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Publications (10 of 86) Show all publications
Liu, H., Waldén, T., Cai, D., Ahl, D., Bertilsson, S., Phillipson, M., . . . Holm, L. (2019). Dietary Fiber in Bilberry Ameliorates Pre-Obesity Events in Rats by Regulating Lipid Depot, Cecal Short-Chain Fatty Acid Formation and Microbiota Composition. Nutrients, 11(6), Article ID 1350.
Open this publication in new window or tab >>Dietary Fiber in Bilberry Ameliorates Pre-Obesity Events in Rats by Regulating Lipid Depot, Cecal Short-Chain Fatty Acid Formation and Microbiota Composition
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2019 (English)In: Nutrients, ISSN 2072-6643, E-ISSN 2072-6643, Vol. 11, no 6, article id 1350Article in journal (Refereed) Published
Abstract [en]

Obesity is linked to non-alcoholic fatty liver disease and risk factors associated to metabolic syndrome. Bilberry (Vaccinium myrtillus) that contains easily fermentable fiber may strengthen the intestinal barrier function, attenuate inflammation and modulate gut microbiota composition, thereby prevent obesity development. In the current study, liver lipid metabolism, fat depot, cecal and serum short-chain fatty acids (SCFAs) and gut microbiome were evaluated in rats fed bilberries in a high-fat (HFD + BB) or low-fat (LFD + BB) setting for 8 weeks and compared with diets containing equal amount of fiber resistant to fermentation (cellulose, HFD and LFD). HFD fed rats did not obtain an obese phenotype but underwent pre-obesity events including increased liver index, lipid accumulation and increased serum cholesterol levels. This was linked to shifts of cecal bacterial community and reduction of major SCFAs. Bilberry inclusion improved liver metabolism and serum lipid levels. Bilberry inclusion under either LFD or HFD, maintained microbiota homeostasis, stimulated interscapular-brown adipose tissue depot associated with increased mRNA expression of uncoupling protein-1; enhanced SCFAs in the cecum and circulation; and promoted butyric acid and butyrate-producing bacteria. These findings suggest that bilberry may serve as a preventative dietary measure to optimize microbiome and associated lipid metabolism during or prior to HFD.

Place, publisher, year, edition, pages
MDPI, 2019
Keywords
adipose tissue, bilberry, butyrate-producing bacteria, gut microbiota, hepatic steatosis, lipid metabolism, obesity-resistant, fermentation, prebiotic dietary fiber, short-chain fatty acids
National Category
Nutrition and Dietetics
Identifiers
urn:nbn:se:uu:diva-390634 (URN)10.3390/nu11061350 (DOI)000474936700156 ()31208043 (PubMedID)
Funder
Swedish Research Council Formas, 222-2006-454Swedish Research CouncilSwedish Society for Medical Research (SSMF)
Available from: 2019-08-21 Created: 2019-08-21 Last updated: 2019-08-21Bibliographically approved
Sedin, J., Giraud, A., Steiner, S. E., Ahl, D., Persson, A. E., Melican, K., . . . Phillipson, M. (2019). High Resolution Intravital Imaging of the Renal Immune Response to Injury and Infection in Mice. Frontiers in Immunology, 10, Article ID 2744.
Open this publication in new window or tab >>High Resolution Intravital Imaging of the Renal Immune Response to Injury and Infection in Mice
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2019 (English)In: Frontiers in Immunology, ISSN 1664-3224, E-ISSN 1664-3224, Vol. 10, article id 2744Article in journal (Refereed) Published
Abstract [en]

We developed an experimental set up that enables longitudinal studies of immune cell behavior in situ in the challenged as well as unchallenged kidney of anesthetized mice over several hours. Using highly controlled vacuum to stabilize the kidney, the superficial renal cortex could continuously be visualized with minimal disruption of the local microenvironment. No visible changes in blood flow or neutrophils and macrophages numbers were observed after several hours of visualizing the unchallenged kidney, indicating a stable tissue preparation without apparent tissue damage. Applying this set up to monocyte/macrophage (CX(3)CR1(GFP/+)) reporter mice, we observed the extensive network of stellate-shaped CX(3)CR1 positive cells (previously identified as renal mononuclear phagocytes). The extended dendrites of the CX(3)CR1 positive cells were found to bridge multiple capillaries and tubules and were constantly moving. Light induced sterile tissue injury resulted in rapid neutrophil accumulation to the site of injury. Similarly, microinfusion of uropathogenic Escherichia coli into a single nephron induced a rapid and massive recruitment of neutrophils to the site of infection, in addition to active bacterial clearance by neutrophils. In contrast, the kidney resident mononuclear phagocytes were observed to not increase in numbers or migrate toward the site of injury or infection. In conclusion, this model allows for longitudinal imaging of responses to localized kidney challenges in the mouse.

Place, publisher, year, edition, pages
Frontiers Media S.A., 2019
Keywords
intravital, renal infection, neutrophils, macrophages, mononuclear phagocytes, sterile injury
National Category
Immunology in the medical area Immunology
Identifiers
urn:nbn:se:uu:diva-402374 (URN)10.3389/fimmu.2019.02744 (DOI)000504216500001 ()31921099 (PubMedID)
Funder
Swedish Foundation for Strategic Research Swedish Research Council, 2018-02552Knut and Alice Wallenberg FoundationRagnar Söderbergs stiftelseNovo Nordisk
Available from: 2020-01-29 Created: 2020-01-29 Last updated: 2020-01-29Bibliographically approved
Liu, H., Waldén, T., Ahl, D., Nyman, M., Bertilsson, S., Phillipson, M. & Holm, L. (2019). High-Fat Diet Enriched with Bilberry Modifies Colonic Mucus Dynamics and Restores Marked Alterations of Gut Microbiome in Rats. Molecular Nutrition & Food Research, 63(20), Article ID 1900117.
Open this publication in new window or tab >>High-Fat Diet Enriched with Bilberry Modifies Colonic Mucus Dynamics and Restores Marked Alterations of Gut Microbiome in Rats
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2019 (English)In: Molecular Nutrition & Food Research, ISSN 1613-4125, E-ISSN 1613-4133, Vol. 63, no 20, article id 1900117Article in journal (Refereed) Published
Abstract [en]

Scope Emerging evidence suggests that high-fat diet (HFD) is associated with gut microbiome dysbiosis and related disorders. Bilberry is a prebiotic food component with known health benefits. Herein, the dynamics of the colonic mucus layer and microbiome during HFD and bilberry supplementation are addressed. Methods and results The effects on colonic mucus thickness in vivo and gut microbiota composition (Illumina sequencing, quantitative real-time PCR) are investigated in young rats fed a low-fat diet or HFD with or without bilberries for 8 weeks (n = 8). HFD induced significant local colonic effects, despite no observed weight gain or systemic inflammation, as HFD causes epithelial upregulation of inducible nitric oxide synthase, which is counteracted by bilberry. The firmly adherent mucus layer becomes thicker and the mRNA levels of Muc2 and Tff3 are increased by HFD with or without bilberry. In parallel, HFD reduced the colonic abundance of mucolytic bacterial species Akkermansia muciniphila and Bacteroides spp. Finally, bilberry prevents HFD-induced microbiota dysbiosis, including expansion of pathobionts, for example, Enterobacteriaceae. Conclusion HFD expand firmly adherent mucus thickness and reduce mucus-foraging bacteria populations in the colon prior to obesity. Enriching HFD with bilberry protects against intestinal inflammation and marked microbiota encroachment.

Place, publisher, year, edition, pages
WILEY, 2019
Keywords
Akkermansia muciniphila, bilberries, gut microbiome, high-fat diet, mucus
National Category
Nutrition and Dietetics
Identifiers
urn:nbn:se:uu:diva-398866 (URN)10.1002/mnfr.201900117 (DOI)000480470800001 ()31336403 (PubMedID)
Funder
Swedish Research CouncilSwedish Research Council Formas, 2006-454Swedish Society for Medical Research (SSMF)Fredrik och Ingrid Thurings Stiftelse
Note

De två första författarna delar förstaförfattarskapet.

Available from: 2019-12-11 Created: 2019-12-11 Last updated: 2019-12-11Bibliographically approved
Öhnstedt, E., Lofton Tomenius, H., Vågesjö, E. & Phillipson, M. (2019). The discovery and development of topical medicines for wound healing. Expert Opinion on Drug Discovery, 14(5), 485-497
Open this publication in new window or tab >>The discovery and development of topical medicines for wound healing
2019 (English)In: Expert Opinion on Drug Discovery, ISSN 1746-0441, E-ISSN 1746-045X, Vol. 14, no 5, p. 485-497Article, review/survey (Refereed) Published
Abstract [en]

Introduction: Chronic, nonhealing skin wounds claim >3% of the health-care budget in industrialized countries, and the incidence is rising. Currently, two parallel trends influence innovations within the field of wound healing: the need to reduce spread of antibiotic resistance and the emerging use of health economy and value-based models.Areas covered: This review focuses on the discovery of drug candidates and development of treatments aiming to enhance wound healing in the heterogeneous group of patients with nonhealing wounds.Expert opinion: Nonhealing wounds are multifaceted and recognized as difficult indications. The majority of products currently in use are medical device dressings, or concepts of negative pressure or hyperbaric oxygen treatment. Global best practice guidelines for the treatment of diabetic foot ulcers recommend debridement, redressing, as well as infection control, and are critical to the lack of coherent clinical evidence for many approved products in active wound care. To accelerate wound healing, there is an emerging trend toward biologics, gene therapy, and novel concepts for drug delivery in research and in the pipeline for clinical trials. Scientific delineation of the therapeutic mechanism of action is, in our opinion, vital for clinical trial success and for an increased fraction of medical products in the pharmaceutical pipeline.

Place, publisher, year, edition, pages
Taylor & Francis, 2019
Keywords
Chronic nonhealing wounds, chemokines, growth factors, immune cells, clinical trials, active wound care
National Category
Surgery
Identifiers
urn:nbn:se:uu:diva-386373 (URN)10.1080/17460441.2019.1588879 (DOI)000467837400008 ()30870037 (PubMedID)
Funder
Swedish Research CouncilEU, Horizon 2020, 804438Ragnar Söderbergs stiftelseKnut and Alice Wallenberg FoundationSwedish Diabetes AssociationErnfors Foundation
Available from: 2019-06-24 Created: 2019-06-24 Last updated: 2019-06-24Bibliographically approved
Phillipson, M. & Kubes, P. (2019). The Healing Power of Neutrophils. Trends in immunology, 40(7), 635-647
Open this publication in new window or tab >>The Healing Power of Neutrophils
2019 (English)In: Trends in immunology, ISSN 1471-4906, E-ISSN 1471-4981, Vol. 40, no 7, p. 635-647Article, review/survey (Refereed) Published
Abstract [en]

Neutrophils promptly accumulate in large numbers at sites of tissue injury. Injuries to the skin or mucosae disrupt barriers against the external environment, and the bactericidal actions of neutrophils are important in preventing microbial invasion. Neutrophils have also been associated with exacerbated inflammation, for example in non-healing wounds or in conditions such as inflammatory bowel disease (IBD). However, additional neutrophil functions important for angiogenesis and tissue restoration have been uncovered in models of sterile and ischemic injury, as well as in tumors. These functions are also relevant in healing skin and mucosal wounds, and can be impaired in conditions associated with non-healing wounds, such as diabetes. Here, we discuss our current understanding of neutrophil contributions to healing, and how the latter can be compromised in disease.

Place, publisher, year, edition, pages
Elsevier, 2019
National Category
Immunology in the medical area
Identifiers
urn:nbn:se:uu:diva-390330 (URN)10.1016/j.it.2019.05.001 (DOI)000473003200010 ()31160208 (PubMedID)
Funder
Swedish Research CouncilKnut and Alice Wallenberg FoundationRagnar Söderbergs stiftelseErnfors FoundationSwedish Diabetes Association
Available from: 2019-08-09 Created: 2019-08-09 Last updated: 2019-08-09Bibliographically approved
Ahl, D., Eriksson, O., Sedin, J., Seignez, C., Schwan, E., Kreuger, J., . . . Phillipson, M. (2019). Turning Up the Heat: Local Temperature Control During in vivo Imaging of Immune Cells. Frontiers in Immunology, 10, Article ID 2036.
Open this publication in new window or tab >>Turning Up the Heat: Local Temperature Control During in vivo Imaging of Immune Cells
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2019 (English)In: Frontiers in Immunology, ISSN 1664-3224, E-ISSN 1664-3224, Vol. 10, article id 2036Article in journal (Refereed) Published
Abstract [en]

Intravital imaging is an invaluable tool for studying the expanding range of immune cell functions. Only in vivo can the complex and dynamic behavior of leukocytes and their interactions with their natural microenvironment be observed and quantified. While the capabilities of high-speed, high-resolution confocal and multiphoton microscopes are well-documented and steadily improving, other crucial hardware required for intravital imaging is often developed in-house and less commonly published in detail. In this report, we describe a low-cost, multipurpose, and tissue-stabilizing in vivo imaging platform that enables sensing and regulation of local tissue temperature. The effect of tissue temperature on local blood flow and leukocyte migration is demonstrated in muscle and skin. Two different models of vacuum windows are described in this report, however, the design of the vacuum window can easily be adapted to fit different organs and tissues.

Place, publisher, year, edition, pages
FRONTIERS MEDIA SA, 2019
Keywords
intravital microscopy, skin, blood flow, leukocytes, vacuum window, confocal microscopy
National Category
Immunology Immunology in the medical area
Identifiers
urn:nbn:se:uu:diva-398848 (URN)10.3389/fimmu.2019.02036 (DOI)000482819900001 ()31507619 (PubMedID)
Funder
Swedish Research Council, 2018-02552Knut and Alice Wallenberg FoundationRagnar Söderbergs stiftelseSwedish Society for Medical Research (SSMF)Göran Gustafsson Foundation for promotion of scientific research at Uppala University and Royal Institute of TechnologyNovo Nordisk
Available from: 2019-12-18 Created: 2019-12-18 Last updated: 2019-12-18Bibliographically approved
Lofton Tomenius, H., Vågesjö, E., Öhnstedt, E., Mortier, A., Roos, S. & Phillipson, M. (2018). A novel drug-delivery system and drug candidate: using probiotic bacteria as bioreactors for delivery of therapeutic chemokines in wound healing. Paper presented at 52nd Annual Scientific Meeting of the European Society for Clinical Investigation “Precision medicine for healthy ageing”, 30th May – 1st June 2018, Barcelona, Spain.. European Journal of Clinical Investigation, 48(S1), 79-79
Open this publication in new window or tab >>A novel drug-delivery system and drug candidate: using probiotic bacteria as bioreactors for delivery of therapeutic chemokines in wound healing
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2018 (English)In: European Journal of Clinical Investigation, ISSN 0014-2972, E-ISSN 1365-2362, Vol. 48, no S1, p. 79-79Article in journal, Meeting abstract (Other academic) Published
National Category
Pharmacology and Toxicology
Identifiers
urn:nbn:se:uu:diva-366624 (URN)10.1111/eci.12926 (DOI)000434100200177 ()
Conference
52nd Annual Scientific Meeting of the European Society for Clinical Investigation “Precision medicine for healthy ageing”, 30th May – 1st June 2018, Barcelona, Spain.
Note

Meeting Abstract: P024-T

Available from: 2018-11-26 Created: 2018-11-26 Last updated: 2018-12-10Bibliographically approved
Vågesjö, E., Öhnstedt, E., Mortier, A., Lofton Tomenius, H., Huss, F., Proost, P., . . . Phillipson, M. (2018). Accelerated wound healing in mice by on-site production and delivery of CXCL12 by transformed lactic acid bacteria. Proceedings of the National Academy of Sciences of the United States of America, 115(8), 1895-1900
Open this publication in new window or tab >>Accelerated wound healing in mice by on-site production and delivery of CXCL12 by transformed lactic acid bacteria
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2018 (English)In: Proceedings of the National Academy of Sciences of the United States of America, ISSN 0027-8424, E-ISSN 1091-6490, Vol. 115, no 8, p. 1895-1900Article in journal (Refereed) Published
Abstract [en]

Impaired wound closure is a growing medical problem associated with metabolic diseases and aging. Immune cells play important roles in wound healing by following instructions from the microenvironment. Here, we developed a technology to bioengineer the wound microenvironment and enhance healing abilities of the immune cells. This resulted in strongly accelerated wound healing and was achieved by transforming Lactobacilli with a plasmid encoding CXCL12. CXCL12-delivering bacteria administrated topically to wounds in mice efficiently enhanced wound closure by increasing proliferation of dermal cells and macrophages, and led to increased TGF-beta expression in macrophages. Bacteria-produced lactic acid reduced the local pH, which inhibited the peptidase CD26 and consequently enhanced the availability of bioactive CXCL12. Importantly, treatment with CXCL12-delivering Lactobacilli also improved wound closure in mice with hyperglycemia or peripheral ischemia, conditions associated with chronic wounds, and in a human skin wound model. Further, initial safety studies demonstrated that the topically applied transformed bacteria exerted effects restricted to the wound, as neither bacteria nor the chemokine produced could be detected in systemic circulation. Development of drugs accelerating wound healing is limited by the proteolytic nature of wounds. Our technology overcomes this by on-site chemokine production and reduced degradation, which together ensure prolonged chemokine bioavailability that instructed local immune cells and enhanced wound healing.

Place, publisher, year, edition, pages
NATL ACAD SCIENCES, 2018
Keywords
macrophage, chemokine, blood flow, diabetes, Lactobacillus reuteri
National Category
Infectious Medicine
Identifiers
urn:nbn:se:uu:diva-349352 (URN)10.1073/pnas.1716580115 (DOI)000425495000072 ()29432190 (PubMedID)
Funder
Swedish Research CouncilSwedish Diabetes AssociationNovo NordiskErnfors FoundationRagnar Söderbergs stiftelseKnut and Alice Wallenberg FoundationVINNOVA
Available from: 2018-04-27 Created: 2018-04-27 Last updated: 2018-04-27Bibliographically approved
Öhnstedt, E., Vågesjö, E., Lofton Tomenius, H., Roos, S. & Phillipson, M. (2018). Bioengineering of the local wound environment accelerates wound healing by increasing macrophage density and induces a phenotype shift in the wound macrophages. Paper presented at 52nd Annual Scientific Meeting of the European Society for Clinical Investigation “Precision medicine for healthy ageing”, 30th May – 1st June 2018, Barcelona, Spain.. European Journal of Clinical Investigation, 48(S1), 79-79
Open this publication in new window or tab >>Bioengineering of the local wound environment accelerates wound healing by increasing macrophage density and induces a phenotype shift in the wound macrophages
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2018 (English)In: European Journal of Clinical Investigation, ISSN 0014-2972, E-ISSN 1365-2362, Vol. 48, no S1, p. 79-79Article in journal, Meeting abstract (Other academic) Published
National Category
Cell and Molecular Biology
Identifiers
urn:nbn:se:uu:diva-366625 (URN)10.1111/eci.12926 (DOI)000434100200176 ()
Conference
52nd Annual Scientific Meeting of the European Society for Clinical Investigation “Precision medicine for healthy ageing”, 30th May – 1st June 2018, Barcelona, Spain.
Note

Meeting Abstract: P023-T

Available from: 2018-11-23 Created: 2018-11-23 Last updated: 2018-12-10Bibliographically approved
Thålin, C., Lundström, S., Seignez, C., Daleskog, M., Lundström, A., Henriksson, P., . . . Demers, M. (2018). Citrullinated histone H3 as a novel prognostic blood marker in patients with advanced cancer. PLoS ONE, 13(1), Article ID e0191231.
Open this publication in new window or tab >>Citrullinated histone H3 as a novel prognostic blood marker in patients with advanced cancer
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2018 (English)In: PLoS ONE, ISSN 1932-6203, E-ISSN 1932-6203, Vol. 13, no 1, article id e0191231Article in journal (Refereed) Published
Abstract [en]

Citrullinated histone H3 (H3Cit) is a central player in the neutrophil release of nuclear chromatin, known as neutrophil extracellular traps (NETs). NETs have been shown to elicit harmful effects on the host, and were recently proposed to promote tumor progression and spread. Here we report significant elevations of plasma H3Cit in patients with advanced cancer compared with age-matched healthy individuals. These elevations were specific to cancer patients as no increase was observed in severely ill and hospitalized patients with a higher non-malignant comorbidity. The analysis of neutrophils from cancer patients showed a higher proportion of neutrophils positive for intracellular H3Cit compared to severely ill patients. Moreover, the presence of plasma H3Cit in cancer patients strongly correlated with neutrophil activation markers neutrophil elastase (NE) and myeloperoxidase (MPO), and the inflammatory cytokines interleukin-6 and -8, known to induce NETosis. In addition, we show that high levels of circulating H3Cit strongly predicted poor clinical outcome in our cohort of cancer patients with a 2-fold increased risk for short-term mortality. Our results also corroborate the association of NE, interleukin-6 and -8 with poor clinical outcome. Taken together, our results are the first to unveil H3Cit as a potential diagnostic and prognostic blood marker associated with an exacerbated inflammatory response in patients with advanced cancer.

National Category
Cancer and Oncology Gastroenterology and Hepatology
Identifiers
urn:nbn:se:uu:diva-343379 (URN)10.1371/journal.pone.0191231 (DOI)000419952400133 ()29324871 (PubMedID)
Funder
Swedish Research CouncilKnut and Alice Wallenberg FoundationRagnar Söderbergs stiftelse
Available from: 2018-02-27 Created: 2018-02-27 Last updated: 2018-03-02Bibliographically approved
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Identifiers
ORCID iD: ORCID iD iconorcid.org/0000-0002-2387-0266

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