica serovar Typhimurium (S. Typhimurium) is one of the leading causes of food-borne illnesses worldwide. To colonize the gastrointestinal tract, S.

Siderophore-mediated zinc acquisition enhances enterobacterial colonization of the inflamed gut.

Zinc is an essential cofactor for bacterial metabolism, and many Enterobacteriaceae express the zinc transporters ZnuABC and ZupT to acquire this metal in the host. However, the probiotic bacterium Escherichia coli Nissle 1917 (or "Nissle") exhibits appreciable growth in zinc-limited media even when these transporters are deleted. Here, we show that Nissle utilizes the siderophore yersiniabactin as a zincophore, enabling Nissle to grow in zinc-limited media, to tolerate calprotectin-mediated zinc sequestration, and to thrive in the inflamed gut.

Proteus mirabilis Employs a Contact-Dependent Killing System against Competing .

Many bacterial species employ systems for interference competition with other microorganisms. Some systems are effective without contact (e.g.

Crossing Kingdoms: How the Mycobiota and Fungal-Bacterial Interactions Impact Host Health and Disease.

The term "microbiota" invokes images of mucosal surfaces densely populated with bacteria. These surfaces and the luminal compartments they form indeed predominantly harbor bacteria. However, research from this past decade has started to complete the picture by focusing on important but largely neglected constituents of the microbiota: fungi, viruses, and archaea.

Protectors of the Neonatal Gut: Clostridia Send Pathogens Packing.

Commensal bacteria are known to provide colonization resistance in the gut. But exactly which ones provide this function? In a recent paper in Science, Kim et al. (2017) revealed that Clostridia added to mouse infant gut microbiota are sufficient to limit colonization of pathogenic Enterobacteriaceae.

Bariatric surgery attenuates colitis in an obese murine model.

Background: Obesity and inflammatory bowel disease (IBD) represent chronic inflammatory conditions. Bariatric surgery improves some obesity-related co-morbidities, but the effects of bariatric surgery on IBD have not been well studied.

Objectives: To examine if bariatric surgery may attenuate colitis in an obese murine model of IBD and study the mechanisms underlying the postsurgical amelioration of intestinal inflammation.

Siderophores: More than Stealing Iron.

Siderophores are small molecular iron chelators that are produced by microbes and whose most notable function is to sequester iron from the host and provide this essential metal nutrient to microbes. Recent studies have proposed additional, noncanonical roles for siderophores, including the acquisition of noniron metals and modulation of host functions. Recently, Holden et al.

Beneficial Effects of Sodium Phenylbutyrate Administration during Infection with Salmonella enterica Serovar Typhimurium.

Sodium phenylbutyrate (PBA) is a derivative of the short-chain fatty acid butyrate and is approved for treatment of urea cycle disorders and progressive familial intrahepatic cholestasis type 2. Previously known functions include histone deacetylase inhibitor, endoplasmic reticulum stress inhibitor, ammonia sink, and chemical chaperone. Here, we show that PBA has a previously undiscovered protective role in host mucosal defense during infection.

Salmonella Mitigates Oxidative Stress and Thrives in the Inflamed Gut by Evading Calprotectin-Mediated Manganese Sequestration.

Neutrophils hinder bacterial growth by a variety of antimicrobial mechanisms, including the production of reactive oxygen species and the secretion of proteins that sequester nutrients essential to microbes. A major player in this process is calprotectin, a host protein that exerts antimicrobial activity by chelating zinc and manganese. Here we show that the intestinal pathogen Salmonella enterica serovar Typhimurium uses specialized metal transporters to evade calprotectin sequestration of manganese, allowing the bacteria to outcompete commensals and thrive in the inflamed gut.

Mucosal immunity to pathogenic intestinal bacteria.

The intestinal mucosa is a particularly dynamic environment in which the host constantly interacts with trillions of commensal microorganisms, known as the microbiota, and periodically interacts with pathogens of diverse nature. In this Review, we discuss how mucosal immunity is controlled in response to enteric bacterial pathogens, with a focus on the species that cause morbidity and mortality in humans. We explain how the microbiota can shape the immune response to pathogenic bacteria, and we detail innate and adaptive immune mechanisms that drive protective immunity against these pathogens.

Exploiting host immunity: the Salmonella paradigm.

Pathogens have evolved clever strategies to evade and in some cases exploit the attacks of an activated immune system. Salmonella enterica is one such pathogen, exploiting multiple aspects of host defense to promote its replication in the host. Here we review recent findings on the mechanisms by which Salmonella establishes systemic and chronic infection, including strategies involving manipulation of innate immune signaling and inflammatory forms of cell death, as well as immune evasion by establishing residency in M2 macrophages.

The cytokine IL-22 promotes pathogen colonization by suppressing related commensal bacteria.

Interleukin-22 (IL-22) is highly induced in response to infections with a variety of pathogens, and its main functions are considered to be tissue repair and host defense at mucosal surfaces. Here we showed that IL-22 has a unique role during infection in that its expression suppressed the intestinal microbiota and enhanced the colonization of a pathogen. IL-22 induced the expression of antimicrobial proteins, including lipocalin-2 and calprotectin, which sequester essential metal ions from microbes.

Keeping the peace: aryl hydrocarbon receptor signaling modulates the mucosal microbiota.

In this issue of Immunity, Zelante et al. (2013) and Qiu et al. (2013) provide mechanistic insights into functional interactions between commensal microbes and innate lymphoid cells via the aryl hydrocarbon receptor.

Probiotics: properties, examples, and specific applications.

Probiotics are beneficial components of the microbiota that have been used for centuries because of the health benefits they confer to the host. Only recently, however, has the contribution of probiotics to modulation of immunological, respiratory, and gastrointestinal functions started to be fully appreciated and scientifically evaluated. Probiotics such as Escherichia coli Nissle 1917 and lactic acid bacteria are currently used to, or have been evaluated for use to, prevent or treat a range of intestinal maladies including inflammatory bowel disease, constipation, and colon cancer.

Phagocyte responses towards Aspergillus fumigatus.

The saprophytic fungus Aspergillus fumigatus is a mold which is ubiquitously present in the environment. It produces large numbers of spores, called conidia that we constantly inhale with the breathing air. Healthy individuals normally do not suffer from true fungal infections with this pathogen.