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  • Henstrom, M., et al. (författare)
  • Functional variants in the sucrase-isomaltase gene associate with increased risk of irritable bowel syndrome
  • 2018
  • Ingår i: Gut. - : BMJ PUBLISHING GROUP. - 0017-5749 .- 1468-3288. ; 67:2, s. 263-270
  • Tidskriftsartikel (refereegranskat)abstract
    • Objective IBS is a common gut disorder of uncertain pathogenesis. Among other factors, genetics and certain foods are proposed to contribute. Congenital sucraseisomaltase deficiency (CSID) is a rare genetic form of disaccharide malabsorption characterised by diarrhoea, abdominal pain and bloating, which are features common to IBS. We tested sucrase-isomaltase (SI) gene variants for their potential relevance in IBS. Design We sequenced SI exons in seven familial cases, and screened four CSID mutations (p.Val557Gly, p. Gly1073Asp, p.Arg1124Ter and p.Phe1745Cys) and a common SI coding polymorphism (p.Val15Phe) in a multicentre cohort of 1887 cases and controls. We studied the effect of the 15Val to 15Phe substitution on SI function in vitro. We analysed p.Val15Phe genotype in relation to IBS status, stool frequency and faecal microbiota composition in 250 individuals from the general population. Results CSID mutations were more common in patients than asymptomatic controls (p=0.074; OR=1.84) and Exome Aggregation Consortium reference sequenced individuals (p=0.020; OR=1.57). 15Phe was detected in 6/7 sequenced familial cases, and increased IBS risk in case-control and population-based cohorts, with best evidence for diarrhoea phenotypes (combined p=0.00012; OR=1.36). In the population-based sample, 15Phe allele dosage correlated with stool frequency (p=0.026) and Parabacteroides faecal microbiota abundance (p=0.0024). The SI protein with 15Phe exhibited 35% reduced enzymatic activity in vitro compared with 15Val (p<0.05). Conclusions SI gene variants coding for disaccharidases with defective or reduced enzymatic activity predispose to IBS. This may help the identification of individuals at risk, and contribute to personalising treatment options in a subset of patients.
  • Thorell, Kaisa, et al. (författare)
  • Isolates from Colonic Spirochetosis in Humans Show High Genomic Divergence and Potential Pathogenic Features but Are Not Detected Using Standard Primers for the Human Microbiota
  • 2019
  • Ingår i: Journal of Bacteriology. - : American Society for Microbiology. - 0021-9193 .- 1098-5530. ; 201:21
  • Tidskriftsartikel (refereegranskat)abstract
    • Colonic spirochetosis, diagnosed based on the striking appearance in histological sections, still has an obscure clinical relevance, and only a few bacterial isolates from this condition have been characterized to date. In a randomized, population-based study in Stockholm, Sweden, 745 healthy individuals underwent colonoscopy with biopsy sampling. Of these individuals, 17 (2.3%) had colonic spirochetosis, which was associated with eosinophilic infiltration and a 3-fold-increased risk for irritable bowel syndrome (IBS). We aimed to culture the bacteria and perform whole-genome sequencing of the isolates from this unique representative population sample. From 14 out of 17 individuals with spirochetosis we successfully isolated, cultured, and performed whole-genome sequencing of in total 17 isolates, including the Brachyspira aalborgi type strain, 513A. Also, 16S analysis of the mucosaassociated microbiota was performed in the cases and nonspirochetosis controls. We found one isolate to be of the species Brachyspira pilosicoli; all remaining isolates were of the species Brachyspira aalborgi. Besides displaying extensive genetic heterogeneity, the isolates harbored several mucin-degrading enzymes and other virulenceassociated genes that could confer a pathogenic potential in the human colon. We also showed that 16S amplicon sequencing using standard primers for human microbiota studies failed to detect Brachyspira due to primer incompatibility. IMPORTANCE This is the first report of whole-genome analysis of clinical isolates from individuals with colonic spirochetosis. This characterization provides new opportunities in understanding the physiology and potentials of these bacteria that densely colonize the gut in the individuals infected. The observation that standard 16S amplicon primers fail to detect colonic spirochetosis may have major implications for studies searching for associations between members of the microbiota and clinical conditions such as irritable bowel syndrome (IBS) and should be taken into consideration in project design and interpretation of gastrointestinal tract microbiota in population-based and clinical settings.
  • Bugaytsova, Jeanna A., et al. (författare)
  • Helicobacter pylori adapts to chronic infection and gastric disease via ph-responsive baba-mediated adherence
  • 2017
  • Ingår i: Cell Host and Microbe. - : CELL PRESS. - 1931-3128 .- 1934-6069. ; 21:3, s. 376-389
  • Tidskriftsartikel (refereegranskat)abstract
    • The BabA adhesin mediates high-affinity binding of Helicobacter pylori to the ABO blood group antigen-glycosylated gastric mucosa. Here we show that BabA is acid responsive-binding is reduced at low pH and restored by acid neutralization. Acid responsiveness differs among strains; often correlates with different intragastric regions and evolves during chronic infection and disease progression; and depends on pH sensor sequences in BabA and on pH reversible formation of high-affinity binding BabA multimers. We propose that BabA's extraordinary reversible acid responsiveness enables tight mucosal bacterial adherence while also allowing an effective escape from epithelial cells and mucus that are shed into the acidic bactericidal lumen and that bio-selection and changes in BabA binding properties through mutation and recombination with babA-related genes are selected by differences among individuals and by changes in gastric acidity over time. These processes generate diverse H. pylori subpopulations, in which BabA's adaptive evolution contributes to H. pylori persistence and overt gastric disease.
  • Wesslén, Lars, et al. (författare)
  • An increase in sudden unexpected cardiac deaths among young Swedish orienteers during 1979-1992
  • 1996
  • Ingår i: European Heart Journal. - 0195-668X .- 1522-9645. ; 17:6, s. 902-910
  • Tidskriftsartikel (refereegranskat)abstract
    • BACKGROUND: Sixteen cases of sudden unexpected cardiac death, 15 males and one female, are known to have occurred among young Swedish orienteers from 1979 to 1992, of which seven cases occurred between 1989 and 1992. This is considered to be indicative of an increased death rate. RESULTS: Histopathological evaluation showed myocarditis in a higher than expected proportion of cases. In one such case, which we studied before the sudden unexpected death occurred, the victim had suffered a Chlamydia pneumoniae infection verified by serology, and a nucleotide sequence was found in the heart and lung by means of the polymerase chain reaction (PCR) that hybridized with a probe specific for that organism. Male Swedish orienteers do not, however, seem to have an increased rate of exposure to this agent. No further sudden unexpected deaths among young orienteers have occurred over the past 3.5 years. At the beginning of that period, attempts were made to modify training habits and attitudes.
  • Sundin, Johanna, et al. (författare)
  • Evidence of altered mucosa-associated and fecal microbiota composition in patients with Irritable Bowel Syndrome
  • 2020
  • Ingår i: Scientific Reports. - 2045-2322. ; 10:1
  • Tidskriftsartikel (refereegranskat)abstract
    • Altered bacterial composition and small intestinal bacterial overgrowth (SIBO) may be associated with irritable bowel syndrome (IBS). This study aimed to determine the fecal and mucosa-associated bacterial composition along the gastrointestinal (GI) tract and to assess SIBO in IBS. Bacterial composition of feces, and mucosa of the duodenum and sigmoid colon was determined by 16S rRNA-amplicon-sequencing. SIBO was evaluated by bacterial culture of duodenal aspirate, glucose and lactulose breath tests. Mucosal antibacterial gene expression was assessed by PCR Array. The bacterial profiles of feces and the mucosa of sigmoid colon, but not duodenum, differed between IBS patients (n = 17) and HS (n = 20). The IBS specific bacterial profiles were linked to the colonic antibacterial gene expression. Fecal bacterial profile differed between IBS subtypes, while the mucosa-associated bacterial profile was associated with IBS symptom severity and breath tests results at baseline (H-2 and/or CH4 >= 15 ppm). The prevalence of SIBO was similar between IBS patients and HS. This study demonstrates that alterations in the bacterial composition of the sigmoid colon of IBS patients were linked to symptoms and immune activation. While breath tests reflected the mucosa-associated bacterial composition, there was no evidence for high prevalence of SIBO or small intestinal bacterial alterations in IBS.
  • Vaga, S., et al. (författare)
  • Compositional and functional differences of the mucosal microbiota along the intestine of healthy individuals
  • 2020
  • Ingår i: Scientific Reports. - : NATURE RESEARCH. - 2045-2322. ; 10:1
  • Tidskriftsartikel (refereegranskat)abstract
    • Gut mucosal microbes evolved closest to the host, developing specialized local communities. There is, however, insufficient knowledge of these communities as most studies have employed sequencing technologies to investigate faecal microbiota only. This work used shotgun metagenomics of mucosal biopsies to explore the microbial communities' compositions of terminal ileum and large intestine in 5 healthy individuals. Functional annotations and genome-scale metabolic modelling of selected species were then employed to identify local functional enrichments. While faecal metagenomics provided a good approximation of the average gut mucosal microbiome composition, mucosal biopsies allowed detecting the subtle variations of local microbial communities. Given their significant enrichment in the mucosal microbiota, we highlight the roles of Bacteroides species and describe the antimicrobial resistance biogeography along the intestine. We also detail which species, at which locations, are involved with the tryptophan/indole pathway, whose malfunctioning has been linked to pathologies including inflammatory bowel disease. Our study thus provides invaluable resources for investigating mechanisms connecting gut microbiota and host pathophysiology.
  • Rodin, S., et al. (författare)
  • Performance of a 70-mer oligonucleotide microarray for genotyping of Campylobacter jejuni
  • 2008
  • Ingår i: BMC Microbiology. - 1471-2180 .- 1471-2180. ; 8
  • Tidskriftsartikel (refereegranskat)abstract
    • BACKGROUND: Campylobacter jejuni is widespread in the environment and is the major cause of bacterial gastroenteritis in humans. In the present study we use microarray-based comparative genomic hybridizations (CGH), pulsed-field gel electrophoresis (PFGE) and multilocus sequence typing (MLST) to analyze closely related C. jejuni isolates from chicken and human infection. RESULTS: With the exception of one isolate, the microarray data clusters the isolates according to the five groups determined by PFGE. In contrast, MLST defines only three genotypes among the isolates, indicating a lower resolution. All methods show that there is no inherit difference between isolates infecting humans and chicken, suggesting a common underlying population of C. jejuni. We further identify regions that frequently differ between isolates, including both previously described and novel regions. Finally, we show that genes that belong to certain functional groups differ between isolates more often than expected by chance. CONCLUSION: In this study we demonstrated the utility of 70-mer oligonucleotide microarrays for genotyping of Campylobacter jejuni isolates, with resolution outperforming MLST.
  • West, Christina E, et al. (författare)
  • Gut microbiome and innate immune response patterns in IgE-associated eczema
  • 2015
  • Ingår i: Clinical and Experimental Allergy. - 0954-7894 .- 1365-2222. ; 45:9, s. 1419-1429
  • Tidskriftsartikel (refereegranskat)abstract
    • Background Gut microbiome patterns have been associated with predisposition to eczema potentially through modulation of innate immune signaling. Objective We examined gut microbiome development in the first year of life in relation to innate immune responses and onset of IgE-associated eczema over the first 2.5 years in predisposed children due to maternal atopy [www.anzctr.org.au, trial ID ACTRN12606000280505]. Methods Microbial composition and diversity were analyzed with barcoded 16S rRNA 454 pyrosequencing in stool samples in pregnancy and at ages 1 week, 1 month and 12 months in infants (n=10) who developed IgE-associated eczema and infants who remained free of any allergic symptoms at 2.5 years of age (n=10). Microbiome data at 1 week and 1 month were analyzed in relation to previously assessed immune responses to TLR 2 and 4 ligands at 6 months of age. Results The relative abundance of Gram-positive Ruminococcaceae was lower at 1 week of age in infants developing IgE-associated eczema, compared with controls (p=0.0047). At that age, the relative abundance of Ruminococcus was inversely associated with TLR2 induced IL-6 (-0.567, p=0.042) and TNF-α (-0.597, p=0.032); there was also an inverse association between the abundance of Proteobacteria (comprising Gram-negative taxa) and TLR4 induced TNF-α (rs= -0.629, p=0.024). This relationship persisted at 1 month, with inverse associations between the relative abundance of Enterobacteriaceae (within the Protebacteria phylum) and TLR4 induced TNF-α (rs=-0.697, p=0.038) and Enterobacteriaceae and IL-6 (rs=-0.709, p=0.035). Mothers whose infants developed IgE-associated eczema had lower α-diversity of Bacteroidetes (p=0.04) although this was not seen later in their infants. At 1 year, α-diversity of Actinobacteria was lower in infants with IgE-associated eczema compared with controls (p=0.002). Conclusion and clinical relevance Our findings suggest that reduced relative abundance of potentially immunomodulatory gut bacteria is associated with exaggerated inflammatory cytokine responses to TLR ligands and subsequent development of IgE-associated eczema. This article is protected by copyright. All rights reserved.
  • Hugerth, Luisa W., et al. (författare)
  • No distinct microbiome signature of irritable bowel syndrome found in a Swedish random population
  • 2020
  • Ingår i: Gut. - 0017-5749 .- 1468-3288. ; 69:6, s. 1076-1084
  • Tidskriftsartikel (refereegranskat)abstract
    • Objective The ethiopathogenesis of irritable bowel syndrome (IBS) is unknown. While a link to the gut microbiome is postulated, the heterogeneity of the healthy gut makes it difficult to draw definitive conclusions. We aimed to describe the faecal and mucosa-associated microbiome (MAM) and health correlates on a community cohort of healthy and IBS individuals with no colonoscopic findings.Design The PopCol study recruited a random sample of 3556 adults; 745 underwent colonoscopy. IBS was defined by Rome IV criteria and organic disease excluded. 16S rRNA gene sequencing was conducted on sigmoid biopsy samples from 376 representative individuals (63 IBS cases) and faecal samples from 185 individuals (32 IBS cases).Results While sigmoid MAM was dominated by Lachnospiraceae, faeces presented a higher relative abundance of Ruminococcaceae. Microbial richness in MAM was linearly correlated to that in faeces from the same individual (R-2=0.255, p<3E-11) as was diversity (R-2=0.06, p=0.0022). MAM diversity decreased with increasing body mass index (BMI; Pearson's r=-0.1, p=0.08) and poorer self-rated health (r=-0.15, p=0.007), but no other health correlates. Faecal microbiome diversity was correlated to stool consistency (r=-0.16, p=0.043). Several taxonomic groups were correlated to age, BMI, depression and self-reported health, including Coprococcus catus associated with lower levels of depression (r=-0.003, p=0.00017). The degree of heterogeneity observed between IBS patients is higher than that observed between healthy individuals.Conclusions No distinct microbial signature was observed in IBS. Individuals presenting with low self-rated health or high BMI have lower gut microbiome richness.
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