Small molecules from the human microbiota

Abstract

Developments in the use of genomics to guide natural product discovery and a recent emphasis on understanding the molecular mechanisms of microbiota-host interactions have converged on the discovery of natural products from the human microbiome. Here, we review what is known about small molecules produced by the human microbiota. Numerous molecules representing each of the major metabolite classes have been found that have a variety of biological activities, including immune modulation and antibiosis. We discuss technologies that will affect how microbiota-derived molecules are discovered in the future, and consider the challenges inherent in finding specific molecules that are critical for driving microbe-host and microbe-microbe interactions and their biological relevance.

The human microbiome, from Achilles armour to Nessus’ shirt

“…Genomics and transcriptomics allow access to microbial communities and their transcriptomic profiles, while highresolution mass spectrometry and metabolomics can provide insight into the underlying biochemistry and metabolic processes. At the same time a variety of model systems and culturing techniques are available for the analysis of selected communities or isolated members, and soon probably also co-culture systems (Donia and Fischbach 2015;Spanogiannopoulos et al 2016;Tralau et al 2015). Challenging as it still might be analysis of microbiome's toxicology has thus become feasible.…”

“…The metabolic and biochemical potential encoded therein far outnumbers that of the human host. First estimates put the number of possible biochemical reactions close to 1400 (including approximately 480 non-human metabolites), some of which are readily fed into our own biochemical pathways (Donia and Fischbach 2015;Ibrahim and Anishetty 2012;Jacobsen et al 2013;Mohammed and Guda 2015). Metabolomic studies already show that in mice, for example, at least 10% of blood metabolites are directly influenced by the gastrointestinal microbiome (Wikoff et al 2009).…”

“…The microbiome project and numerous concomitant research activities start to draw a picture of a commensalic metacommunity which not only influences our digestive system and its biochemistry and physiology but also has a major impact on behaviour, immune function, reproduction, neurodevelopment, our endocrine and circadian system (Dai et al 2015;Donia and Fischbach 2015;Leone et al 2015;Meinl et al 2009). Similarly to eukaryotic phase I and phase II metabolism prokaryotic interference with drugs can lead to substance inactivation, activation or toxicity.…”

GUT-the Trojan Horse in Remote Organs’ Autoimmunity

“…Intricate hostmicrobe symbiotic relationships in the human gut have evolved during the long-term coevolution between the two. It resulted in fine-tuned inter-kingdom molecular adaptations that benefit both sides, in an ideal symbiotic way [11]. This led to remarkable co-dependence and blurred the distinction between self and non-self.…”

Insights into study design and statistical analyses in translational microbiome studies

“…The microbiome can serve as a diagnostic adjunct to traditional clinical and laboratory measures (23,(27)(28)(29), a determinant of treatment-response (30), a window into the side-effects of exposure to antibiotics (25), a baseline measurement prior to the initiation of therapy (31), and a signature of immune processes such as inflammation (23,32). Furthermore, it can be used to guide nutrition and preventive interventions (33), monitor the severity, progression or recovery from disease (34), track treatment-outcomes (35), and identify small-molecule drugs (36) and mechanisms of pathogenesis which can then be targeted for therapeutic interventions (37).…”