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Schoultz, I. & Keita, Å. V. (2019). Cellular and Molecular Therapeutic Targets in Inflammatory Bowel Disease-Focusing on Intestinal Barrier Function. Cells, 8(2), Article ID 193.
Open this publication in new window or tab >>Cellular and Molecular Therapeutic Targets in Inflammatory Bowel Disease-Focusing on Intestinal Barrier Function
2019 (English)In: Cells, ISSN 2073-4409, Vol. 8, no 2, article id 193Article, review/survey (Refereed) Published
Abstract [en]

The human gut relies on several cellular and molecular mechanisms to allow for an intact and dynamical intestinal barrier. Normally, only small amounts of luminal content pass the mucosa, however, if the control is broken it can lead to enhanced passage, which might damage the mucosa, leading to pathological conditions, such as inflammatory bowel disease (IBD). It is well established that genetic, environmental, and immunological factors all contribute in the pathogenesis of IBD, and a disturbed intestinal barrier function has become a hallmark of the disease. Genetical studies support the involvement of intestinal barrier as several susceptibility genes for IBD encode proteins with key functions in gut barrier and homeostasis. IBD patients are associated with loss in bacterial diversity and shifts in the microbiota, with a possible link to local inflammation. Furthermore, alterations of immune cells and several neuro-immune signaling pathways in the lamina propria have been demonstrated. An inappropriate immune activation might lead to mucosal inflammation, with elevated secretion of pro-inflammatory cytokines that can affect the epithelium and promote a leakier barrier. This review will focus on the main cells and molecular mechanisms in IBD and how these can be targeted in order to improve intestinal barrier function and reduce inflammation.

Place, publisher, year, edition, pages
MDPI, 2019
Keywords
Crohn's disease, ulcerative colitis, intestinal permeability therapeutic targets, innate and adaptive immunity
National Category
Medical Biotechnology (with a focus on Cell Biology (including Stem Cell Biology), Molecular Biology, Microbiology, Biochemistry or Biopharmacy)
Identifiers
urn:nbn:se:oru:diva-73341 (URN)10.3390/cells8020193 (DOI)000460896000115 ()30813280 (PubMedID)
Note

Funding Agencies:

LIONS international Foundation  

Örebro University 

Available from: 2019-03-26 Created: 2019-03-26 Last updated: 2019-03-26Bibliographically approved
Rajan, S. K., Lindqvist, C. M., Brummer, R. J., Schoultz, I. & Repsilber, D. (2019). Phylogenetic microbiota profiling in fecal samples depends on combination of sequencing depth and choice of NGS analysis method. PLoS ONE, 14(9), Article ID e0222171.
Open this publication in new window or tab >>Phylogenetic microbiota profiling in fecal samples depends on combination of sequencing depth and choice of NGS analysis method
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2019 (English)In: PLoS ONE, ISSN 1932-6203, E-ISSN 1932-6203, Vol. 14, no 9, article id e0222171Article in journal (Refereed) Published
Abstract [en]

The human gut microbiota is well established as an important factor in health and disease. Fecal sample microbiota are often analyzed as a proxy for gut microbiota, and characterized with respect to their composition profiles. Modern approaches employ whole genome shotgun next-generation sequencing as the basis for these analyses. Sequencing depth as well as choice of next-generation sequencing data analysis method constitute two main interacting methodological factors for such an approach. In this study, we used 200 million sequence read pairs from one fecal sample for comparing different taxonomy classification methods, using default and custom-made reference databases, at different sequencing depths. A mock community data set with known composition was used for validating the classification methods. Results suggest that sequencing beyond 60 million read pairs does not seem to improve classification. The phylogeny prediction pattern, when using the default databases and the consensus database, appeared to be similar for all three methods. Moreover, these methods predicted rather different species. We conclude that the choice of sequencing depth and classification method has important implications for taxonomy composition prediction. A multi-method-consensus approach for robust gut microbiota NGS analysis is recommended.

Place, publisher, year, edition, pages
PLOS, 2019
National Category
Bioinformatics and Systems Biology
Identifiers
urn:nbn:se:oru:diva-76641 (URN)10.1371/journal.pone.0222171 (DOI)31527871 (PubMedID)
Available from: 2019-09-24 Created: 2019-09-24 Last updated: 2019-09-24Bibliographically approved
Ganda Mall, J.-P., Östlund-Lagerström, L., Lindqvist, C. M., Algilani, S., Rasoal, D., Repsilber, D., . . . Schoultz, I. (2018). Are self-reported gastrointestinal symptoms among older adults associated with increased intestinal permeability and psychological distress?. BMC Geriatrics, 18(1), Article ID 75.
Open this publication in new window or tab >>Are self-reported gastrointestinal symptoms among older adults associated with increased intestinal permeability and psychological distress?
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2018 (English)In: BMC Geriatrics, ISSN 1471-2318, E-ISSN 1471-2318, Vol. 18, no 1, article id 75Article in journal (Refereed) Published
Abstract [en]

BACKGROUND: Despite the substantial number of older adults suffering from gastrointestinal (GI) symptoms little is known regarding the character of these complaints and whether they are associated with an altered intestinal barrier function and psychological distress. Our aim was to explore the relationship between self-reported gut health, intestinal permeability and psychological distress among older adults.

METHODS: Three study populations were included: 1) older adults with GI symptoms (n = 24), 2) a group of older adults representing the general elderly population in Sweden (n = 22) and 3) senior orienteering athletes as a potential model of healthy ageing (n = 27). Questionnaire data on gut-health, psychological distress and level of physical activity were collected. Intestinal permeability was measured by quantifying zonulin in plasma. The level of systemic and local inflammation was monitored by measuring C-reactive protein (CRP), hydrogen peroxide in plasma and calprotectin in stool samples. The relationship between biomarkers and questionnaire data in the different study populations was illustrated using a Principal Component Analysis (PCA).

RESULTS: Older adults with GI symptoms displayed significantly higher levels of both zonulin and psychological distress than both general older adults and senior orienteering athletes. The PCA analysis revealed a separation between senior orienteering athletes and older adults with GI symptoms and showed an association between GI symptoms, psychological distress and zonulin.

CONCLUSIONS: Older adults with GI symptoms express increased plasma levels of zonulin, which might reflect an augmented intestinal permeability. In addition, this group suffer from higher psychological distress compared to general older adults and senior orienteering athletes. This relationship was further confirmed by a PCA plot, which illustrated an association between GI symptoms, psychological distress and intestinal permeability.

Place, publisher, year, edition, pages
BioMed Central, 2018
Keywords
Older adults; Gastrointestinal symptoms; Intestinal barrier function; Psychological distress
National Category
Geriatrics
Identifiers
urn:nbn:se:oru:diva-66053 (URN)10.1186/s12877-018-0767-6 (DOI)000428260300001 ()29554871 (PubMedID)2-s2.0-85044174344 (Scopus ID)
Funder
Knowledge Foundation, 20110225
Note

Funding Agencies:

Bo Rydins stiftelse  F0514 

Faculty of Medicine and Health at Örebro University  

Diarrheal Disease Research Centre, Linköping University  

Available from: 2018-03-27 Created: 2018-03-27 Last updated: 2018-08-20Bibliographically approved
Ganda Mall, J. P., Löfvendahl, L., Lindqvist, C. M., Brummer, R. J., Keita, Å. V. & Schoultz, I. (2018). Differential effects of dietary fibres on colonic barrier function in elderly individuals with gastrointestinal symptoms. Scientific Reports, 8(1), Article ID 13404.
Open this publication in new window or tab >>Differential effects of dietary fibres on colonic barrier function in elderly individuals with gastrointestinal symptoms
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2018 (English)In: Scientific Reports, ISSN 2045-2322, E-ISSN 2045-2322, Vol. 8, no 1, article id 13404Article in journal (Refereed) Published
Abstract [en]

Gastrointestinal problems are common in elderly and often associated with psychological distress and increased levels of corticotrophin-releasing hormone, a hormone known to cause mast cell (MC) degranulation and perturbed intestinal barrier function. We investigated if dietary fibres (non-digestible polysaccharides [NPS]) could attenuate MC-induced colonic hyperpermeability in elderly with gastrointestinal (GI) symptoms. Colonic biopsies from elderly with diarrhoea and/or constipation (n = 18) and healthy controls (n = 19) were mounted in Ussing chambers and pre-stimulated with a yeast-derived beta (β)-glucan (0.5 mg/ml) or wheat-derived arabinoxylan (0.1 mg/ml) before the addition of the MC-degranulator Compound (C) 48/80 (10 ng/ml). Permeability markers were compared pre and post exposure to C48/80 in both groups and revealed higher baseline permeability in elderly with GI symptoms. β-glucan significantly attenuated C48/80-induced hyperpermeability in elderly with GI symptoms but not in healthy controls. Arabinoxylan reduced MC-induced paracellular and transcellular hyperpermeability across the colonic mucosa of healthy controls, but did only attenuate transcellular permeability in elderly with GI symptoms. Our novel findings indicate that NPS affect the intestinal barrier differently depending on the presence of GI symptoms and could be important in the treatment of moderate constipation and/or diarrhoea in elderly.

Place, publisher, year, edition, pages
Nature Publishing Group, 2018
National Category
Gastroenterology and Hepatology Nutrition and Dietetics
Identifiers
urn:nbn:se:oru:diva-68799 (URN)10.1038/s41598-018-31492-5 (DOI)000444022800008 ()30194322 (PubMedID)2-s2.0-85053008629 (Scopus ID)
Available from: 2018-09-10 Created: 2018-09-10 Last updated: 2018-09-28Bibliographically approved
Keita, A. V., Lindqvist, C. M., Ost, A., Magana, C. D., Schoultz, I. & Halfvarson, J. (2018). Gut barrier dysfunction: a primary defect in twins with Crohn's disease predominantly caused by genetic predisposition. Journal of Crohn's & Colitis, 12(Suppl. 1), S1-S1
Open this publication in new window or tab >>Gut barrier dysfunction: a primary defect in twins with Crohn's disease predominantly caused by genetic predisposition
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2018 (English)In: Journal of Crohn's & Colitis, ISSN 1873-9946, E-ISSN 1876-4479, Vol. 12, no Suppl. 1, p. S1-S1Article in journal, Meeting abstract (Other academic) Published
Place, publisher, year, edition, pages
Oxford University Press, 2018
National Category
Gastroenterology and Hepatology
Identifiers
urn:nbn:se:oru:diva-66756 (URN)000427318900002 ()
Available from: 2018-04-25 Created: 2018-04-25 Last updated: 2018-04-25Bibliographically approved
Keita, Å. V., Lindqvist, C. M., Öst, Å., Magana, C. D. L., Schoultz, I. & Halfvarson, J. (2018). Gut barrier dysfunction: a primary defect in twins with Crohn's disease predominantly caused by genetic predisposition. Journal of Crohn's & Colitis, 12(10), 1200-1209
Open this publication in new window or tab >>Gut barrier dysfunction: a primary defect in twins with Crohn's disease predominantly caused by genetic predisposition
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2018 (English)In: Journal of Crohn's & Colitis, ISSN 1873-9946, E-ISSN 1876-4479, Vol. 12, no 10, p. 1200-1209Article in journal (Refereed) Published
Abstract [en]

Background and aims: The aetiology of Crohn's disease is poorly understood. By investigating twin pairs discordant for Crohn's disease we aimed to assess if the dysregulated barrier represents a cause or a consequence of inflammation and to evaluate the impact of genetic predisposition on barrier function.

Methods: Ileal biopsies from 15 twin pairs discordant for Crohn's disease (monozygotic n=9, dizygotic n=6) and 10 external controls were mounted in Ussing chambers to assess paracellular permeability to51Chromium (Cr)-EDTA and trancellular passage to non-pathogenic E. coli K-12. Experiments were performed with and without provocation with acetylsalicylic acid. Immunofluorescence and ELISA were used to quantify the expression level of tight junction proteins.

Results: Healthy co-twins and affected twins displayed increased 51Cr-EDTA permeability at 120 min both with Acetylsalicylic acid (p<0.001) and without (p<0.001) when compared to controls. A significant increase in 51Cr-EDTA flux was seen already at 20 minutes in healthy monozygotic co-twins compared to controls (p≤0.05) when stratified by zygosity, but not in healthy dizygotic co-twins. No difference in E. coli passage was observed between groups. Immunofluorescence of the tight junction proteins claudin-5 and tricellulin showed lower levels in healthy co-twins (p<0.05) and affected twins (p<0.05) compared to external controls, while ELISA only showed lower tricellulin in Crohn's disease twins (p<0.05).

Conclusion: Our results suggest that barrier dysfunction is a primary defect in Crohn's disease, since changes were predominantly seen in healthy monozygotic co-twins. Passage of E. coli seems to be a consequence of inflammation rather than representing a primary defect.

Place, publisher, year, edition, pages
Elsevier, 2018
Keywords
Crohn's disease, barrier function, genetics
National Category
Gastroenterology and Hepatology
Identifiers
urn:nbn:se:oru:diva-66791 (URN)10.1093/ecco-jcc/jjy045 (DOI)000455271000008 ()29659773 (PubMedID)2-s2.0-85056415292 (Scopus ID)
Funder
Swedish Research Council, VR-MH 2014-02537 521-2011-2764
Note

Funding Agency:

Region Östergötland, ALF research funds of Linköping University 

Available from: 2018-04-27 Created: 2018-04-27 Last updated: 2019-01-23Bibliographically approved
Yakymenko, O., Schoultz, I., Gullberg, E., Ström, M., Almer, S., Wallon, C., . . . Söderholm, J. D. (2018). Infliximab restores colonic barrier to adherent-invasive E. coli in Crohn's disease via effects on epithelial lipid rafts. Scandinavian Journal of Gastroenterology, 53(6), 677-684
Open this publication in new window or tab >>Infliximab restores colonic barrier to adherent-invasive E. coli in Crohn's disease via effects on epithelial lipid rafts
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2018 (English)In: Scandinavian Journal of Gastroenterology, ISSN 0036-5521, E-ISSN 1502-7708, Vol. 53, no 6, p. 677-684Article in journal (Refereed) Published
Abstract [en]

OBJECTIVE: Infliximab is important in the therapeutic arsenal of Crohn's disease (CD). However, its effect on mucosal barrier function is not fully understood. Adherent-invasive Escherichia coli (AIEC) are important in CD pathophysiology, but the transmucosal uptake routes are partly unknown. We investigated effects of infliximab on uptake of colon-specific AIEC HM427 across CD colonic mucosa.

MATERIALS AND METHODS: Cr-EDTA) and transmucosal passage of GFP-expressing HM427 were studied. Mechanisms of HM427 transepithelial transport were investigated in Caco-2 monolayers treated with TNF, in the presence of infliximab and/or endocytosis inhibitors.

RESULTS: Cr-EDTA permeability were increased in CD (p < .05), but were restored to control levels by infliximab (CD: 150 (18.8-1069)). In TNF-exposed Caco-2 monolayers HM427 transport and lipid rafts/HM427 co-localization was decreased by infliximab. The lipid raft inhibitor methyl-β-cyclodextrin decreased HM427 transport.

CONCLUSION: Infliximab restored the colonic barrier to AIEC in CD; an effect partially mediated by blocking lipid rafts in epithelial cells. This ability likely contributes to infliximab's clinical efficacy in colonic CD.

Place, publisher, year, edition, pages
Oxfordshire, United Kingdom: Taylor & Francis, 2018
Keywords
Inflammatory bowel disease: microbiology: large intestine: intestinal barrier function: adherent invasive E: coli
National Category
Gastroenterology and Hepatology
Identifiers
urn:nbn:se:oru:diva-66790 (URN)10.1080/00365521.2018.1458146 (DOI)000438146900008 ()29688802 (PubMedID)2-s2.0-85046040952 (Scopus ID)
Funder
Swedish Research Council, VR-MH 2014-02537
Note

Funding Agency:

ALF Grants Region Östergötland

Available from: 2018-04-27 Created: 2018-04-27 Last updated: 2018-07-27Bibliographically approved
Ganda Mall, J.-P., Casado-Bedmar, M., Winberg, M. E., Brummer, R. J., Schoultz, I. & Keita, Å. V. (2017). A β-Glucan-Based Dietary Fiber Reduces Mast Cell-Induced Hyperpermeability in Ileum From Patients With Crohn's Disease and Control Subjects. Inflammatory Bowel Diseases, 24(1), 166-178
Open this publication in new window or tab >>A β-Glucan-Based Dietary Fiber Reduces Mast Cell-Induced Hyperpermeability in Ileum From Patients With Crohn's Disease and Control Subjects
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2017 (English)In: Inflammatory Bowel Diseases, ISSN 1078-0998, E-ISSN 1536-4844, Vol. 24, no 1, p. 166-178Article in journal (Refereed) Published
Abstract [en]

Background: Administration of β-glucan has shown immune-enhancing effects. Our aim was to investigate whether β-glucan could attenuate mast cell (MC)-induced hyperpermeability in follicle-associated epithelium (FAE) and villus epithelium (VE) of patients with Crohn's disease (CD) and in noninflammatory bowel disease (IBD)-controls. Further, we studied mechanisms of β-glucan uptake and effects on MCs in vitro.

Methods: Segments of FAE and VE from 8 CD patients and 9 controls were mounted in Ussing chambers. Effects of the MC-degranulator compound 48/80 (C48/80) and yeast-derived β-1,3/1,6 glucan on hyperpermeability were investigated. Translocation of β-glucan and colocalization with immune cells were studied by immunofluorescence. Caco-2-cl1- and FAE-cultures were used to investigate β-glucan-uptake using endocytosis inhibitors and HMC-1.1 to study effects on MCs.

Results: β-glucan significantly attenuated MC-induced paracellular hyperpermeability in CD and controls. Transcellular hyperpermeability was only significantly attenuated in VE. Baseline paracellular permeability was higher in FAE than VE in both groups, P<0.05, and exhibited a more pronounced effect by C48/80 and β-glucan P<0.05. No difference was observed between CD and controls. In vitro studies showed increased passage, P<0.05, of β-glucan through FAE-culture compared to Caco-2-cl1. Passage was mildly attenuated by the inhibitor methyl-β-cyclodextrin. HMC-1.1 experiments showed a trend to decreasing MC-degranulation and levels of TNF-α but not IL-6 by β-glucan. Immunofluorescence revealed more β-glucan-uptake and higher percentage of macrophages and dendritic cells close to β-glucan in VE of CD compared to controls.

Conclusions: We demonstrated beneficial effects of β-glucan on intestinal barrier function and increased β-glucan-passage through FAE model. Our results provide important and novel knowledge on possible applications of β-glucan in health disorders and diseases characterized by intestinal barrier dysfunction.

Place, publisher, year, edition, pages
Lippincott-Raven Publishers, 2017
Keywords
Crohn’s disease, intestinal permeability, β-glucan
National Category
Gastroenterology and Hepatology
Identifiers
urn:nbn:se:oru:diva-63994 (URN)10.1093/ibd/izx002 (DOI)000427524400018 ()29272475 (PubMedID)
Funder
Swedish Foundation for Strategic Research , RB13-016Swedish Research Council, 2014-02537
Note

Funding Agency:

LIONS research foundation

Available from: 2018-01-09 Created: 2018-01-09 Last updated: 2018-08-13Bibliographically approved
Algilani, S., Östlund-Lagerström, L., Schoultz, I., Brummer, R. J. & Kihlgren, A. (2016). Increasing the qualitative understanding of optimal functionality in older adults: a focus group based study. BMC Geriatrics, 16(1), Article ID 70.
Open this publication in new window or tab >>Increasing the qualitative understanding of optimal functionality in older adults: a focus group based study
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2016 (English)In: BMC Geriatrics, ISSN 1471-2318, E-ISSN 1471-2318, Vol. 16, no 1, article id 70Article in journal (Refereed) Published
Abstract [en]

Background: Decreased independence and loss of functional ability are issues regarded as inevitably connected to old age. This ageism may have negative influences on older adults' beliefs about aging, making it difficult for them to focus on their current ability to maintain a good health. It is therefore important to change focus towards promoting Optimal Functionality (OF). OF is a concept putting the older adult's perspective on health and function in focus, however, the concept is still under development. Hence, the aim was to extend the concept of optimal functionality in various groups of older adults.

Methods: A qualitative study was conducted based on focus group discussions (FGD). In total 6 FGDs were performed, including 37 older adults from three different groups: group 1) senior athletes, group 2) free living older adults, group 3) older adults living in senior living homes. All data was transcribed verbatim and analyzed following the process of deductive content analysis.

Results: The principal outcome of the analysis was "to function as optimally as you possibly can", which was perceived as the core of the concept. Further, the concept of OF was described as multifactorial and several new factors could be added to the original model of OF. Additionally the findings of the study support that all three cornerstones comprising OF have to occur simultaneously in order for the older adult to function as optimal as possible.

Conclusions: OF is a multifaceted and subjective concept, which should be individually defined by the older adult. This study further makes evident that older adults as a group are heterogeneous in terms of their preferences and views on health and should thus be approached as such in the health care setting. Therefore it is important to promote an individualized approach as a base when caring for older adults.

Place, publisher, year, edition, pages
London, United Kingdom: BioMed Central, 2016
Keywords
Older adults, optimal functionality, person centered care, focus group discussions
National Category
Geriatrics
Research subject
Geriatrics
Identifiers
urn:nbn:se:oru:diva-49605 (URN)10.1186/s12877-016-0244-z (DOI)000372822200002 ()27007861 (PubMedID)
Funder
Knowledge Foundation, 20110225
Note

Funding Agencies:

Olle Engkvist Byggmästare Foundation

Faculty of Medicine and Health at Örebro University

Available from: 2016-04-02 Created: 2016-04-02 Last updated: 2018-04-27Bibliographically approved
Östlund-Lagerström, L., Kihlgren, A., Repsilber, D., Björkstén, B., Brummer, R. J. & Schoultz, I. (2016). Probiotic administration among free-living older adults: a double blinded, randomized, placebo-controlled clinical trial. Nutrition Journal, 15, Article ID 80.
Open this publication in new window or tab >>Probiotic administration among free-living older adults: a double blinded, randomized, placebo-controlled clinical trial
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2016 (English)In: Nutrition Journal, ISSN 1475-2891, E-ISSN 1475-2891, Vol. 15, article id 80Article in journal (Refereed) Published
Abstract [en]

Background: Diseases of the digestive system have been found to contribute to a higher symptom burden in older adults. Thus, therapeutic strategies able to treat gastrointestinal discomfort might impact the overall health status and help older adults to increase their overall health status and optimal functionality.

Objective: The aim of this double-blinded, randomized, placebo-controlled clinical trial was to evaluate the effect of the probiotic strain Lactobacillus reuteri on digestive health and wellbeing in older adults.

Methods: The study enrolled general older adults (>65 years). After eligibility screening qualified subjects (n = 290) participated in a 2-arm study design, with each arm consisting of 12 weeks of intervention of either active or placebo product. Primary outcome measure was set to changes in gastrointestinal symptoms and secondary outcome measures were changes in level of wellbeing, anxiety and stress. Follow up was performed at 8 and 12 weeks.

Results: No persistent significant effects were observed on the primary or secondary outcome parameters of the study. A modest effect was observed in the probiotic arm, were levels of stress decreased at week 8 and 12. Similarly, we found that subjects suffering from indigestion and abdominal pain, respectively, showed a significant decrease of anxiety at week 8 after probiotic treatment, but not at week 12.

Conclusion: The RCT failed to show any improvement in digestive health after daily intake of a probiotic supplement containing L. reuteri. Neither was any significant improvement in wellbeing, stress or anxiety observed. Even though the RCT had a negative outcome, the study highlights issues important to take into consideration when designing trials among older adults.

Place, publisher, year, edition, pages
London, United Kingdom: BioMed Central, 2016
Keywords
Older adults, Digestive health, Wellbeing, Lactobacillus reuteri, Probiotics
National Category
Public Health, Global Health, Social Medicine and Epidemiology Nutrition and Dietetics
Research subject
Nutrition
Identifiers
urn:nbn:se:oru:diva-52175 (URN)10.1186/s12937-016-0198-1 (DOI)000383425100001 ()27612653 (PubMedID)
Funder
Knowledge Foundation, 20110225
Note

Funding Agency:

Faculty of Medicine at Örebro University

Available from: 2016-09-21 Created: 2016-09-14 Last updated: 2018-07-16Bibliographically approved
Organisations
Identifiers
ORCID iD: ORCID iD iconorcid.org/0000-0002-8391-1576

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