Histamine Derived from Probiotic Lactobacillus reuteri Suppresses TNF via Modulation of PKA and ERK Signaling

Beneficial microbes and probiotic species, such as Lactobacillus reuteri, produce biologically active compounds that can modulate host mucosal immunity. Previously, immunomodulatory factors secreted by L. reuteri ATCC PTA 6475 were unknown. A combined metabolomics and bacterial genetics strategy was utilized to identify small compound(s) produced by L. reuteri that were TNF-inhibitory. Hydrophilic interaction liquid chromatography-high performance liquid chromatography (HILIC-HPLC) separation isolated TNF-inhibitory compounds, and HILIC-HPLC fraction composition was determined by NMR and mass spectrometry analyses. Histamine was identified and quantified in TNF-inhibitory HILIC-HPLC fractions. Histamine is produced from L-histidine via histidine decarboxylase by some fermentative bacteria including lactobacilli. Targeted mutagenesis of each gene present in the histidine decarboxylase gene cluster in L. reuteri 6475 demonstrated the involvement of histidine decarboxylase pyruvoyl type A (hdcA), histidine/histamine antiporter (hdcP), and hdcB in production of the TNF-inhibitory factor. The mechanism of TNF inhibition by L. reuteri-derived histamine was investigated using Toll-like receptor 2 (TLR2)-activated human monocytoid cells. Bacterial histamine suppressed TNF production via activation of the H2 receptor. Histamine from L. reuteri 6475 stimulated increased levels of cAMP, which inhibited downstream MEK/ERK MAPK signaling via protein kinase A (PKA) and resulted in suppression of TNF production by transcriptional regulation. In summary, a component of the gut microbiome, L. reuteri, is able to convert a dietary component, L-histidine, into an immunoregulatory signal, histamine, which suppresses pro-inflammatory TNF production. The identification of bacterial bioactive metabolites and their corresponding mechanisms of action with respect to immunomodulation may lead to improved anti-inflammatory strategies for chronic immune-mediated diseases

Doped, Defect-Enriched Carbon Nanotubes as an Efficient Oxygen Reduction Catalyst for Anion Exchange Membrane Fuel Cells

Bond polarization of doped atoms and carbon and lattice defects are considered important aspects in the catalytic mechanisms of oxygen reduction reaction (ORR) on heteroatom‐doped carbon catalysts. Previous work on metal‐free catalysts has focused either on bond polarization or lattice defects. Here multi‐heteroatom doped defect‐enriched carbon nanotubes (MH‐DCNTs) that combine both effects to enhance ORR activity are designed. Lattice defects in MH‐DCNTs are enriched by unzipping and length‐shortening of carbon nanotubes, and also by creating carbon vacancies via decomposition of doped F atoms. Electrochemical analysis using rotating disc electrode voltammetry shows that the ORR kinetic current density of MH‐DCNT increases with lattice‐defect density, the latter of which is verified by Raman spectroscopy, while the onset potential increases with annealing temperatures. An optimized MH‐DCNT ORR catalyst exhibits a half‐wave potential of 0.81 V versus reversible hydrogen electrode and limiting current density of 5.0 mA cm−2 at an electrode rotation speed of 1600 rpm in 0.1 m KOH. Further, it is demonstrated that MH‐DCNT, as a cathode catalyst layer in an anion exchange membrane fuel cell (AEMFC), delivers a peak power density of 250 mW cm−2, which is ≈70% the performance of an AEMFC using a conventional Pt/C catalyst