Approaches to discern if microbiome associations reflect causation in metabolic and immune disorders

Abstract

Our understanding of microorganisms residing within our gut and their roles in the host metabolism and immunity advanced greatly over the past 20 years. Currently, microbiome studies are shifting from association and correlation studies to studies demonstrating causality of identified microbiome signatures and identification of molecular mechanisms underlying these interactions. This transformation is crucial for the efficient translation into clinical application and development of targeted strategies to beneficially modulate the intestinal microbiota. As mechanistic studies are still quite challenging to perform in humans, the causal role of microbiota is frequently evaluated in animal models that need to be appropriately selected. Here, we provide a comprehensive overview on approaches that can be applied in addressing causality of host-microbe interactions in five major animal model organisms ( Caenorhabditis elegans, Drosophila melanogaster , zebrafish, rodents, and pigs). We particularly focused on discussing methods available for studying the causality ranging from the usage of gut microbiota transfer, diverse models of metabolic and immune perturbations involving nutritional and chemical factors, gene modifications and surgically induced models, metabolite profiling up to culture-based approached. Furthermore, we addressed the impact of the gut morphology, physiology as well as diet on the microbiota composition in various models and resulting species specificities. Finally, we conclude this review with the discussion on models that can be applied to study the causal role of the gut microbiota in the context of metabolic syndrome and host immunity. We hope this review will facilitate important considerations for appropriate animal model selection.

Impact of Gut Microbiota on the Peripheral Nervous System in Physiological, Regenerative and Pathological Conditions

“…This is also envisioned by a new approach for specific depletion of well selected bacterial species in the human GM [7]. The strict use of highly standardized GFmodels or gnotobiotic models appears more promising in this than the "simple" depletion and modification of the GM by systemic antibiosis [179].…”

Signaling Modifications Associated with Obesity and Dysbiosis and Their Impact on Metabolic Disorders

“…Finding that gut microbiota plays a direct role in promoting adipose inflammation, Caesar and colleagues reported that germ-free mice reduced macrophage accumulation in adipose tissue and improved glucose metabolism compared to their conventionally engineered counterparts [15]. Although the causal role of gut microbiota has generally been studied in animal models, cross-sectional studies have identified microbiota profiles associated with metabolic diseases in humans [16]. In this sense, recent studies support the role of dysbiotic alterations in metabolic diseases such as obesity [17] and T2D [18] and suggest that the gut microbiota may be a novel therapeutic target for the amelioration of T2D and related diseases [18].…”

Microbiotoxicity: antibiotic usage and its unintended harm to the microbiome

“…Compared with conventional mice, germ-free mice display profound immune defects and impaired growth [39 ▪ ]. Moreover, in mouse models for obesity, inflammatory bowel disease and asthma, germ-free mice develop the disease phenotype after receiving stool transplantation from diseased mice, with some evidence of clinical improvement following microbial restoration [40 ▪ ]. Antibiotics can induce or worsen a pathological phenotype in mice (such as allergic sensitization [41 ▪ ] or experimentally induced colitis [42]).…”