Gut microbiota regulation of P-glycoprotein in the intestinal epithelium in maintenance of homeostasis

BACKGROUND: P-glycoprotein (P-gp) plays a critical role in protection of the intestinal epithelia by mediating efflux of drugs/xenobiotics from the intestinal mucosa into the gut lumen. Recent studies bring to light that P-gp also confers a critical link in communication between intestinal mucosal barrier function and the innate immune system. Yet, despite knowledge for over 10 years that P-gp plays a central role in gastrointestinal homeostasis, the precise molecular mechanism that controls its functional expression and regulation remains unclear. Here, we assessed how the intestinal microbiome drives P-gp expression and function. RESULTS: We have identified a functional core microbiome of the intestinal gut community, specifically genera within the Clostridia and Bacilli classes, that is necessary and sufficient for P-gp induction in the intestinal epithelium in mouse models. Metagenomic analysis of this core microbial community revealed that short-chain fatty acid and secondary bile acid production positively associate with P-gp expression. We have further shown these two classes of microbiota-derived metabolites synergistically upregulate P-gp expression and function in vitro and in vivo. Moreover, in patients suffering from ulcerative colitis (UC), we find diminished P-gp expression coupled to the reduction of epithelial-derived anti-inflammatory endocannabinoids and luminal content (e.g., microbes or their metabolites) with a reduced capability to induce P-gp expression. CONCLUSION: Overall, by means of both in vitro and in vivo studies as well as human subject sample analysis, we identify a mechanistic link between cooperative functional outputs of the complex microbial community and modulation of P-gp, an epithelial component, that functions to suppress overactive inflammation to maintain intestinal homeostasis. Hence, our data support a new cross-talk paradigm in microbiome regulation of mucosal inflammation. Video abstract

Genome-wide analysis of 53,400 people with irritable bowel syndrome highlights shared genetic pathways with mood and anxiety disorders

Funder: Kennedy Trust Rheumatology Research Prize StudentshipFunder: DFG Cluster of Excellence “Precision Medicine in Chronic In-flammation” (PMI; ID: EXC2167)Funder: EC | EC Seventh Framework Programm | FP7 Ideas: European Research Council (FP7-IDEAS-ERC - Specific Programme: “Ideas” Implementing the Seventh Framework Programme of the European Community for Research, Technological Development and Demonstration Activities (2007 to 2013)); doi: https://doi.org/10.13039/100011199; Grant(s): 715772Funder: NWO-VIDI grant 016.178.056, the Netherlands Heart Foundation CVON grant 2018-27, and NWO Gravitation grant ExposomeNLFunder: Li Ka Shing Foundation (Li Ka Shing Foundation Limited); doi: https://doi.org/10.13039/100007421Abstract: Irritable bowel syndrome (IBS) results from disordered brain–gut interactions. Identifying susceptibility genes could highlight the underlying pathophysiological mechanisms. We designed a digestive health questionnaire for UK Biobank and combined identified cases with IBS with independent cohorts. We conducted a genome-wide association study with 53,400 cases and 433,201 controls and replicated significant associations in a 23andMe panel (205,252 cases and 1,384,055 controls). Our study identified and confirmed six genetic susceptibility loci for IBS. Implicated genes included NCAM1, CADM2, PHF2/FAM120A, DOCK9, CKAP2/TPTE2P3 and BAG6. The first four are associated with mood and anxiety disorders, expressed in the nervous system, or both. Mirroring this, we also found strong genome-wide correlation between the risk of IBS and anxiety, neuroticism and depression (rg > 0.5). Additional analyses suggested this arises due to shared pathogenic pathways rather than, for example, anxiety causing abdominal symptoms. Implicated mechanisms require further exploration to help understand the altered brain–gut interactions underlying IBS

Effect of remote ischaemic conditioning on clinical outcomes in patients with acute myocardial infarction (CONDI-2/ERIC-PPCI): a single-blind randomised controlled trial.

BACKGROUND: Remote ischaemic conditioning with transient ischaemia and reperfusion applied to the arm has been shown to reduce myocardial infarct size in patients with ST-elevation myocardial infarction (STEMI) undergoing primary percutaneous coronary intervention (PPCI). We investigated whether remote ischaemic conditioning could reduce the incidence of cardiac death and hospitalisation for heart failure at 12 months. METHODS: We did an international investigator-initiated, prospective, single-blind, randomised controlled trial (CONDI-2/ERIC-PPCI) at 33 centres across the UK, Denmark, Spain, and Serbia. Patients (age >18 years) with suspected STEMI and who were eligible for PPCI were randomly allocated (1:1, stratified by centre with a permuted block method) to receive standard treatment (including a sham simulated remote ischaemic conditioning intervention at UK sites only) or remote ischaemic conditioning treatment (intermittent ischaemia and reperfusion applied to the arm through four cycles of 5-min inflation and 5-min deflation of an automated cuff device) before PPCI. Investigators responsible for data collection and outcome assessment were masked to treatment allocation. The primary combined endpoint was cardiac death or hospitalisation for heart failure at 12 months in the intention-to-treat population. This trial is registered with ClinicalTrials.gov (NCT02342522) and is completed. FINDINGS: Between Nov 6, 2013, and March 31, 2018, 5401 patients were randomly allocated to either the control group (n=2701) or the remote ischaemic conditioning group (n=2700). After exclusion of patients upon hospital arrival or loss to follow-up, 2569 patients in the control group and 2546 in the intervention group were included in the intention-to-treat analysis. At 12 months post-PPCI, the Kaplan-Meier-estimated frequencies of cardiac death or hospitalisation for heart failure (the primary endpoint) were 220 (8·6%) patients in the control group and 239 (9·4%) in the remote ischaemic conditioning group (hazard ratio 1·10 [95% CI 0·91-1·32], p=0·32 for intervention versus control). No important unexpected adverse events or side effects of remote ischaemic conditioning were observed. INTERPRETATION: Remote ischaemic conditioning does not improve clinical outcomes (cardiac death or hospitalisation for heart failure) at 12 months in patients with STEMI undergoing PPCI. FUNDING: British Heart Foundation, University College London Hospitals/University College London Biomedical Research Centre, Danish Innovation Foundation, Novo Nordisk Foundation, TrygFonden

Ligand Influence on the Redox Chemistry of Organosamarium Complexes: Experimental and Theoretical Studies of the Reactions of (C5Me5)(2)Sm(THF)(2) and (C4Me4P)(2)Sm with Pyridine and Acridine

International audienceThe reactions of the samarium(II) complexes Tmp2Sm (Tmp = 2,3,4,5-tetramethyl-1H-phosphol-1-yl) and Cp*2Sm(THF)2 (Cp* = 1,2,3,4,5-tetramethyl-2,4-cyclopentadien-1-yl) with pyridine were found to be different, despite the fact that the Cp* and Tmp π-ligands are similar in size. With Tmp2Sm, a simple adduct, Tmp2Sm(pyridine)2 is isolated, while with Cp*2Sm(THF)2 pyridine is dimerized with concomitant oxidation of samarium to form [Cp*2Sm(C5H5N)]2[μ-(NC5H5-C5H5N)]. However, reaction of Tmp2Sm with acridine, a better π-acceptor than pyridine, did result in acridine dimerization and the isolation of [Tmp2Sm]2[μ-(NC13H9-C13H9N)]. DFT calculations on the model structures of Tmp2Sm and Cp*2Sm, and on the single electron transfer step from Sm to pyridine and acridine in these ligand environments, confirmed that, even though the Sm−π-ligand bonds are mostly ionic, the different electronic properties of the Tmp ligand versus that of Cp are responsible for the difference in reactivity of Tmp2Sm and Cp*2Sm

Ligand Influence on the Redox Chemistry of Organosamarium Complexes: Experimental and Theoretical Studies of the Reactions of (C₅Me₅)₂Sm(THF)₂ and (C₄Me₄P)₂Sm with Pyridine and Acridine

The reactions of the samarium­(II) complexes Tmp₂Sm (Tmp = 2,3,4,5-tetramethyl-1<i>H</i>-phosphol-1-yl) and Cp*₂Sm­(THF)₂ (Cp* = 1,2,3,4,5-tetramethyl-2,4-cyclopentadien-1-yl) with pyridine were found to be different, despite the fact that the Cp* and Tmp π-ligands are similar in size. With Tmp₂Sm, a simple adduct, Tmp₂Sm­(pyridine)₂ is isolated, while with Cp*₂Sm­(THF)₂ pyridine is dimerized with concomitant oxidation of samarium to form [Cp*₂Sm­(C₅H₅N)]₂[μ-(NC₅H₅–C₅H₅N)]. However, reaction of Tmp₂Sm with acridine, a better π-acceptor than pyridine, did result in acridine dimerization and the isolation of [Tmp₂Sm]₂[μ-(NC₁₃H₉–C₁₃H₉N)]. DFT calculations on the model structures of Tmp₂Sm and Cp*₂Sm, and on the single electron transfer step from Sm to pyridine and acridine in these ligand environments, confirmed that, even though the Sm−π-ligand bonds are mostly ionic, the different electronic properties of the Tmp ligand versus that of Cp are responsible for the difference in reactivity of Tmp₂Sm and Cp*₂Sm

Ligand Influence on the Redox Chemistry of Organosamarium Complexes: Experimental and Theoretical Studies of the Reactions of (C₅Me₅)₂Sm(THF)₂ and (C₄Me₄P)₂Sm with Pyridine and Acridine

The reactions of the samarium­(II) complexes Tmp₂Sm (Tmp = 2,3,4,5-tetramethyl-1<i>H</i>-phosphol-1-yl) and Cp*₂Sm­(THF)₂ (Cp* = 1,2,3,4,5-tetramethyl-2,4-cyclopentadien-1-yl) with pyridine were found to be different, despite the fact that the Cp* and Tmp π-ligands are similar in size. With Tmp₂Sm, a simple adduct, Tmp₂Sm­(pyridine)₂ is isolated, while with Cp*₂Sm­(THF)₂ pyridine is dimerized with concomitant oxidation of samarium to form [Cp*₂Sm­(C₅H₅N)]₂[μ-(NC₅H₅–C₅H₅N)]. However, reaction of Tmp₂Sm with acridine, a better π-acceptor than pyridine, did result in acridine dimerization and the isolation of [Tmp₂Sm]₂[μ-(NC₁₃H₉–C₁₃H₉N)]. DFT calculations on the model structures of Tmp₂Sm and Cp*₂Sm, and on the single electron transfer step from Sm to pyridine and acridine in these ligand environments, confirmed that, even though the Sm−π-ligand bonds are mostly ionic, the different electronic properties of the Tmp ligand versus that of Cp are responsible for the difference in reactivity of Tmp₂Sm and Cp*₂Sm

The critically endangered flapper skate (Dipturus intermedius): Recommendations from the first flapper skate working group meeting

The flapper skate, Dipturus intermedius (Parnell, 1837), is the largest of all European skate and rays (Superorder: Batoidea). It is found in coastal waters of the European continental shelf and slopes in the North-East (NE) Atlantic. With the 2006 IUCN Red List of Threatened Species classification of ‘common skate’ as Critically Endangered, and the recognition in 2010 that this name masked two species (flapper skate and blue skate D. batis (Linnaeus, 1758)), and to better support conservation on this regional scale, the Flapper Skate Working Group (SWG) was formed. The SWG is a consortium of government, NGOs, sport-fishing associates and academics, including participants from the UK, Ireland and the Netherlands. The purpose of the SWG is to consolidate relevant research, advocacy and policy expertize for the purpose of flapper skate conservation. The first SWG workshop took place in Belfast, November 2019, with discussions focussed on conservation in the NE Atlantic. Following two days of talks, workshops and discussions, we present the SWG’s key recommendations for future collaborative conservation

The Iceland Greenland seas project

The Iceland Greenland Seas Project (IGP) is a coordinated atmosphere–ocean research program investigating climate processes in the source region of the densest waters of the Atlantic meridional overturning circulation. During February and March 2018, a field campaign was executed over the Iceland and southern Greenland Seas that utilized a range of observing platforms to investigate critical processes in the region, including a research vessel, a research aircraft, moorings, sea gliders, floats, and a meteorological buoy. A remarkable feature of the field campaign was the highly coordinated deployment of the observing platforms, whereby the research vessel and aircraft tracks were planned in concert to allow simultaneous sampling of the atmosphere, the ocean, and their interactions. This joint planning was supported by tailor-made convection-permitting weather forecasts and novel diagnostics from an ensemble prediction system. The scientific aims of the IGP are to characterize the atmospheric forcing and the ocean response of coupled processes; in particular, cold-air outbreaks in the vicinity of the marginal ice zone and their triggering of oceanic heat loss, and the role of freshwater in the generation of dense water masses. The campaign observed the life cycle of a long-lasting cold-air outbreak over the Iceland Sea and the development of a cold-air outbreak over the Greenland Sea. Repeated profiling revealed the immediate impact on the ocean, while a comprehensive hydrographic survey provided a rare picture of these subpolar seas in winter. A joint atmosphere–ocean approach is also being used in the analysis phase, with coupled observational analysis and coordinated numerical modeling activities underway