Pathways and functions of gut microbiota metabolism impacting host physiology
Graphical abstract
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.
Section snippets
Metabolic functions and outputs of the gut microbiota
Substrates metabolized by the gut microbiota include dietary residues, mucosal macromolecules (e.g. mucins), endogenous metabolites (notably bile acids), and xenobiotic chemicals. The major classes of dietary substrates (Figure 1) comprise carbohydrates, amino acids, certain lipids (e.g. polyunsaturated fatty acids [15]), and phytochemicals [16].
Manipulation of gut microbial populations
Because of ethical concerns and practical limitations of manipulating the gut microbiota in human subjects, GF and gnotobiotic mice have featured prominently as experimental model systems. Administration of broad-spectrum antibiotics via drinking water has also been used, but the results can be difficult to reproduce. While gavage feeding of the antibiotics improves reproducibility [38], this can severely stress the animal, presenting difficulties for long-term studies. Another strategy for
Conclusions
Microbiome research continues to advance at a rapid pace, and significant progress has been achieved towards understanding the metabolic functions performed by the gut microbiota. However, many questions remain regarding the enzymatic pathways and species responsible for the metabolites that mediate host–microbiota interactions. Moreover, it is probably that the metabolites characterized to date represent only a fraction of the bioactive chemicals produced by the microbiota. A recent analysis
References and recommended reading
Papers of particular interest, published within the period of review, have been highlighted as:
• of special interest
•• of outstanding interest
Acknowledgements
This work was in part supported by grants from the National Institutes of Health (R21 GM106251) and National Science Foundation (1264502).
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