INTRODUCTION: Nonalcoholic fatty liver disease (NAFLD) is an obesity-related disorder that is rapidly increasing in incidence and is considered the hepatic manifestation of the metabolic syndrome. The gut microbiome plays a role in metabolism and maintaining gut barrier integrity. Studies have found differences in the microbiota between NAFLD and healthy patients and increased intestinal permeability in patients with NAFLD. Fecal microbiota transplantation (FMT) can be used to alter the gut microbiome. It was hypothesized that an FMT from a thin and healthy donor given to patients with NAFLD would improve insulin resistance (IR), hepatic proton density fat fraction (PDFF), and intestinal permeability. METHODS: Twenty-one patients with NAFLD were recruited and randomized in a ratio of 3:1 to either an allogenic (n = 15) or an autologous (n = 6) FMT delivered by using an endoscope to the distal duodenum. IR was calculated by HOMA-IR, hepatic PDFF was measured by MRI, and intestinal permeability was tested using the lactulose:mannitol urine test. Additional markers of metabolic syndrome and the gut microbiota were examined. Patient visits occurred at baseline, 2, 6 weeks, and 6 months post-FMT. RESULTS: There were no significant changes in HOMA-IR or hepatic PDFF in patients who received the allogenic or autologous FMT. Allogenic FMT patients with elevated small intestinal permeability (>0.025 lactulose:mannitol, n = 7) at baseline had a significant reduction 6 weeks after allogenic FMT. DISCUSSION: FMT did not improve IR as measured by HOMA-IR or hepatic PDFF but did have the potential to reduce small intestinal permeability in patients with NAFLD.
Hutchinson-Gilford progeria syndrome (HGPS) is an extremely rare genetic disorder that causes premature, rapid aging shortly after birth. Recently, de novo point mutations in the Lmna gene have been found in individuals with HGPS. Lmna encodes lamin A and C, the A-type lamins, which are an important structural component of the nuclear envelope. The most common HGPS mutation is located at codon 608 (G608G). This mutation creates a cryptic splice site within exon 11, which deletes a proteolytic cleavage site within the expressed mutant lamin A. Incomplete processing of prelamin A results in nuclear lamina abnormalities that can be observed in immunofluorescent studies of HGPS cells. Mouse models, such as Lmna knockout, Zmpste24 knockout, and Lmna L530P knockin will help the study of progeria. Lmna mutations have also recently been found in patients with atypical forms of progeria. The discovery of the HGPS mutations brings the total number of diseases caused by mutant Lmna to nine, underscoring the astonishing spectrum of laminopathies. Future research into HGPS could also provide important clues about the general process of aging and aging-related diseases.
Very high intakes of foods rich in soluble fiber lower blood cholesterol levels even when the main dietary modifiers of blood lipids--namely, saturated fat and cholesterol--are greatly reduced.
The underlying disease mechanisms likely include mutation effects on the nuclear envelope and on interactions between lamins and transcription factors. At the same time, can a simple genomic attribute -- for instance, mutation position within the LMNA sequence -- predict the complex phenotypic effects? In order to assess this, hierarchical cluster analysis (HCA) was used for assembling 16 laminopathies into two classes based on organ system involvement. Ninety-one reported causative LMNA mutations in these laminopathies were then classified according to their position upstream or downstream of the nuclear localization signal sequence (NLS). Contingency analysis was used in order to assess a non-random relationship between HCA laminopathy class and LMNA mutation position relative to the NLS. HCA laminopathy class and LMNA mutation position were strongly associated (p < 0.0001). The odds ratio for general association between an HCA class 1 laminopathy and a mutation upstream of the NLS sequence was 8.4 (95% confidence interval = 2.9 - 24.7, p < 0.0001). Although the underlying molecular biology is complex, the findings support the hypothesis that laminopathy phenotype and LMNA genotype are non-randomly associated. Furthermore, HCA may be a tool to help with the study of phenotype - genotype associations, or 'phenomics'.
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