African American communities disproportionately bear the burden of complications of diabetes. Early intervention can significantly improve the prognosis. Progress in overcoming disparities has been partially impaired by mistrust between the African American community and researchers. For this reason, minority men are often underrepresented in biomedical research studies that serve as the basis for the development of biomarkers for diagnosis and therapeutics. Overcoming this disparity calls for the development of culturally sensitive approaches that leverage partnerships with health care providers in minority serving clinics. A unique level of trust exists between African American communities and Historically Black Colleges and Universities (HBCUs). HBCU's are thus in a unique position to develop partnerships with clinical researchers to increase participation of African American men in research to promote healthy living and develop biomarkers for diseases that disproportionately affect their communities. In the current study, North Carolina A&T State University, one of the largest HBCU's in North Carolina, has partnered with the Cone Health Community Health and Wellness Center to build infrastructure to engage African American men in community participatory research. The research is designed to: (i) empower African American men to prevent and/or manage diabetes in order to prevent progression to complications, such as diabetic nephropathy and (ii) to increase collection of biological samples from African American men for biomarker development. Diabetic nephropathy (DN) is the most common complication of diabetes and is the leading cause of end stage renal disease. With the rising incidences of obesity, diabetes is becoming an epidemic in the African American community. While efforts are being made to develop biomarkers for early diagnosis of DN, participation of African American men in these studies has been minimal. By partnering with a community clinic that serves uninsured and underinsured patients, many of whom are from minority ethnic groups, we were able to engage diabetic African American men in biomedical research and collect biological samples for development of biomarkers of diabetic nephropathy. These samples will be subjected to proteomic and metabolomics analysis to identify biomarkers of diabetic nephropathy representative of the African American male population. Support or Funding Information NIH/NIHMD #U54MD008621 Sub‐Award # HU‐14004NIH/NIHMD U54MD008621 Sub‐Award # HU‐150006
Abstract Background Upper gastrointestinal (GI) disorders and abdominal pain afflict between 12 and 30% of the worldwide population and research suggests these conditions are linked to the gut microbiome. Although large-intestine microbiota have been linked to several GI diseases, the microbiota of the human small intestine and its relation to human disease has been understudied. The small intestine is the major site for immune surveillance in the gut, and compared with the large intestine, it has greater than 100 times the surface area and a thinner and more permeable mucus layer. Results Using quantitative sequencing, we evaluated total and taxon-specific absolute microbial loads from 250 duodenal-aspirate samples and 21 paired duodenum-saliva samples from participants in the REIMAGINE study. Log-transformed total microbial loads spanned 5 logs and were normally distributed. Paired saliva-duodenum samples suggested potential transmission of oral microbes to the duodenum, including organisms from the HACEK group. Several taxa, including Klebsiella, Escherichia , Enterococcus , and Clostridium , seemed to displace strict anaerobes common in the duodenum, so we refer to these taxa as disruptors. Disruptor taxa were enriched in samples with high total microbial loads and in individuals with small intestinal bacterial overgrowth (SIBO). Absolute loads of disruptors were associated with more severe GI symptoms, highlighting the value of absolute taxon quantification when studying small-intestine health and function. Conclusion This study provides the largest dataset of the absolute abundance of microbiota from the human duodenum to date. The results reveal a clear relationship between the oral microbiota and the duodenal microbiota and suggest an association between the absolute abundance of disruptor taxa, SIBO, and the prevalence of severe GI symptoms.
Diabetic nephropathy (DN) is the leading cause of end stage renal disease, and is associated with high morbidity and mortality rates. The pathophysiology of DN includes both glomerular and tubulointerstitial damage. Meprins are metalloproteinases which are most abundantly expressed in the brush border membranes of proximal kidney tubules. Meprins are also expressed in leukocytes (monocytes and macrophages) and podocytes. Meprins have been implicated in the pathology of acute and chronic kidney injury. Single nucleotide polymorphisms (SNPs) in the meprin β gene were associated in human DN in the Pima Indians, suggesting a role for meprins in the pathophysiology of DN. The current study was done to determine the mechanisms by which meprins modulate the progression of DN in mice. Low dose streptozotocin (STZ) was used to induce type 1 diabetes in 8 week old male wild‐type (WT) and meprin β knockout mice (βKO) on a C57BL/6 background. Control mice were injected with sodium citrate buffer. Urine and blood samples were collected at 4 and 8 weeks post STZ injection. The mice were sacrificed at 8 weeks post‐STZ injection and kidney tissue harvested for analysis using metabolomics and proteomic approaches. Enzyme‐linked immunosorbent assays (ELISA) were used to determine the levels of two tubular kidney injury markers, neutrophil gelatinase associated lipocalin (NGAL) and kidney injury molecule 1 (KIM‐1). When compared to non‐diabetic controls, meprin β KO mice with STZ‐induced type 1 diabetes had significantly higher levels of plasma NGAL at 4 weeks but not at 8 weeks post STZ injection. The levels of urinary KIM‐1 were significantly higher in meprin βKO mice at both 4 weeks and 8 weeks when compared to their wild‐type counterparts. Taken together, the data suggest that presence of meprin β partially protects mice from the tubular kidney injury associated with diabetes. This is in contrast to outcomes in ischemia/reperfusion induced acute kidney injury where meprin deficiency was previously shown to be protective. Further analysis will determine the kidney meprin targets and metabolic pathways which play a role in the progression of DN. Support or Funding Information NIH/NIGMS # SC3GM102049
Diabetes is the leading cause of chronic kidney disease. African Americans are disproportionately burdened by diabetic kidney disease (DKD) and end stage renal disease (ESRD). Disparities in DKD have genetic and socioeconomic components, yet its prevalence in African Americans is not adequately studied. The current study used multiple biomarkers of DKD to evaluate undiagnosed DKD in uninsured and underinsured African American men in Greensboro, North Carolina. Participants consisted of three groups: nondiabetic controls, diabetic patients without known kidney disease, and diabetic patients with diagnosed DKD. Our data reveal undiagnosed kidney injury in a significant proportion of the diabetic patients, based on levels of both plasma and urinary biomarkers of kidney injury, namely, urinary albumin to creatinine ratio, kidney injury molecule-1, cystatin C, and neutrophil gelatinase-associated lipocalin. We also found that the urinary levels of meprin A, meprin B, and two kidney meprin targets (nidogen-1 and monocytes chemoattractant protein-1) increased with severity of kidney injury, suggesting a potential role for meprin metalloproteases in the pathophysiology of DKD in this subpopulation. The study also demonstrates a need for more aggressive tests to assess kidney injury in uninsured diabetic patients to facilitate early diagnosis and targeted interventions that could slow progression to ESRD.
Sepsis is a systematic inflammatory response syndrome which accounts for 51% of reported cases of acute kidney injuries (AKI) in intensive care units (ICU) and is associated with high morbidity and mortality. The high mortality rate associated with AKI is partly due to the fact that underlying mechanisms are not fully understood. Meprins are metalloproteinases of the astacin family which are most highly expressed in the brush border membranes of proximal kidney tubules. Meprins are also expressed in leukocytes (monocytes and macrophages). Meprins have been shown to play a role in the pathophysiology of acute kidney injury and in leukocyte infiltration. This study was designed to determine how meprin expression impacts the pathology of AKI induced by sepsis. To this end, cecal ligation and puncture (CLP) was used to induce multi‐bacterial sepsis in 12‐week old wild‐type (WT) and meprin β knockout (βKO) mice on a C57BL/6 background. The mice were sacrificed at 18 h post‐CLP. Blood samples were collected by tail nicking at 0 h and by cardiac puncture at 18 h post‐CLP. For biochemical assessment of kidney injury, enzyme linked immunosorbent assays were used to measure plasma neutrophil gelatinase‐associated lipocalin (NGAL) and cystatin C levels. The 18 h post‐CLP survival rates were comparable for WT and meprin βKO mice. The levels of cystatin C at 18 h post‐CLP were significantly higher in both genotypes for mice subjected to CLP when compared to sham operated controls (p≤0.0001). More importantly, WT mice subjected to CLP had significantly higher levels of plasma cystatin C when compared to the meprin βKO counterparts. Furthermore, there was a significant increase in NGAL levels in WT mice subjected to CLP but not in meprin βKO counterparts (p≤0.05). The results indicate that meprin β plays a detrimental role in sepsis‐induced acute kidney injury. The data further suggests that when compared to NGAL, cystatin C is a better biomarker for kidney injury induced by sepsis. Support or Funding Information This study was supported by the National Institutes of Health (NIH)/National Institute of General Medical Sciences (NIGMS) under Award # SC3GM102049 to Elimelda Moige Ongeri.
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