Abstract
The intestinal microbiota is a complex community that consists of an ecosystem with a dynamic interplay between bacteria, fungi, archaea, and viruses. Recent advances in model systems have revealed that the gut microbiome is critical for maintaining homeostasis through metabolic digestive function, immune regulation, and intestinal barrier integrity. Taxonomic shifts in the intestinal microbiota are strongly correlated with a multitude of human diseases, including inflammatory bowel disease (IBD). However, many of these studies have been descriptive, and thus the understanding of the cause and effect relationship often remains unclear. Using non-human experimental model systems such as gnotobiotic mice, probiotic mono-colonization, or prebiotic supplementation, researchers have defined numerous species-level functions of the intestinal microbiota that have produced therapeutic candidates for IBD. Despite these advances, the molecular mechanisms responsible for the function of much of the microbiota and the interplay with host cellular processes remain areas of tremendous research potential. In particular, future research will need to unlock the functional molecular units of the microbiota in order to utilize this untapped resource of bioactive molecules for therapy. This review will highlight the advances and remaining challenges of microbiota-based functional studies and therapeutic discovery, specifically in IBD. One of the limiting factors for reviewing this topic is the nascent development of this area with information on some drug candidates still under early commercial development. We will also highlight the current and evolving strategies, including in the biotech industry, used for the discovery of microbiota-derived bioactive molecules in health and disease.
Highlights
Most externally exposed mucosal surfaces and cavities in the human body are characterized by the presence of microbial communities composed of bacteria, archaea, viruses, and fungi [1]
Because of its inability to directly identify microbial genes, its limitations in taxonomic resolution, and the introduction of primer bias due to its use of PCR, the value of the exclusive use of 16S ribosomal RNA (rRNA) sequencing in the search for new microbiota-derived drugs is problematic (Table 2) [80,81]. It has been demonstrated by multiple studies that low-abundance bacteria in microbial communities are poorly detected by 16S sequencing, and techniques such as shotgun metagenomics are more suited for this purpose [82,83,84]
This study identified that the most pronounced IBDspecific dysbiosis at the RNA level occurs within R. gnavus, which shows a significantly increased abundance of RNA transcripts in both ulcerative colitis (UC) and Crohn’s disease (CD) compared to non-inflammatory bowel disease (IBD), despite the much smaller increases in DNA abundance [11]
Summary
Most externally exposed mucosal surfaces and cavities in the human body are characterized by the presence of microbial communities composed of bacteria, archaea, viruses, and fungi [1]. Disruption in the gut microbiota composition, known as gut dysbiosis, has been linked with a number of chronic conditions ranging from metabolic disorders, such as obesity and type 2 diabetes, to immune-related diseases such as inflammatory bowel disease (IBD), arthritis, celiac disease, irritable bowel syndrome, food allergy, and asthma. In this narrative review, we will focus our discussion on IBD as it is furthest along the development pipeline for microbiota-based therapies.
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