The human gut microbiome is a critical component of digestion, breaking down complex carbohydrates, proteins, and to a lesser extent fats that reach the lower gastrointestinal tract. This process results in a multitude of microbial metabolites that can act both locally and systemically (after being absorbed into the bloodstream). The impact of these biochemicals on human health is complex, as both potentially beneficial and potentially toxic metabolites can be yielded from such microbial pathways, and in some cases, these effects are dependent upon the metabolite concentration or organ locality. The aim of this review is to summarize our current knowledge of how macronutrient metabolism by the gut microbiome influences human health. Metabolites to be discussed include short-chain fatty acids and alcohols (mainly yielded from monosaccharides); ammonia, branched-chain fatty acids, amines, sulfur compounds, phenols, and indoles (derived from amino acids); glycerol and choline derivatives (obtained from the breakdown of lipids); and tertiary cycling of carbon dioxide and hydrogen. Key microbial taxa and related disease states will be referred to in each case, and knowledge gaps that could contribute to our understanding of overall human wellness will be identified. Electronic supplementary material The online version of this article (10.1186/s40168-019-0704-8) contains supplementary material, which is available to authorized users.

A role for type A Clostridium perfringens in acute hemorrhagic and necrotizing gastroenteritis in dogs and in necrotizing enterocolitis of neonatal foals has long been suspected but incompletely characterized. The supernatants of an isolate made from a dog and from a foal that died from these diseases were both found to be highly cytotoxic for an equine ovarian (EO) cell line. Partial genome sequencing of the canine isolate revealed three novel putative toxin genes encoding proteins related to the pore-forming Leukocidin/Hemolysin Superfamily; these were designated netE, netF, and netG. netE and netF were located on one large conjugative plasmid, and netG was located with a cpe enterotoxin gene on a second large conjugative plasmid. Mutation and complementation showed that only netF was associated with the cytotoxicity. Although netE and netG were not associated with cytotoxicity, immunoblotting with specific antisera showed these proteins to be expressed in vitro. There was a highly significant association between the presence of netF with type A strains isolated from cases of canine acute hemorrhagic gastroenteritis and foal necrotizing enterocolitis. netE and netF were found in all cytotoxic isolates, as was cpe, but netG was less consistently present. Pulsed-field gel electrophoresis showed that netF-positive isolates belonged to a clonal population; some canine and equine netF-positive isolates were genetically indistinguishable. Equine antisera to recombinant Net proteins showed that only antiserum to rNetF had high supernatant cytotoxin neutralizing activity. The identifica-tion of this novel necrotizing toxin is an important advance in understanding the virulence of type A C. perfringens in specific enteric disease of animals.

The extensive impact of the human gut microbiota on its human host calls for a need to understand the types of communication that occur among the bacteria and their host. A metabolomics approach can provide a snapshot of the microbe-microbe interactions occurring as well as variations in the microbes from different hosts. In this study, metabolite profiles from an anaerobic continuous stirred-tank reactors (CSTR) system supporting the growth of several consortia of bacteria representative of the human gut were established and compared. Cell-free supernatant samples were analyzed by 1D (1)H nuclear magnetic resonance (NMR) spectroscopy, producing spectra representative of the metabolic activity of a particular community at a given time. Using targeted profiling, specific metabolites were identified and quantified on the basis of NMR analyses. Metabolite profiles discriminated each bacterial community examined, demonstrating that there are significant differences in the microbiota metabolome between each cultured community. We also found unique compounds that were identifying features of individual bacterial consortia. These findings are important because they demonstrate that metabolite profiles of gut microbial ecosystems can be constructed by targeted profiling of NMR spectra. Moreover, examination of these profiles sheds light on the type of microbes present in the gut and their metabolic interactions.

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Microbial community assembly is a complex process shaped by multiple factors, including habitat filtering, species assortment and stochasticity. Understanding the relative importance of these drivers would enable scientists to design strategies initiating a desired reassembly for e.g., remediating low diversity ecosystems. Here, we aimed to examine if a human fecal-derived defined microbial community cultured in bioreactors assembled deterministically or stochastically, by completing replicate experiments under two growth medium conditions characteristic of either high fiber or high protein diets. Then, we recreated this defined microbial community by matching different strains of the same species sourced from distinct human donors, in order to elucidate whether coadaptation of strains within a host influenced community dynamics. Each defined microbial ecosystem was evaluated for composition using marker gene sequencing, and for behavior using 1 H-NMR-based metabonomics. We found that stochasticity had the largest influence on the species structure when substrate concentrations varied, whereas habitat filtering greatly impacted the metabonomic output. Evidence of coadaptation was elucidated from comparisons of the two communities; we found that the artificial community tended to exclude saccharolytic Firmicutes species and was enriched for metabolic intermediates, such as Stickland fermentation products, suggesting overall that polysaccharide utilization by Firmicutes is dependent on cooperation.

Myocardial infarction (MI) leading to heart failure (HF) is a major cause of death worldwide. Previous studies revealed that the circadian system markedly impacts cardiac repair post-MI, and that light is an important environmental factor modulating the circadian influence over healing. Recent studies suggest that gut physiology also affects the circadian system, but how it contributes to cardiac repair post-MI and in HF is not well understood. To address this question, we first used a murine coronary artery ligation MI model to reveal that an intact gut microbiome is important for cardiac repair. Specifically, gut microbiome disruption impairs normal inflammatory responses in infarcted myocardium, elevates adverse cardiac gene biomarkers, and leads to worse HF outcomes. Conversely, reconstituting the microbiome post-MI in mice with prior gut microbiome disruption improves healing, consistent with the notion that normal gut physiology contributes to cardiac repair. To investigate a role for the circadian system, we initially utilized circadian mutant Clock ∆19/∆19 mice, revealing that a functional circadian mechanism is necessary for gut microbiome benefits on post-MI cardiac repair and HF. Finally, we demonstrate that circadian-mediated gut responses that benefit cardiac repair can be conferred by time-restricted feeding, as wake time feeding of MI mice improves HF outcomes, but these benefits are not observed in MI mice fed during their sleep time. In summary, gut physiology is important for cardiac repair, and the circadian system influences the beneficial gut responses to improve post-MI and HF outcomes.

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