Antibiotics are often used in the clinic to treat bacterial infections, but the effects of these drugs on microbiota composition and on intestinal immunity are poorly understood. Citrobacter ...rodentium was used as a model enteric pathogen to investigate the effect of microbial perturbation on intestinal barriers and susceptibility to colitis. Streptomycin and metronidazole were used to induce alterations in the composition of the microbiota prior to infection with C. rodentium. Metronidazole pretreatment increased susceptibility to C. rodentium-induced colitis over that of untreated and streptomycin-pretreated mice, 6 days postinfection. Both antibiotic treatments altered microbial composition, without affecting total numbers, but metronidazole treatment resulted in a more dramatic change, including a reduced population of Porphyromonadaceae and increased numbers of lactobacilli. Disruption of the microbiota with metronidazole, but not streptomycin treatment, resulted in an increased inflammatory tone of the intestine characterized by increased bacterial stimulation of the epithelium, altered goblet cell function, and thinning of the inner mucus layer, suggesting a weakened mucosal barrier. This reduction in mucus thickness correlates with increased attachment of C. rodentium to the intestinal epithelium, contributing to the exacerbated severity of C. rodentium-induced colitis in metronidazole-pretreated mice. These results suggest that antibiotic perturbation of the microbiota can disrupt intestinal homeostasis and the integrity of intestinal defenses, which protect against invading pathogens and intestinal inflammation.
Despite recent advances in our understanding of the pathogenesis of attaching and effacing (A/E) Escherichia coli infections, the mechanisms by which the host defends against these microbes are ...unclear. The goal of this study was to determine the role of goblet cell-derived Muc2, the major intestinal secretory mucin and primary component of the mucus layer, in host protection against A/E pathogens. To assess the role of Muc2 during A/E bacterial infections, we inoculated Muc2 deficient (Muc2(-/-)) mice with Citrobacter rodentium, a murine A/E pathogen related to diarrheagenic A/E E. coli. Unlike wildtype (WT) mice, infected Muc2(-/-) mice exhibited rapid weight loss and suffered up to 90% mortality. Stool plating demonstrated 10-100 fold greater C. rodentium burdens in Muc2(-/-) vs. WT mice, most of which were found to be loosely adherent to the colonic mucosa. Histology of Muc2(-/-) mice revealed ulceration in the colon amid focal bacterial microcolonies. Metabolic labeling of secreted mucins in the large intestine demonstrated that mucin secretion was markedly increased in WT mice during infection compared to uninfected controls, suggesting that the host uses increased mucin release to flush pathogens from the mucosal surface. Muc2 also impacted host-commensal interactions during infection, as FISH analysis revealed C. rodentium microcolonies contained numerous commensal microbes, which was not observed in WT mice. Orally administered FITC-Dextran and FISH staining showed significantly worsened intestinal barrier disruption in Muc2(-/-) vs. WT mice, with overt pathogen and commensal translocation into the Muc2(-/-) colonic mucosa. Interestingly, commensal depletion enhanced C. rodentium colonization of Muc2(-/-) mice, although colonic pathology was not significantly altered. In conclusion, Muc2 production is critical for host protection during A/E bacterial infections, by limiting overall pathogen and commensal numbers associated with the colonic mucosal surface. Such actions limit tissue damage and translocation of pathogenic and commensal bacteria across the epithelium.
Are noncommunicable diseases communicable? Finlay, B B
Science (American Association for the Advancement of Science),
01/2020, Letnik:
367, Številka:
6475
Journal Article
Recenzirano
Numerous noncommunicable diseases could have a transmissible microbial component
The past century has seen a profound decrease in mortality rates across the world, accompanied by a marked shift from ...communicable diseases (caused by infectious microbes) to noncommunicable diseases (NCDs) such as cardiovascular diseases, cancer, and respiratory diseases. NCDs—defined as diseases that are not transmissible directly from one person to another—account for more than 70% (41 million) of all deaths globally (
1
). The definition of NCDs rules out microbial involvement and instead focuses on genetic, environmental, and lifestyle factors. Data increasingly show that the microbiota is dysbiotic (altered) in individuals with various NCDs. In animal models of NCDs, transplantation of dysbiotic microbiota into healthy animals results in disease, and microbiota composition is shaped by close contact with others. Therefore, we propose that some NCDs could have a microbial component and, if so, might be communicable via the microbiota.
Indigenous microbiota are an essential component in the modern concept of human health, but the composition and functional characteristics of a healthy microbiome remain to be precisely defined. ...Patterns of microbial colonization associated with disease states have been documented, but the health-associated microbial patterns and their functional characteristics are less clear. A healthy microbiome, considered in the context of body habitat or body site, could be described in terms of ecologic stability (i.e., ability to resist community structure change under stress or to rapidly return to baseline following a stress-related change), by an idealized (presumably health-associated) composition or by a desirable functional profile (including metabolic and trophic provisions to the host). Elucidation of the properties of healthy microbiota would provide a target for dietary interventions and/or microbial modifications aimed at sustaining health in generally healthy populations and improving the health of individuals exhibiting disrupted microbiota and associated diseases.
Human diseases are increasingly linked with an altered or “dysbiotic” gut microbiota, but whether such changes are causal, consequential, or bystanders to disease is, for the most part, unresolved. ...Human microbiota-associated (HMA) rodents have become a cornerstone of microbiome science for addressing causal relationships between altered microbiomes and host pathology. In a systematic review, we found that 95% of published studies (36/38) on HMA rodents reported a transfer of pathological phenotypes to recipient animals, and many extrapolated the findings to make causal inferences to human diseases. We posit that this exceedingly high rate of inter-species transferable pathologies is implausible and overstates the role of the gut microbiome in human disease. We advocate for a more rigorous and critical approach for inferring causality to avoid false concepts and prevent unrealistic expectations that may undermine the credibility of microbiome science and delay its translation.
Walter and colleagues argue that human-microbiota-associated rodent experiments are generally overinterpreted and misused. In this Perspective, they provide a framework for improving the rigor of these gold-standard experiments to sort out truly causal microbiome-disease relationships.
Escherichia coli is a remarkable and diverse organism. This normally harmless commensal needs only to acquire a combination of mobile genetic elements to become a highly adapted pathogen capable of ...causing a range of diseases, from gastroenteritis to extraintestinal infections of the urinary tract, bloodstream and central nervous system. The worldwide burden of these diseases is staggering, with hundreds of millions of people affected annually. Eight E. coli pathovars have been well characterized, and each uses a large arsenal of virulence factors to subvert host cellular functions to potentiate its virulence. In this Review, we focus on the recent advances in our understanding of the different pathogenic mechanisms that are used by various E. coli pathovars and how they cause disease in humans.
Multicellular organisms possess very sophisticated defense mechanisms that are designed to effectively counter the continual microbial insult of the environment within the vertebrate host. However, ...successful microbial pathogens have in turn evolved complex and efficient methods to overcome innate and adaptive immune mechanisms, which can result in disease or chronic infections. Although the various virulence strategies used by viral and bacterial pathogens are numerous, there are several general mechanisms that are used to subvert and exploit immune systems that are shared between these diverse microbial pathogens. The success of each pathogen is directly dependant on its ability to mount an effective anti-immune response within the infected host, which can ultimately result in acute disease, chronic infection, or pathogen clearance. In this review, we highlight and compare some of the many molecular mechanisms that bacterial and viral pathogens use to evade host immune defenses.
Sphingolipids are structural membrane components and important eukaryotic signaling molecules. Sphingolipids regulate inflammation and immunity and were recently identified as the most differentially ...abundant metabolite in stool from inflammatory bowel disease (IBD) patients. Commensal bacteria from the Bacteroidetes phylum also produce sphingolipids, but the impact of these metabolites on host pathways is largely uncharacterized. To determine whether bacterial sphingolipids modulate intestinal health, we colonized germ-free mice with a sphingolipid-deficient Bacteroides thetaiotaomicron strain. A lack of Bacteroides-derived sphingolipids resulted in intestinal inflammation and altered host ceramide pools in mice. Using lipidomic analysis, we described a sphingolipid biosynthesis pathway and revealed a variety of Bacteroides-derived sphingolipids including ceramide phosphoinositol and deoxy-sphingolipids. Annotating Bacteroides sphingolipids in an IBD metabolomic dataset revealed lower abundances in IBD and negative correlations with inflammation and host sphingolipid production. These data highlight the role of bacterial sphingolipids in maintaining homeostasis and symbiosis in the gut.
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•Colonization with a sphingolipid-deficient Bacteroides strain is pro-inflammatory•Metabolomics describe Bacteroides sphingolipids and their biosynthetic pathway•IBD patients have decreased Bacteroides sphingolipids but increased host sphingolipids
In this issue, Brown et al. discover a number of bacterial sphingolipid metabolites and demonstrate that sphingolipid production by Bacteroides species in the gut microbiome promotes symbiosis with the host. Bacterial sphingolipid deficiency correlates with inflammatory bowel disease and increased host-produced sphingolipid abundance in the human intestine.
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