| 1. |
- Bachmann, Radu, et al.
(författare)
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Akkermansia muciniphila Reduces Peritonitis and Improves Intestinal Tissue Wound Healing after a Colonic Transmural Defect by a MyD88-Dependent Mechanism
- 2022
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Ingår i: Cells. - : MDPI. - 2073-4409. ; 11:17
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Tidskriftsartikel (refereegranskat)abstract
- Anastomotic leakage is a major complication following colorectal surgery leading to peritonitis, complications, and mortality. Akkermansia muciniphila has shown beneficial effects on the gut barrier function. Whether A. muciniphila reduces peritonitis and mortality during colonic leakage is unknown. Whether A. muciniphila can directly modulate the expression of genes in the colonic mucosa in humans has never been studied. We investigated the effects of a pretreatment (14 days) with live A. muciniphila prior to surgical colonic perforation on peritonitis, mortality, and wound healing. We used mice with an inducible intestinal-epithelial-cell-specific deletion of MyD88 (IEC-MyD88 KO) to investigate the role of the innate immune system in this context. In a proof-of-concept pilot study, healthy humans were exposed to A. muciniphila for 2 h and colonic biopsies taken before and after colonic instillation for transcriptomic analysis. Seven days after colonic perforation, A.-muciniphila-treated mice had significantly lower mortality and severity of peritonitis. This effect was associated with significant improvements of wound histological healing scores, higher production of IL22, but no changes in the mucus layer thickness or genes involved in cell renewal, proliferation, or differentiation. All these effects were abolished in IEC-MyD88 KO mice. Finally, human subjects exposed to A. muciniphila exhibited an increased level of the bacterium at the mucus level 2 h after instillation and significant changes in the expression of different genes involved in the regulation of cell cycling, gene transcription, immunity, and inflammation in their colonic mucosa. A. muciniphila improves wound healing during transmural colonic wall defect through mechanisms possibly involving IL22 signaling and requiring MyD88 in the intestinal cells. In healthy humans, colonic administration of A. muciniphila is well tolerated and changes the expression of genes involved in the immune pathways.
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| 2. |
- Bron, Peter A., et al.
(författare)
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Can probiotics modulate human disease by impacting intestinal barrier function?
- 2017
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Ingår i: British Journal of Nutrition. - Cambridge, United Kingdom : Cambridge University Press. - 0007-1145 .- 1475-2662. ; 117:1, s. 93-107
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Forskningsöversikt (refereegranskat)abstract
- Intestinal barrier integrity is a prerequisite for homeostasis of mucosal function, which is balanced to maximise absorptive capacity, while maintaining efficient defensive reactions against chemical and microbial challenges. Evidence is mounting that disruption of epithelial barrier integrity is one of the major aetiological factors associated with several gastrointestinal diseases, including infection by pathogens, obesity and diabetes, necrotising enterocolitis, irritable bowel syndrome and inflammatory bowel disease. The notion that specific probiotic bacterial strains can affect barrier integrity fuelled research in which in vitro cell lines, animal models and clinical trials are used to assess whether probiotics can revert the diseased state back to homeostasis and health. This review catalogues and categorises the lines of evidence available in literature for the role of probiotics in epithelial integrity and, consequently, their beneficial effect for the reduction of gastrointestinal disease symptoms.
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| 3. |
- Caesar, Robert, 1973, et al.
(författare)
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Gut-derived lipopolysaccharide augments adipose macrophage accumulation but is not essential for impaired glucose or insulin tolerance in mice
- 2012
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Ingår i: Gut. - : BMJ. - 0017-5749 .- 1468-3288. ; 61:12, s. 1701-1707
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Tidskriftsartikel (refereegranskat)abstract
- Background Obesity is associated with accumulation of macrophages in white adipose tissue (WAT), which contribute to the development of insulin resistance. Germ-free (GF) mice have reduced adiposity and are protected against diet-induced obesity, Objective To investigate whether the gut microbiota and, specifically, gut-derived lipopolysaccharide (LPS) promote WAT inflammation and contribute to impaired glucose metabolism. Method Macrophage composition and expression of proinflammatory and anti-inflammatory markers were compared in WAT of GF, conventionally raised and Escherichia coli-monocolonised mice. Additionally, glucose and insulin tolerance in these mice was determined. Results The presence of a gut microbiota resulted in impaired glucose metabolism and increased macrophage accumulation and polarisation towards the proinflammatory M1 phenotype in WAT. Monocolonisation of GF mice for 4 weeks with E. coli W3110 or the isogenic strain MLK1067 (which expresses LPS with reduced immunogenicity) resulted in impaired glucose and insulin tolerance and promoted M1 polarisation of CD11b cells in WAT. However, colonisation with E. coli W3110 but not MLK1067 promoted macrophage accumulation and upregulation of proinflammatory and anti-inflammatory gene expression as well as JNK phosphorylation. Conclusion Gut microbiota induced LPS-dependent macrophage accumulation in WAT, whereas impairment of systemic glucose metabolism was not dependent on LPS. These results indicate that macrophage accumulation in WAT does not always correlate with impaired glucose metabolism.
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| 4. |
- Kallin, Anders, et al.
(författare)
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SREBP-1 regulates the expression of heme oxygenase 1 and the phosphatidylinositol-3 kinase regulatory subunit p55 gamma
- 2007
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Ingår i: Journal of Lipid Research. - 0022-2275 .- 1539-7262. ; 48:7, s. 1628-1636
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Tidskriftsartikel (refereegranskat)abstract
- Sterol-regulatory element binding proteins (SREBPs) control the expression of genes involved in fatty acid and cholesterol biosynthesis. Using microarrays, we observed that mature SREBP-1 also induced the expression of genes unrelated to lipid metabolism, such as heme oxygenase 1 (HMOX1), plasma glutathione peroxidase, the phosphatidylinositol-3 kinase regulatory subunit p55 gamma, synaptic vesicle glycoprotein 2A, and COTE1. The expression of these genes was repressed upon addition of sterols, which block endogenous SREBP cleavage, and was induced by the statin drug mevinolin. Stimulation of fibroblasts with platelet-derived growth factor, which activates SREBP-1, had a similar effect. Fasted mice that were refed with a high-carbohydrate diet presented an increased expression of HMOX1 and p55 gamma in the liver. Overall, the transcriptional signature of SREBP-1 in fibroblasts stimulated by growth factors was very similar to that described in liver cells. We analyzed the HMOX1 promoter and found one SREBP binding site of the E-box type, which was required for regulation by SREBP-1a and SREBP-1c but was insensitive to SREBP-2. In conclusion, our data suggest that SREBP-1 regulates the expression of stress response and signaling genes, which could contribute to the metabolic response to insulin and growth factors in various tissues.
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| 5. |
- König, Julia, 1983-, et al.
(författare)
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Human Intestinal Barrier Function in Health and Disease
- 2016
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Ingår i: Clinical and Translational Gastroenterology. - New York : Nature Publishing Group. - 2155-384X. ; 7:10
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Forskningsöversikt (refereegranskat)abstract
- The gastrointestinal tract consists of an enormous surface area that is optimized to efficiently absorb nutrients, water, and electrolytes from food. At the same time, it needs to provide a tight barrier against the ingress of harmful substances, and protect against a reaction to omnipresent harmless compounds. A dysfunctional intestinal barrier is associated with various diseases and disorders. In this review, the role of intestinal permeability in common disorders such as infections with intestinal pathogens, inflammatory bowel disease, irritable bowel syndrome, obesity, celiac disease, non-celiac gluten sensitivity, and food allergies will be discussed. In addition, the effect of the frequently prescribed drugs proton pump inhibitors and non-steroidal anti-inflammatory drugs on intestinal permeability, as well as commonly used methods to assess barrier function will be reviewed.
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| 6. |
- Muccioli, Giulio G, et al.
(författare)
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The endocannabinoid system links gut microbiota to adipogenesis.
- 2010
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Ingår i: Molecular systems biology. - : EMBO. - 1744-4292. ; 6:392
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Tidskriftsartikel (refereegranskat)abstract
- Obesity is characterised by altered gut microbiota, low-grade inflammation and increased endocannabinoid (eCB) system tone; however, a clear connection between gut microbiota and eCB signalling has yet to be confirmed. Here, we report that gut microbiota modulate the intestinal eCB system tone, which in turn regulates gut permeability and plasma lipopolysaccharide (LPS) levels. The impact of the increased plasma LPS levels and eCB system tone found in obesity on adipose tissue metabolism (e.g. differentiation and lipogenesis) remains unknown. By interfering with the eCB system using CB(1) agonist and antagonist in lean and obese mouse models, we found that the eCB system controls gut permeability and adipogenesis. We also show that LPS acts as a master switch to control adipose tissue metabolism both in vivo and ex vivo by blocking cannabinoid-driven adipogenesis. These data indicate that gut microbiota determine adipose tissue physiology through LPS-eCB system regulatory loops and may have critical functions in adipose tissue plasticity during obesity.
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| 7. |
- Paone, Paola, et al.
(författare)
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Human milk oligosaccharide 2'-fucosyllactose protects against high-fat diet-induced obesity by changing intestinal mucus production, composition and degradation linked to changes in gut microbiota and faecal proteome profiles in mice.
- 2024
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Ingår i: Gut. - 0017-5749 .- 1468-3288.
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Tidskriftsartikel (refereegranskat)abstract
- Objective: To decipher the mechanisms by which the major human milk oligosaccharide (HMO), 2'-fucosyllactose (2'FL), can affect body weight and fat mass gain on high-fat diet (HFD) feeding in mice. We wanted to elucidate whether 2'FL metabolic effects are linked with changes in intestinal mucus production and secretion, mucin glycosylation and degradation, as well as with the modulation of the gut microbiota, faecal proteome and endocannabinoid (eCB) system. Results: 2'FL supplementation reduced HFD-induced obesity and glucose intolerance. These effects were accompanied by several changes in the intestinal mucus layer, including mucus production and composition, and gene expression of secreted and transmembrane mucins, glycosyltransferases and genes involved in mucus secretion. In addition, 2'FL increased bacterial glycosyl hydrolases involved in mucin glycan degradation. These changes were linked to a significant increase and predominance of bacterial genera Akkermansia and Bacteroides, different faecal proteome profile (with an upregulation of proteins involved in carbon, amino acids and fat metabolism and a downregulation of proteins involved in protein digestion and absorption) and, finally, to changes in the eCB system. We also investigated faecal proteomes from lean and obese humans and found similar changes observed comparing lean and obese mice. Conclusion: Our results show that the HMO 2'FL influences host metabolism by modulating the mucus layer, gut microbiota and eCB system and propose the mucus layer as a new potential target for the prevention of obesity and related disorders.
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| 8. |
- Shen, Melissa, et al.
(författare)
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Three of a Kind: Control of the Expression of Liver-Expressed Antimicrobial Peptide 2 (LEAP2) by the Endocannabinoidome and the Gut Microbiome
- 2022
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Ingår i: MOLECULES. - : MDPI AG. - 1420-3049. ; 27:1
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Tidskriftsartikel (refereegranskat)abstract
- The endocannabinoidome (expanded endocannabinoid system, eCBome)-gut microbiome (mBIome) axis plays a fundamental role in the control of energy intake and processing. The liver-expressed antimicrobial peptide 2 (LEAP2) is a recently identified molecule acting as an antagonist of the ghrelin receptor and hence a potential effector of energy metabolism, also at the level of the gastrointestinal system. Here we investigated the role of the eCBome-gut mBIome axis in the control of the expression of LEAP2 in the liver and, particularly, the intestine. We confirm that the small intestine is a strong contributor to the circulating levels of LEAP2 in mice, and show that: (1) intestinal Leap2 expression is profoundly altered in the liver and small intestine of 13 week-old germ-free (GF) male mice, which also exhibit strong alterations in eCBome signaling; fecal microbiota transfer (FMT) from conventionally raised to GF mice completely restored normal Leap2 expression after 7 days from this procedure; in 13 week-old female GF mice no significant change was observed; (2) Leap2 expression in organoids prepared from the mouse duodenum is elevated by the endocannabinoid noladin ether, whereas in human Caco-2/15 epithelial intestinal cells it is elevated by PPAR gamma activation by rosiglitazone; (3) Leap2 expression is elevated in the ileum of mice with either high-fat diet-or genetic leptin signaling deficiency-(i.e., ob/ob and db/db mice) induced obesity. Based on these results, we propose that LEAP2 originating from the small intestine may represent a player in eCBome- and/or gut mBIome-mediated effects on food intake and energy metabolism.
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| 9. |
- von Hertzen, Leena, et al.
(författare)
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Helsinki alert of biodiversity and health
- 2015
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Ingår i: Annals of Medicine. - : Informa UK Limited. - 1365-2060 .- 0785-3890. ; 47:3, s. 218-225
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Forskningsöversikt (refereegranskat)abstract
- Urban living in built environments, combined with the use of processed water and food, may not provide the microbial stimulation necessary for a balanced development of immune function. Many chronic inflammatory disorders, including allergic, autoimmune, metabolic, and even some behavioural disorders, are linked to alteration in the human commensal microbiota. Sedentary lifestyle is associated with reduced exposure to a broad spectrum of environmental micro-organisms and surplus energy balance, both risk factors of chronic inflammatory disorders. According to the Biodiversity Hypothesis, an environment with diverse macrobiota and microbiota modifies and enriches the human microbiota, which in turn is crucial in the development and maintenance of appropriate immune function. These issues were discussed in the symposium 'Chronic Inflammation, Lifestyle and Environment ', held in Helsinki, 20 - 22 August 2014, under the sponsorship of the Yrjo Jahnsson Foundation. This paper briefly outlines the recent findings in the context of the environment, lifestyle, and health; discusses the forces that undermine immune tolerance in urban environments; and highlights the possibilities to restore broken immune tolerance among urban dwellers, summarizing the main messages in four statements and calling for actions to combat major public health threats.
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| 10. |
- 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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