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- Plassais, Jocelyn, et al.
(författare)
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Natural and human-driven selection of a single non-coding body size variant in ancient and modern canids
- 2022
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Ingår i: Current Biology. - : Elsevier BV. - 0960-9822 .- 1879-0445. ; 32:4, s. 889-897
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Tidskriftsartikel (refereegranskat)abstract
- Domestic dogs (Canis lupus familiaris) are the most variable-sized mammalian species on Earth, displaying a 40-fold size difference between breeds.1 Although dogs of variable size are found in the archeological record,2, 3, 4 the most dramatic shifts in body size are the result of selection over the last two centuries, as dog breeders selected and propagated phenotypic extremes within closed breeding populations.5 Analyses of over 200 domestic breeds have identified approximately 20 body size genes regulating insulin processing, fatty acid metabolism, TGFβ signaling, and skeletal formation.6, 7, 8, 9, 10 Of these, insulin-like growth factor 1 (IGF1) predominates, controlling approximately 15% of body size variation between breeds.8 The identification of a functional mutation associated with IGF1 has thus far proven elusive.6,10,11 Here, to identify and elucidate the role of an ancestral IGF1 allele in the propagation of modern canids, we analyzed 1,431 genome sequences from 13 species, including both ancient and modern canids, thus allowing us to define the evolutionary history of both ancestral and derived alleles at this locus. We identified a single variant in an antisense long non-coding RNA (IGF1-AS) that interacts with the IGF1 gene, creating a duplex. While the derived mutation predominates in both modern gray wolves and large domestic breeds, the ancestral allele, which predisposes to small size, was common in small-sized breeds and smaller wild canids. Our analyses demonstrate that this major regulator of canid body size nearly vanished in Pleistocene wolves, before its recent resurgence resulting from human-imposed selection for small-sized breed dogs.
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- Wells, Jerry M., et al.
(författare)
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Homeostasis of the Gut Barrier and Potential Biomarkers
- 2017
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Ingår i: American Journal of Physiology - Gastrointestinal and Liver Physiology. - Bethesda, USA : American Physiological Society. - 0193-1857 .- 1522-1547. ; 312:3, s. G171-G193
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Tidskriftsartikel (refereegranskat)abstract
- The gut barrier plays a crucial role by spatially compartmentalizing bacteria to the lumen through the production of secreted mucus and is fortified by the production of sIgA and antimicrobial peptides and proteins. With exception of sIgA the expression of these protective barrier factors is largely controlled by innate immune recognition of microbial molecular ligands. Several specialized adaptations and checkpoints are operating in the mucosa to scale the immune response according to the threat and prevent overreaction to the trillions of symbionts inhabiting the human intestine. A healthy microbiota plays a key role influencing epithelial barrier functions. However, perturbation of gut barrier homeostasis can lead to increased inflammatory signaling, increased epithelial permeability and dysbiosis of the microbiota, which are recognized to play a role in the pathophysiology of gastrointestinal disorders. Additionally, the gut-brain signaling may be affected by prolonged mucosal immune activation, leading to increased afferent sensory signaling and abdominal symptoms. In turn, neuronal mechanisms can affect the intestinal barrier partly by activation of the HPA-axis and both mast cell-dependent as well as mast cell- independent mechanisms. Several biomarkers have been used to measure gut permeability and loss of barrier integrity in patients but there remains a need to explore their use in assessing impact of nutritional factors on gut barrier function. Future studies should aim to establish normal ranges of the available biomarkers and their predictive value for gut health in human cohorts.
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- Bennet, Sean, et al.
(författare)
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Altered intestinal antibacterial gene expression response profile in irritable bowel syndrome is linked to bacterial composition and immune activation
- 2018
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Ingår i: Neurogastroenterology and Motility. - : Wiley. - 1350-1925. ; 30:12
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Tidskriftsartikel (refereegranskat)abstract
- Background Immune activity and gut microbiota may impact the pathophysiology of irritable bowel syndrome (IBS). We aimed to determine whether antibacterial gene expression of immune activity-defined IBS patients differed compared to healthy subjects (HS) and ulcerative colitis (UC) patients and whether antibacterial profiles reflected gut microbiota composition and IBS symptoms. Methods Key Results Expression of 84 antibacterial genes in biopsies from HS, IBS patients (clustered according to immune activity (systemic and intestinal cytokines): immunonormal or immunoactive), and UC patients was assessed by Human Antibacterial Response RT2 Profiler PCR Array. In IBS patients, 16S rRNA gene sequencing of fecal and mucosal bacteria was performed and symptom pattern and severity were assessed. Intestinal antibacterial gene expression profiles differed between IBS patients (n = 31) and HS (n = 16), but did not differ between IBS subgroups based on bowel habit predominance or symptom severity. Based on previously identified IBS clusters, IBS patients with normal (n = 15) and enhanced immune activity (n = 16) had clearly separate antibacterial gene expression profiles from active UC patients (n = 12) and differed compared to each other and to HS. The differences in antibacterial gene expression profiles between immunonormal and immunoactive IBS patients were also reflected in distinct fecal and mucosal microbiota composition profiles, but not in symptom pattern or severity. Conclusions & Inferences This study demonstrates an altered antibacterial gene expression profile in IBS patients compared to HS and UC patients. While not linked to symptoms, immune activity-defined IBS clusters showed different intestinal antibacterial gene expression and distinct fecal and mucosal bacterial profiles.
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- Derrien, M., et al.
(författare)
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Fasting breath H-2 and gut microbiota metabolic potential are associated with the response to a fermented milk product in irritable bowel syndrome
- 2019
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Ingår i: Plos One. - : Public Library of Science (PLoS). - 1932-6203. ; 14:4
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Tidskriftsartikel (refereegranskat)abstract
- Objectives Aim of this study was to assess the effect of a fermented milk product containing Bifidobacterium lactis CNCM I-2494 (FMP) on gastrointestinal (GI) symptoms and exhaled H-2 and CH4 during a nutrient and lactulose challenge in patients with irritable bowel syndrome (IBS). We included 125 patients with IBS (Rome III). Fasted subjects were served a 400ml liquid test meal containing 25g lactulose. The intensity of eight GI symptoms and the amount of exhaled H-2 and CH4 were assessed before and during 4h after meal intake. The challenge was repeated after 14 days consumption of FMP or a control product in a double-blind, randomized, parallel design. The metabolic potential of fecal microbiota was profiled using 16S MiSeq analysis of samples obtained before and after the intervention. 106 patients with IBS were randomized. No difference between FMP or control groups was found on GI symptoms or breath H-2 and CH4 in the whole cohort. A post-hoc analysis in patients stratified according to their fasting H-2 levels showed that in high H-2 producers (fasting H-2 level >= 10ppm, n = 35), FMP consumption reduced fasting H-2 levels (p = 0.003) and H-2 production during the challenge (p = 0.002) and tended to decrease GI discomfort (p = 0.05) vs. control product. The Prevotella /Bacteroides metabolic potential at baseline was higher in high H-2 producers (p<0.05) vs. low H-2 producers and FMP consumption reduced this ratio (p<0.05) vs. control product. The response to a fermented milk product containing Bifidobacterium lactis CNCM I-2494 (FMP) in patients with IBS seems to be associated with the metabolic potential of the gut microbiota.
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