81 Augmented Creatinine Clearance in Severely Injured Burn Patients

Abstract Introduction Most trauma surgeons assume that serum creatinine (SCr) reflects glomerular filtration rate (GFR). However, new evidence suggests augmented renal clearance (ARC= creatinine clearance (CLCr) >130 ml/min) occurs in up to 60% of critically ill patients. ARC is associated with subtherapeutic drug concentrations, may lead to adverse clinical outcomes, and has yet to be reported in the burn population. Unfortunately, actual CLCr is usually not measured in the burn ICU and estimates of glomerular filtration rate (eGFR) have not been validated in critically ill burn ICU patients. To fill this gap, we test the hypothesis that ARC is common in burn ICU patients and is dissociated from eGFR. Methods In 15 consecutive burn ICU patients with total body surface area burns (TBSA) > 10%, 24 hr CLCr was correlated with demographics, iatrogenic factors, and clinical estimates of GFR: Cockroft-Gault (CG), modification of diet in renal disease (MDRD), and chronic kidney disease epidemiology (CKD-EPI). Univariate and multivariate logistic regression were used to identify risk factors of ARC. Values are M±SD if parametric and median [interquartile range] otherwise. Differences are assessed at p<0.05. Results The study population was 43 ± 16y, 60% males, 47% Caucasian, BMI 28.8 ± 8 kg/m2, with TBSA of 23[13–42]%. Length of stay was 26 ± 14d and overall mortality was 20% (n=3). Serum creatinine was 0.74[0.69–1.11] mg/dL and CLCr was 139 ± 66 ml/min. Urine output was 0.93 ± 0.43 cc/kg/h. In this sample of 15 patients, 67% (n=10) had ARC, 7% (n=1) had normal GFR, and 27% (n=4) were in acute renal failure. Hypertension, diabetes, age, amount of crystalloid in the first 24 hours and fluid balance were all associated with ARC on univariate analysis (all p<0.05), but TBSA, gender, race, smoking history, pressor use, weight, mechanical ventilation, admission vitals and creatinine were not. After controlling for confounders, none of these factors were independent risk factors for ARC. CKD-EPI, MDRD, and CG, underestimated CLCr by an average of 12% (p<0.031), 7% (p<0.071), and 9%, (p<0.0001), respectively. Conclusions These preliminary data are the first demonstration that ARC is common in critically-ill burn ICU patients, is independent of patient-specific and iatrogenic factors, and is not accurately detected by current clinical estimates. Applicability of Research to Practice Increased renal clearance can have adverse effects on drug concentrations, such as antibiotics and thromboprophylaxis, and ultimately clinical outcomes. More accurate estimates of CLCr are needed to minimize treatment failure in this population, and further studies are warranted to assess clinical outcomes of this phenomenon

Intestinal IL-22RA1 signaling regulates intrinsic and systemic lipid and glucose metabolism to alleviate obesity-associated disorders

Abstract IL-22 is critical for ameliorating obesity-induced metabolic disorders. However, it is unknown where IL-22 acts to mediate these outcomes. Here we examine the importance of tissue-specific IL-22RA1 signaling in mediating long-term high fat diet (HFD) driven metabolic disorders. To do so, we generated intestinal epithelium-, liver-, and white adipose tissue (WAT)-specific Il22ra1 knockout and littermate control mice. Intestinal epithelium- and liver-specific IL-22RA1 signaling upregulated systemic glucose metabolism. Intestinal IL-22RA1 signaling also mediated liver and WAT metabolism in a microbiota-dependent manner. We identified an association between Oscillibacter and elevated WAT inflammation, likely induced by Mmp12 expressing macrophages. Mechanistically, transcription of intestinal lipid metabolism genes is regulated by IL-22 and potentially IL-22-induced IL-18. Lastly, we show that Paneth cell-specific IL-22RA1 signaling, in part, mediates systemic glucose metabolism after HFD. Overall, these results elucidate a key role of intestinal epithelium-specific IL-22RA1 signaling in regulating intestinal metabolism and alleviating systemic obesity-associated disorders

Reducing gut microbiome-driven adipose tissue inflammation alleviates metabolic syndrome

Abstract Background The gut microbiota contributes to macrophage-mediated inflammation in adipose tissue with consumption of an obesogenic diet, thus driving the development of metabolic syndrome. There is a need to identify and develop interventions that abrogate this condition. The hops-derived prenylated flavonoid xanthohumol (XN) and its semi-synthetic derivative tetrahydroxanthohumol (TXN) attenuate high-fat diet-induced obesity, hepatosteatosis, and metabolic syndrome in C57Bl/6J mice. This coincides with a decrease in pro-inflammatory gene expression in the gut and adipose tissue, together with alterations in the gut microbiota and bile acid composition. Results In this study, we integrated and interrogated multi-omics data from different organs with fecal 16S rRNA sequences and systemic metabolic phenotypic data using a Transkingdom Network Analysis. By incorporating cell type information from single-cell RNA-seq data, we discovered TXN attenuates macrophage inflammatory processes in adipose tissue. TXN treatment also reduced levels of inflammation-inducing microbes, such as Oscillibacter valericigenes, that lead to adverse metabolic phenotypes. Furthermore, in vitro validation in macrophage cell lines and in vivo mouse supplementation showed addition of O. valericigenes supernatant induced the expression of metabolic macrophage signature genes that are downregulated by TXN in vivo. Conclusions Our findings establish an important mechanism by which TXN mitigates adverse phenotypic outcomes of diet-induced obesity and metabolic syndrome. TXN primarily reduces the abundance of pro-inflammatory gut microbes that can otherwise promote macrophage-associated inflammation in white adipose tissue. Video Abstrac

Reducing gut microbiome-driven adipose tissue inflammation alleviates metabolic syndrome

Abstract Background The gut microbiota contributes to macrophage-mediated inflammation in adipose tissue with consumption of an obesogenic diet, thus driving the development of metabolic syndrome. There is a need to identify and develop interventions that abrogate this condition. The hops-derived prenylated flavonoid xanthohumol (XN) and its semi-synthetic derivative tetrahydroxanthohumol (TXN) attenuate high-fat diet-induced obesity, hepatosteatosis, and metabolic syndrome in C57Bl/6J mice. This coincides with a decrease in pro-inflammatory gene expression in the gut and adipose tissue, together with alterations in the gut microbiota and bile acid composition. Results In this study, we integrated and interrogated multi-omics data from different organs with fecal 16S rRNA sequences and systemic metabolic phenotypic data using a Transkingdom Network Analysis. By incorporating cell type information from single-cell RNA-seq data, we discovered TXN attenuates macrophage inflammatory processes in adipose tissue. TXN treatment also reduced levels of inflammation-inducing microbes, such as Oscillibacter valericigenes, that lead to adverse metabolic phenotypes. Furthermore, in vitro validation in macrophage cell lines and in vivo mouse supplementation showed addition of O. valericigenes supernatant induced the expression of metabolic macrophage signature genes that are downregulated by TXN in vivo. Conclusions Our findings establish an important mechanism by which TXN mitigates adverse phenotypic outcomes of diet-induced obesity and metabolic syndrome. TXN primarily reduces the abundance of pro-inflammatory gut microbes that can otherwise promote macrophage-associated inflammation in white adipose tissue. Video Abstract</span

Additional file 3 of Reducing gut microbiome-driven adipose tissue inflammation alleviates metabolic syndrome

Additional file 3. Processed data of the single cell RNA sequencing from adipose tissue (WAT_filtered_feature_bc_matrix.h5)

Additional file 1 of Reducing gut microbiome-driven adipose tissue inflammation alleviates metabolic syndrome

Additional file 1: Supplementary Figure S1. Myeloid cells are the primary cell type affected by TXN in the adipose tissue. Supplementary Figure S2. TXN treatment alters fecal microbiota composition and some Oscillibacter features. Supplementary Figure S3.  TXN treatment increases mitochondrial gene expression. Figure S4. Identification of overlapping gene expression between adipose tissue from TXN-treated mice vs. O.valericigenes supernatant-treated macrophage cell lines. Figure S5. Gene expression from in vitro titration of O. valericigenes and L. gasseri cell free supernatant on a IMM cell line

Additional file 2 of Reducing gut microbiome-driven adipose tissue inflammation alleviates metabolic syndrome

Additional file 2: Table S1. Number of parameters per data type in each category in the network. Table S2. Summary table of parameters, including statistical information, cell type information, microbiota dependence/independence for genes, abundance of microbes, and network information. Table S3. IMM/RAW cell with Oscillibacter supplementation (data from GSE203488, GSE203516). Table S4. In vivo validation of O. valericigenes gavage (data from GSE215226). Table S5. RT-PCR  data from in vitro cell free  Oscillibacter supernatant titration on IMM cells