Pathways and functions of gut microbiota metabolism impacting host physiology

Highlights

• Intestinal microbiota performs diverse metabolic functions essential for host physiology.

• Small molecule products of microbiota metabolism act as nutrients and signaling molecules.

• Microbiota products modulate lipid metabolism, immune cell reactivity, and neuroendocrine pathways.

• Functional characterization of microbiota metabolites will benefit from pathway-oriented analyses and integration of analytical approaches.

• Metabolic models could facilitate data integration to relate microbiota composition and function.

The bacterial populations in the human intestine impact host physiological functions through their metabolic activity. In addition to performing essential catabolic and biotransformation functions, the gut microbiota produces bioactive small molecules that mediate interactions with the host and contribute to the neurohumoral axes connecting the intestine with other parts of the body. This review discusses recent progress in characterizing the metabolic products of the gut microbiota and their biological functions, focusing on studies that investigate the responsible bacterial pathways and cognate host receptors. Several key areas are highlighted for future development: context-based analysis targeting pathways; integration of analytical approaches; metabolic modeling; and synthetic systems for in vivo manipulation of microbiota functions. Prospectively, these developments could further our mechanistic understanding of host–microbiota interactions.

Introduction

Colonized at birth, the adult human gastrointestinal (GI) tract harbors ∼10¹⁴ bacteria belonging to at least several hundred species [1]. Collectively termed the gut microbiota, these bacterial populations impact an array of physiological functions in the GI tract, including digestion and immune response to foodborne pathogens. A well-known digestive function of the microbiota is the fermentation of complex carbohydrates to short chain fatty acids (SCFAs). Recent metabolomic studies have detected SCFAs and many other bioactive microbiota-derived metabolites in systemic circulation [2], supporting the view that these molecules constitute part of the neurohumoral communication axes that link the intestine with other organs such as the liver and brain.

Significant alteration in the microbial populations, or dysbiosis, correlates with not only GI diseases, but also other chronic diseases such as diabetes, cancer, and asthma. While it is difficult to establish causation, the case for dysbiosis as a contributing mechanism for some diseases has become increasingly compelling. Seminal work by the Gordon laboratory identified a pattern of dysbiosis in obesity that is characterized by a greater capacity for energy harvest [3]. Psychiatric disorders such as autism spectrum disorder (ASD) are frequently accompanied by changes to the intestinal microbiota composition [4, 5]. Using a murine model of ASD, Hsiao et al. showed that alterations to the serum metabolite profile resulting from dysbiosis correlate with behavioral abnormalities; administration of a probiotic attenuated these abnormalities while reducing the serum levels of microbiota metabolites elevated in ASD mice [6^••].

These studies provide firm evidence that dysbiosis dramatically impacts host physiology; moreover, the functional consequences reflect alterations in the profile of microbiota-derived metabolic products. Many of these metabolites show activity as signaling molecules [7], and engage various host receptors and regulatory molecules in vitro and in vivo [8, 9]; however, specific functions have been identified for only a small subset of these metabolites [10]. Aided by advances in sequencing and data analysis pipelines [11], the catalog of annotated genomes for bacteria found in humans [12, 13] and model organisms [14] has rapidly expanded over the past several years. These developments present an exciting opportunity to integrate compositional data with measurements on the functional outputs of the microbiota to address fundamental questions regarding molecular mechanisms mediating host–microbiota interactions.

In this review, we discuss recent progress in characterizing the metabolic products of the gut microbiota and their biological functions in the context of host physiology. We focus on studies that investigate the responsible enzymatic pathways and bacterial groups. We also discuss representative methods and models, including metabolic models that could facilitate the integration of different types of data on microbiota composition and functional readouts.