Drug Discovery Today: Disease Models最新文献

Our body is inhabited by a large community of microorganisms referred to as our microbiota that influences almost all aspects of human physiology, including the response to thereapeutic drugs. Drugs can affect microbiota composition and the microbiota can modulate the drug response in the host. A major challenge is to determine which bacteria affect the response to which drugs, and to elucidate the mechanisms involved. Here, we discuss the emergence of the nematode Caenorhabditis elegans and its bacterial diet as an interspecies model system with which the effects of bacteria on the drug response in the host can be studied both at broad systems and at deep mechanistic levels. We will discuss the strengths and limitations of this system and will present future perspectives.

Ascidians are marine invertebrates closely related to vertebrates. These animals have been studied to address complex processes, including evolution of the immune system and developmental biology. As holobionts, housing millions of bacteria in a close relationship that drives adaptive fitness to environmental conditions, ascidians are successful invaders and dominant components of the benthic communities. Further, tunicates and their associated microbiota are recognized as producers of chemical structures with pharmacological potential, and over 1000 such molecules have been described so far. This review covers aspects of ascidian biology that make them promising model organisms in various fields and important for drug discovery.

This contribution describes the current state of experimental model development and use as a strategy for gaining insight into the form and function of certain types of host-microbe associations. Development of quality models for the study of symbiotic systems will be critical not only to facilitate an understanding of mechanisms underlying symbiosis, but also for providing insights into how drug development can promote healthy animal–microbe interactions as well as the treatment of pathogenic infections. Because of the growing awareness over the last decade of the importance of symbiosis in biology, a number of model systems has emerged to examine how these partnerships are maintained within and across generations of the host. The focus here will be upon host-bacterial symbiotic systems that, as in humans, (i) are acquired from the environment each generation, or horizontally transmitted, and (ii) are defined by interactions at the interface of their cellular boundaries, i.e., extracellular symbiotic associations. As with the use of models in other fields of biology where complexity is daunting (e.g., developmental biology or brain circuitry), each model has its strengths and weaknesses, i.e., no one model system will provide easy access to all the questions defining what is conserved in cell–cell interactions in symbiosis and what creates diversity within such partnerships. Rather, as discussed here, the more models explored, the richer our understanding of these associations is likely to be.

Gut microbes have recently been appreciated to be a possible source of future therapeutics. They have been shown to be associated with a variety of diseases from diverse etiologies. The microbiome can change during the progression of some diseases, and in some cases is linked with disease severity. Following these findings, fecal transplantation has been integrated into treating Clostridium difficile infections with high success rates. These results have become a driving force for studies demonstrating the therapeutic potential of gut bacteria in other clinical indications. However, extensive research and clinical trials are still needed in order to reach the goal of using defined live microbial therapeutics for treatment. A mechanistic understanding of the effects of individual strains and bacterial consortia on the mammalian host, their colonization dynamics, and long-term impact, on both the gut ecosystem and their host, is thus required. In this review, we discuss the potential of individual bacteria or bacterial consortia in therapeutics, mouse models for such studies, and the future directions for deriving valuable therapeutics from the gut microbial armory.

Drosophila is an excellent system to investigate how the presence and composition of the gut microbiome influences the efficacy of therapeutic drugs and downstream consequences for host health. These opportunities derive from two key attributes of Drosophila. First, Drosophila is amenable for microbiome research, with simple, standardized methods to produce large numbers of microbiologically-sterile flies and flies with a standardized gut microbiome, thereby facilitating experimental reproducibility. Second, Drosophila is a well-established genetic model that is increasingly used to elucidate the molecular and physiological basis of lesions associated with human disease alleles; this provides the opportunity to link microbiome/drug interactions to previously-described processes shaping health and disease. In this way, Drosophila can fast-track understanding of fundamental biology to generate precise hypotheses for testing in mammalian systems. Drosophila is particularly well-suited to investigate the incidence of microbiome/drug interactions mediated by different mechanisms, including microbial drug metabolism (to active, inactive or toxic derivatives), microbial production of compounds that inhibit drug efficacy, and off-target effects of the drug on the microbiome, resulting in dysbiosis and host ill-health. Drosophila can also be used to investigate how interactions between the microbiome and host genotype may shape responses to therapeutic drugs, informing the reliability of precision medicine based exclusively on human genomic markers.

One approach to understanding gut microbiome–host interactions, described in this review, is to examine how natural variation in a model organism, where environmental factors can be controlled, affects the microbiome and, in turn, how the microbiome is associated with physiological or clinical traits. A variation of this approach, termed “systems genetics” is to characterize both the microbiome and the host using various high throughput technologies, such as metabolomics or gene expression of the microbiome and the host. By relating variation in the microbiome and host functions to such “molecular phenotypes”, hypotheses can be generated and then experimentally tested. To model human gut microbiome–host interactions in this way, the mouse is particularly useful given the extensive body of genetic resources and experimental tools that are available.

Studies in gnotobiotic mice have dramatically expanded our understanding of the functional importance of microbiota in the pathogenesis of chronic intestinal inflammation. This brief review describes several strategies by which gnotobiotic mice models can be used to efficiently discover and validate protective components from the resident microbiota for potential therapeutic applications. We provide highly targeted examples of studies that use each of the various strategies to illustrate effective approaches, discuss challenges to implementing these approaches and suggest future directions to accelerate this increasingly important line of research and improve the clinical applications of results.

Studies over the past few decades demonstrated that gnotobiotic (Gn) pigs provide an unprecedented translational model to study human intestinal health and diseases. Due to the high degree of anatomical, physiological, metabolic, immunological, and developmental similarity, the domestic pig closely mimics the human intestinal microenvironment. Also, Gn piglets can be efficiently transplanted with human microbiota from infants, children and adults with resultant microbial profiles remarkably similar to the original human samples, a feat consistently not achievable in rodent models. Finally, Gn and human microbiota-associated (HMA) piglets are susceptible to human enteric viral pathogens (including human rotavirus, HRV) and can be fed authentic human diets, which further increases the translational potential of these models. In this review, we will focus on recent studies that evaluated the pathophysiology of protein malnutrition and the associated dysbiosis and immunological dysfunction in neonatal HMA piglets. Additionally, we will discuss studies of potential dietary interventions that moderate the effects of malnutrition and dysbiosis on antiviral immunity and HRV vaccines in HMA pigs. Such studies provide novel models and novel mechanistic insights critical for development of drug interventions.

Animal models are critical for forensic science research, particularly in studies of decomposition. This review examines the studies that have led to the development of using microbiome tools to predict the time since death, or postmortem interval (PMI), of human remains. Estimating PMI is crucial for forensic investigations, and most traditional tools are no longer effective after the first few days postmortem. The development of microbiome tools to estimate PMI has relied on rodents and swine to model human decomposition. The use of these model organisms provides several advantages over studies utilizing human remains, including ease of procurement, large sample sizes, and the ability to control variables. Through studies using model organisms, researchers have been able to answer many fundamental questions regarding postmortem microbial decomposition, including the impacts of soil type, cadaver mass, cadaver clothing, and sampling location. Generally, these studies have been used to provide a proof-of-concept and narrow hypotheses before conducting studies on human remains. Evidence suggests that rodents and swine accurately model human microbial decomposition, but further study should be conducted to directly compare these outcomes. An important open topic that could be addressed with animal models is the role of drugs in changing cadaver-associated microbiomes during decomposition.