Beyond phylotyping: understanding the impact of gut microbiota on host biology

Abstract

Background: Microbial constituents of the gut microbiome interact with each other and the host to alter the luminal environment and impact development, motility, and homeostasis of the gut. Powerful methods are becoming available to investigate connections between the gut microbiome and human health. While high-throughput sequencing of 16S rRNA genes can be used to identify and enumerate microbes in the gut, advances in several techniques (e.g., metagenomics, metatranscriptomics, metabolomics, and metaproteomics) are providing a clearer view as to the specific activities of the microbiota in the context of functional host-microbe interactions. Testing emergent hypotheses regarding microbial effects on host biology, which arise from analyses of 'Big Data' generated from massive parallel high-throughput sequencing technology and spectroscopic techniques, to guide translational research is an important goal for the future. Insights regarding the fundamental operating principles of the gut microbiota should lay the foundation for rational manipulation of the microbiota to promote human health.

Purpose: In this review, we provide an overview of current research on the gut microbiome emphasizing current state-of-the-art technologies, approaches, and directions for improvement of our understanding of the impact of the gut microbiota with specific focus on gastrointestinal motility disorders.

Figure 1. Multi-omic and gnotobiotic approaches to host-microbial interaction

High-throughput analyses of host and microbial DNA, RNA, proteins and metabolites can be performed using metagenomics, metatranscriptomics, metaproteomics and metabolomics, respectively, to investigate interrelationships between host and microbial factors. Hypotheses that emerge from multi-omic studies can be tested using gnotobiotics through colonization of germ-free mice with characterized microbial consortia or human gut microbiota. This approach will help to elucidate effects on host biology of factors that modulate the gut microbiota including environment (e.g., geography, hygiene), diet, host genotype, physiological states (e.g., pregnancy) and disease states.

Figure 2. Microbial products with putative effects on GI motility

GI motility depends on the complex interaction of multiple cell types including enteric neurons, interstitial cells of Cajal, smooth muscle, and immune cells (e.g., macrophages). Luminal gases mediate GI motility; methane and hydrogen sulfide have inhibitory effects on GI transit potentially due to an effect on smooth muscle cells, and molecular hydrogen increases colonic motility by an unidentified mechanism. Lipopolysaccharide produced by Gram-negative bacteria has been suggested to promote survival of enteric nitrergic neurons and motility through Toll-like receptor 4 signaling. The bacterial metabolite, tryptamine, mimics stimulatory effects on motility of serotonin. Luminal short chain fatty acids such as butyrate and acetate promote GI motility through several mechanisms including direct effects on smooth muscle and production of mucosal 5-HT. Production of microbial products regulating motility depends on the availability of specific dietary compounds. 5-HT, serotonin; 5-HT₄R, serotonin receptor; TLR4, Toll-like receptor 4; ICC, interstitial cells of Cajal; LPS, lipopolysaccharide.