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- 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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| 2. |
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| 3. |
- Kling Bäckhed, Helene
(författare)
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Genetic adaptations of Helicobacter pylori during gastric disease progression
- 2009
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Doktorsavhandling (övrigt vetenskapligt/konstnärligt)abstract
- Helicobacter pylori colonizes the stomachs of approximately half of all humans. In the absence of treatment, H. pylori can persist throughout the life of the host. Although most infected individuals are asymptomatic, a significant proportion develops peptic ulcer disease, chronic atrophic gastritis (ChAG) or gastric adenocarcinoma. ChAG is considered to be a precursor to gastric cancer and is characterized by loss of acidproducing parietal cells and pepsinogen-secreting zymogenic cells, and an accompanying amplification of gastric stem cells in the gastric mucosa. The precise mechanisms by which H. pylori causes gastric cancer are unknown. This thesis aimed to identify genetic adaptations of H. pylori to the atrophic gastric environment of hosts with ChAG during disease progression, and to examine the impact of H. pylori isolates on gastric stem cell biology. To obtain information concerning the long-term adaptation of H. pylori to an acid-free gastric environment, we examined genomic and transcriptional adaptations of the ChAG-associated strain HPAG1, which was isolated from a Swedish patient with ChAG. We found that the 1,596,366 bp HPAG1 genome is smaller than the two previously sequenced H. pylori genomes 26695 and J99 due to deletions of strain-specific plasticity zone-associated genes. Interestingly, a number of the missing genes have been shown to be acidregulated. The loss of these genes might illustrate a genomic adaptation and a streamlining of the genome size to an acid-free gastric environment where these genes are no longer needed. Whole-genome genotyping of additional ChAG-associated strains revealed that outer membrane proteins (OMPs) and genes involved in metal utilization were over-represented among ChAG-associated genes. The enrichment of these genes indicates that they play important roles in the adhesive adjustments and nutrient adaptations of H. pylori in the setting of ChAG. Further, we assessed the diversity and structural adjustments of the surface-exposed LPS-molecule and of Lewis antigens to varying gastric conditions in individuals during disease progression and in two mouse models. We observed extensive diversity in H. pylori Lewis antigen expression both within and between individuals, however the proportions of presented Lewis epitopes appeared relatively stable over a time-period of four years. Interestingly, we noted that Lewis antigen expression differed between H. pylori isolates obtained after an experimental infection of two types of mice with distinct gastric pH. Thus, the LPS diversity within the bacterial population provides a means for H. pylori to adapt to changes in the gastric environment and enables modulation of the inflammatory response. A genome-wide comparison of deep draft assemblies of 24 H. pylori genomes collected from six patients at two time points with a four-year interval was performed. We found that genomic variations clustered by host rather than disease state, and that intra-individual strains exhibited remarkable stability over the four years. Functional genomic studies of both host and microbial responses to H. pylori infection of a mouse gastric epithelial progenitor (mGEP) cell line, disclosed host transcriptional responses enriched in genes related to cell proliferation and gastric carcinogenesis, as well as bacterial genes encoding OMPs and genes involved in metal ion binding. Our findings have provided new insights on H. pylori´s genetic and functional adaptations to ChAG. Varying expression and composition of surfaceexposed structures as well as regulating genes involved in metal ion utilization, are associated with this disease state. The intimate association with GEP cells may be important for survival in a gastric ecosystem that lacks parietal cells. However, this dangerous liaison may also increase the risk of tumorigenesis.
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| 4. |
- Koren, O., et al.
(författare)
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Host Remodeling of the Gut Microbiome and Metabolic Changes during Pregnancy
- 2012
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Ingår i: Cell. - : Elsevier BV. - 0092-8674. ; 150:3, s. 470-480
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Tidskriftsartikel (refereegranskat)abstract
- Many of the immune and metabolic changes occurring during normal pregnancy also describe metabolic syndrome. Gut microbiota can cause symptoms of metabolic syndrome in nonpregnant hosts. Here, to explore their role in pregnancy, we characterized fecal bacteria of 91 pregnant women of varying prepregnancy BMIs and gestational diabetes status and their infants. Similarities between infant-mother microbiotas increased with children's age, and the infant microbiota was unaffected by mother's health status. Gut microbiota changed dramatically from first (T1) to third (T3) trimesters, with vast expansion of diversity between mothers, an overall increase in Proteobacteria and Actinobacteria, and reduced richness. T3 stool showed strongest signs of inflammation and energy loss; however, microbiome gene repertoires were constant between trimesters. When transferred to germ-free mice, T3 microbiota induced greater adiposity and insulin insensitivity compared to T1. Our findings indicate that host-microbial interactions that impact host metabolism can occur and may be beneficial in pregnancy.
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| 6. |
- Sjöwall, Johanna, et al.
(författare)
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Neoehrlichia mikurensis & nbsp;Causing Thrombosis and Relapsing Fever in a Lymphoma Patient Receiving Rituximab
- 2021
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Ingår i: Microorganisms. - : MDPI AG. - 2076-2607. ; 9:10
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Tidskriftsartikel (refereegranskat)abstract
- Neoehrlichia (N.) mikurensis, an intracellular tick-borne bacterium not detected by routine blood culture, is prevalent in ticks in Scandinavia, Central Europe and Northern Asia, and may cause long-standing fever, nightly sweats, migrating pain, skin rashes and thromboembolism, especially in patients treated with rituximab. The multiple symptoms may raise suspicion of both infection, inflammation and malignancy, and lead in most cases to extensive medical investigations across many medical specialist areas and a delay of diagnosis. We describe a complex, albeit typical, case of neoehrlichiosis in a middle-aged splenectomised male patient with a malignant lymphoma, receiving treatment with rituximab. The multifaceted clinical picture associated with this tick-borne disease is addressed, and longitudinal clinical and laboratory data, as well as imaging, are provided. Longstanding relapsing fever in combination with thrombosis in superficial and deep veins in an immunocompromised patient living in a tick-endemic region should raise the suspicion of the emerging tick-borne disease neoehrlichiosis. Given the varied clinical presentation and the risk of delay in diagnosis and treatment, we believe it is important to raise clinicians' awareness of this emerging infection, which is successfully treated with doxycycline.
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