ObjectiveAmple evidence exists for the role of abnormal gut microbiota composition and increased gut permeability (‘leaky gut’) in chronic inflammation that commonly co-occurs in the gut in both obesity and diabetes, yet the detailed mechanisms involved in this process have remained elusive.DesignIn this study, we substantiate the causal role of the gut microbiota by use of faecal conditioned media along with faecal microbiota transplantation. Using untargeted and comprehensive approaches, we discovered the mechanism by which the obese microbiota instigates gut permeability, inflammation and abnormalities in glucose metabolism.ResultsWe demonstrated that the reduced capacity of the microbiota from both obese mice and humans to metabolise ethanolamine results in ethanolamine accumulation in the gut, accounting for induction of intestinal permeability. Elevated ethanolamine increased the expression of microRNA-miR-101a-3pby enhancing ARID3a binding on the miR promoter. IncreasedmiR-101a-3pdecreased the stability of zona occludens-1 (Zo1) mRNA, which in turn, weakened intestinal barriers and induced gut permeability, inflammation and abnormalities in glucose metabolism. Importantly, restoring ethanolamine-metabolising activity in gut microbiota using a novel probiotic therapy reduced elevated gut permeability, inflammation and abnormalities in glucose metabolism by correcting the ARID3a/miR-101a/Zo1axis.ConclusionOverall, we discovered that the reduced capacity of obese microbiota to metabolise ethanolamine instigates gut permeability, inflammation and glucose metabolic dysfunctions, and restoring ethanolamine-metabolising capacity by a novel probiotic therapy reverses these abnormalities.Trial registration numberNCT02869659andNCT03269032.

Electron−nuclear double resonance (ENDOR) studies of radical intermediates formed by the oxidative decarboxylation of pyruvate by pyruvate:ferredoxin oxidoreductase were carried out to characterize their electronic structure and elucidate aspects of the recently proposed catalytic mechanism (Menon, S.; Ragsdale, S. W. Biochemistry 1997, 36, 8484−8494). The EPR spectrum of the PFOR/pyruvate adduct at 4 K displays a narrow resonance centered at g = 2.008 that has been attributed to a hydroxyethyl thiamine pyrophosphate (HE-TPP) radical. This spectral feature is superimposed on a broad, complex line shape characteristic of magnetically coupled [Fe4S4] clusters. The ENDOR spectrum at g = 2.008 reveals a broad peak with a complex line shape that can be analyzed, assuming that it arises from a composite of two axially symmetric proton hyperfine couplings. The principle coupling values for these two hyperfine tensors were:  A ∥(1) = 18.9 MHz, A ⊥(1) = 12.6 MHz; and A ∥(2) = 20.3 MHz, A ⊥(2) = 14.9 MHz. The assignment of these features to the methyl protons of the pyruvate substrate was made using isotopic substitution. The temperature independence of these 1H ENDOR line shapes from 4 to 200 K indicates that the methyl group of pyruvate undergoes rapid rotation even at 4 K. The ENDOR spectrum at g = 2.008 also shows a pair of derivative peaks centered about the 31P Larmor frequency that are assigned to a weak hyperfine coupling with the phosphorus nuclei of the TPP cofactor. Two models for the electronic structure of the radical intermediate are discussed. A σ radical model which postulates a pyruvate-derived acetyl-type radical where little unpaired spin density resides on the TPP cofactor, and a π radical model that calls for more extensive delocalization of the unpaired electron spin over the HE-TPP framework. Both models require association of the radical center with the pyrophosphate group of TPP to interpret the observed 31P hyperfine coupling.

The role of the microbiome in the development and propagation of head and neck squamous cell cancer (HNSCC) is largely unknown and the surrounding knowledge lags behind what has been discovered related to the microbiome and other malignancies. In this review, the authors performed a structured analysis of the available literature from several databases. The authors discuss the merits and detriments of several studies discussing the microbiome of the structures of the aerodigestive system throughout the development of HNSCC, the role of the microbiome in the development of malignancies (generally and in HNSCC) and clinical applications of the microbiome in HNSCC. Further studies will be needed to adequately describe the relationship between HNSCC and the microbiome, and to push this relationship into a space where it is clinically relevant outside of a research environment.

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