Lars Engstrand Group

The human intestinal microbiome, Helicobacter pylori and gastrointestinal disease development

Introduction:

The work of our group aims at creating a scientific translational environment with a broad interdisciplinary approach to the interface between epidemiology and the microbiological, immunological and genetic aspects of chronic diseases in the gastrointestinal tract to clarify the pathogenic mechanisms and to improve the prospects for primary prevention.

The long-term objective is to identify and characterize factors (both microbial and host related) that determine or modify the excess risk of disease outcome observed in people infected with various pathogenic microorganisms in the gut. Identification and characterization of determinants of Helicobacter pylori -associated gastro-duodenal disease has been the main focus for > 20 years and the set-up of this project is an example how we promote interdepartmental and interdisciplinary collaborations. The projects combine population-based epidemiology for which the conditions in Sweden are uniquely favorable with clinical and basic microbiological science, including molecular biology and genomics.

 

Research Projects

              

Next generation sequencing, NGS-based microbial community analysis

PCR amplification, cloning and sequencing of 16S rRNA genes directly from the environment has revolutionized our understanding of microbial diversity. We have implemented the 16S sequencing approach in a high-throughput NGS format using the Illumina platform, enabling detailed analysis of a large amount of samples in parallel. We collaborate with a number of research groups in Sweden and abroad and a partly automated pipeline for microbiome profiling is now up-and-running at MTC and Science for Life Laboratory in Solna. Optimization of DNA-preparation, sequencing protocols and bioinformatics tools for analyses are ongoing and our goal is to establish a bioinformatic team dedicated to microbiology and microbiome projects at KI and SciLifeLab.

 

Dynamics and development of the human gut microbiota and its impact on health and disease

While the sequencing of the human genome has provided invaluable knowledge, it is difficult to change our own genetic makeup. The human microbiome, in contrast, is much more easily changed through simple means such as healthful probiotic cultures, bacteriotherapy and other lifestyle interventions. Up to 20 percent of the small molecules in our bloodstream appear to be synthesized by microbes. The microbiome thus may provide some of the most important medical breakthroughs of our era e.g. the human microbiome may be as important to our health as the human genome.

The long-term objective is to identify and characterize factors (both microbial and host related) that determine or modify the excess risk of disease outcome e.g. to determine the relationship between human health and changes in our gut microbiome. The projects combine population-based epidemiology, for which the conditions in Sweden are uniquely favorable, with clinical and basic microbiological science, including molecular biology and genomics. We have applied next generation sequencing platforms for large-scale studies of the human gut microbiome in health and disease (see above).

The establishment of the gut microbiome in early life is critical and microbiota disruption during this time-period could lead to metabolic consequences later in life. Factors such as antibiotic treatment and delivery by Caesarian section that could alter the intestinal microbiota have been investigated and long-term consequences of a disturbed microbiota i.e. dysbiosis are monitored in ongoing studies. 

 

Characterization of the human gastric microbiota and lactobacilli involvement in gastrointestinal diseases

The discovery of Helicobacter pylori and the introduction of molecular-based methods to determine the microbiota have also increased the interest in studies of the gastric microbiota. The possible impact of the non-H. pylori microbiota in the stomach needs to be defined as well as options to manipulate the gastric microbiota to prevent gastro-duodenal diseases. There are still many questions to be answered. We do not know whether a majority of the non-H. pylori microbiota in the stomach colonizes or just pass the gastric niche and how acid suppressive drugs open up for bacterial overgrowth in the stomach. The aim is to narrow in on the true colonizers of the stomach e.g. the bacteria that interacts and may be involved in pathogenesis of atrophic gastritis and gastric cancer. We will also determine the lactobacilli population present in the human stomach and if lactobacilli co-exist with H. pylori and adhere to human gastric mucus. If this is the case we will investigate if these lactobacilli have antagonistic effects on H. pylori. Thus, administration of lactobacilli to H. pylori-infected individuals may become an alternative treatment option for these patients.

 

Evolution of Helicobacter pylori and its significance in the development of gastric cancer

H. pylori infection has been estimated to contribute to about 65% and 80% of non-cardia gastric cancers in developed and less developed countries, respectively. H. pylori colonize approximately 3 billions people, whereas only 1 million incident gastric cancers occur each year nowadays. The genetic determinants, from both the bacterial and the host, that have an impact on the gastric cancer outcome of H. pylori infection have been less studied compared to the peptic ulcer disease link. The dynamic picture of bacterial-host interaction that usually lasts for decades raises obstacle in exploring the etiology of H. pylori-associated gastric cancer. Using archived formalin-fixed paraffin-embedded biopsies, and the unique Swedish national registers together with unique long-term follow up samples we aim to identify the genetic determinants for gastric cancer at the whole-bacterial-genome level, as well as important host-genetic factors from the host.

Project Groups within the Lars Engstrand Group

Sven Hoffner Project

 

The Centre for Translational Microbiome Research (CTMR)

The Centre for Translational Microbiome Research (CTMR) website

CTMR aims to better understand the contribution of the human microbiome to physiology and pathophysiology with the goal to open opportunities for development of novel therapies in the area of gastroenterology, reproductive health and neonatology.

 

The Clinical Genomics facility

The Clinical Genomics facility provides a dedicated research infrastructure for projects utilising massively parallel sequencing technologies. All projects are carried out in close collaboration with the Swedish healthcare system. The facility serves as a competence center assisting the translation of genomics-based tools to routine clinical care. All work is carried out in close collaboration with medical expertise provided by the clinical diagnostic laboratories and patients’ managing physicians. Also, the facility aims to improve the capacity of the public health microbiology for national surveillance of infectious diseases and for epidemic preparedness.

www.scilifelab.se

Clinical Genomics Facility

 

Publications

Faecal microbiota composition associates with abdominal pain in the general population.
Hadizadeh F, Bonfiglio F, Belheouane M, Vallier M, Sauer S, Bang C, et al
Gut 2017 Aug;():

Time to review the gold standard for genotyping vancomycin-resistant enterococci in epidemiology: Comparing whole-genome sequencing with PFGE and MLST in three suspected outbreaks in Sweden during 2013-2015.
Lytsy B, Engstrand L, Gustafsson Ă, Kaden R
Infect. Genet. Evol. 2017 Jun;54():74-80

Draft Genome Sequences of Six Strains of Streptococcus pneumoniae from Serotypes 5, 6A, 6B, 18C, 19A, and 23F.
Jakobsson H, Salvà-Serra F, Thorell K, Karlsson R, Gonzales-Silès L, Boulund F, et al
Genome Announc 2017 Apr;5(14):

Helicobacter pylori eradication in the Swedish population.
Doorakkers E, Lagergren J, Gajulapuri V, Callens S, Engstrand L, Brusselaers N
Scand. J. Gastroenterol. ;52(6-7):678-685

Intestinal dysbiosis in preterm infants preceding necrotizing enterocolitis: a systematic review and meta-analysis.
Pammi M, Cope J, Tarr P, Warner B, Morrow A, Mai V, et al
Microbiome 2017 Mar;5(1):31

The Role of the Skin Microbiome in Atopic Dermatitis: A Systematic Review.
Dybboe R, Bandier J, Skov L, Engstrand L, Johansen J
Br. J. Dermatol. 2017 Feb;():

Genomic structure and insertion sites of Helicobacter pylori prophages from various geographical origins.
Vale F, Nunes A, Oleastro M, Gomes J, Sampaio D, Rocha R, et al
Sci Rep 2017 Feb;7():42471

Helicobacter pylori infection, chronic corpus atrophic gastritis and pancreatic cancer risk in the European Prospective Investigation into Cancer and Nutrition (EPIC) cohort: A nested case-control study.
Huang J, Zagai U, Hallmans G, Nyrén O, Engstrand L, Stolzenberg-Solomon R, et al
Int. J. Cancer 2017 Apr;140(8):1727-1735

Functional variants in the sucrase-isomaltase gene associate with increased risk of irritable bowel syndrome.
Henström M, Diekmann L, Bonfiglio F, Hadizadeh F, Kuech E, von Köckritz-Blickwede M, et al
Gut 2016 Nov;():

Helicobacter pylori infection, chronic corpus atrophic gastritis and pancreatic cancer risk in the European Prospective Investigation into Cancer and Nutrition (EPIC) cohort: A nested case-control study.
Huang J, Zagai U, Hallmans G, Nyrén O, Engstrand L, Stolzenberg-Solomon R, et al
Int. J. Cancer 2017 Apr;140(8):1727-1735

Functional variants in the sucrase-isomaltase gene associate with increased risk of irritable bowel syndrome.
Henström M, Diekmann L, Bonfiglio F, Hadizadeh F, Kuech E, von Köckritz-Blickwede M, et al
Gut 2016 Nov;():

Towards a healthy stomach? Helicobacter pylori prevalence has dramatically decreased over 23 years in adults in a Swedish community.
Agréus L, Hellström P, Talley N, Wallner B, Forsberg A, Vieth M, et al
United European Gastroenterol J 2016 Oct;4(5):686-696

First case of human bacteraemia by Catabacter hongkongensis in Scandinavia.
Kaden R, Thelander M, Engstrand L, Herrmann B
New Microbes New Infect 2017 Jan;15():6-8

Eradication of Helicobacter pylori and Gastric Cancer: A Systematic Review and Meta-analysis of Cohort Studies.
Doorakkers E, Lagergren J, Engstrand L, Brusselaers N
J. Natl. Cancer Inst. 2016 Sep;108(9):

Draft Genome Sequence of Streptococcus gordonii Type Strain CCUG 33482T.
Salvà-Serra F, Jakobsson H, Thorell K, Gonzales-Siles L, Hallbäck E, Jaén-Luchoro D, et al
Genome Announc 2016 Mar;4(2):

The 5300-year-old Helicobacter pylori genome of the Iceman.
Maixner F, Krause-Kyora B, Turaev D, Herbig A, Hoopmann M, Hallows J, et al
Science 2016 Jan;351(6269):162-165

Dormant phages of Helicobacter pylori reveal distinct populations in Europe.
Vale F, Vadivelu J, Oleastro M, Breurec S, Engstrand L, Perets T, et al
Sci Rep 2015 Sep;5():14333

Composition of human faecal microbiota in resistance to Campylobacter infection.
Kampmann C, Dicksved J, Engstrand L, Rautelin H
Clin. Microbiol. Infect. 2016 Jan;22(1):61.e1-8

Gut microbiome and innate immune response patterns in IgE-associated eczema.
West C, Rydén P, Lundin D, Engstrand L, Tulic M, Prescott S
Clin. Exp. Allergy 2015 Sep;45(9):1419-29

Deviations in human gut microbiota: a novel diagnostic test for determining dysbiosis in patients with IBS or IBD.
Casén C, Vebø H, Sekelja M, Hegge F, Karlsson M, Ciemniejewska E, et al
Aliment. Pharmacol. Ther. 2015 Jul;42(1):71-83

Intestinal dysbiosis in children with short bowel syndrome is associated with impaired outcome.
Engstrand Lilja H, Wefer H, Nyström N, Finkel Y, Engstrand L
Microbiome 2015 ;3():18

Increase in the Prevalence of Atrophic Gastritis Among Adults Age 35 to 44 Years Old in Northern Sweden Between 1990 and 2009.
Song H, Held M, Sandin S, Rautelin H, Eliasson M, Söderberg S, et al
Clin. Gastroenterol. Hepatol. 2015 Sep;13(9):1592-600.e1

Increase in the Prevalence of Atrophic Gastritis Among Adults Age 35 to 44 Years Old in Northern Sweden Between 1990 and 2009.
Song H, Held M, Sandin S, Rautelin H, Eliasson M, Söderberg S, et al
Clin. Gastroenterol. Hepatol. 2015 Sep;13(9):1592-600.e1

Psoriasis is not an autoimmune disease?
Fry L, Baker B, Powles A, Engstrand L
Exp. Dermatol. 2015 Apr;24(4):241-4

No difference in small bowel microbiota between patients with irritable bowel syndrome and healthy controls.
Dlugosz A, Winckler B, Lundin E, Zakikhany K, Sandström G, Ye W, et al
Sci Rep 2015 Feb;5():8508

Colonic spirochetosis is associated with colonic eosinophilia and irritable bowel syndrome in a general population in Sweden.
Walker M, Talley N, Inganäs L, Engstrand L, Jones M, Nyhlin H, et al
Hum. Pathol. 2015 Feb;46(2):277-83

 

Group Members

Fredrik BoulundPostdoc
Nele BrusselaersAssistant professor
Hanna DanielssonResearch assistant
Juan DuPostdoc
Lars EngstrandHead of office, Professor/senior physician
Emma FranssonSenior research specialist
Joseph KirangwaAssociated
Frank MaixnerAssociated
Stefanie Prast-NielsenPostdoc
Ina Schuppe KoistinenDirector
Saeed ShoaiePostdoc
Johanna SiminGraduate Student
Renate Slind OlsenAssociated
Kaisa ThorellPostdoc
Jing WangAssociated
Luisa Warchavchik HugerthPostdoc

Associated members

 

Collaborations and Group Funding

Collaborations

Cross-departmental collaborations have been developed with a number research centers, including the Dept. of Medicine, Baylor College of Medicine (David Graham), Houston, Tx, Center for Genome Sciences and Systems Biology (Jeffrey Gordon), Washington University School of Medicine, St. Louis, and Dept. of Medicine, New York University School of Medicine (Martin Blaser), NY, USA. Lars Engstrand has faculty positions (adjunct professor) at these three universities with co-PI positions in collaboration projects. We have also collaborations with a number of research groups in Sweden including translational research projects within the Clinical Genomics facility organization. Some Swedish collaborators in the microbiology field are Weimin Ye, Olof Nyren, Lars Agreus and Mauro DAmato (KI), Jonas Halvarsson (Örebro), Andreas Matussek (Jönköping), Mathias Uhlén, Anders Andersson (KTH, Stockholm), Hilpi Rautelin, Dan Andersson, Åke Gustavsson (Uppsala), Jens Nielsen (Chalmers, Gothenburg), Håkan Hanberger (Linköping), Thomas Borén (Umeå), Helena Enroth (Skövde) and Karin Tegmark-Wisell (Public Healt Agency, Stockholm). Lars Engstrand was appointed Director of Center for Translational Microbiome Research, CTMR - an open academic research collaboration between Ferring Pharmaceuticals and Lars Engstrands group at KI

Projects in Lars Engstrand´s group receive funding from the following sources:

  • Karolinska Institutet
  • Ferring Pharmaceuticals
  • VetenskapsrĂĄdet - The Swedish Research Council
  • Cancerfonden
  • EuroNanoMed
  • Söderbergs stiftelse

Useful links

Washington University, School of Medicin
http://www.scilifelab.se
http://www.med.nyu.edu/medicine/labs/blaserlab/
https://gordonlab.wustl.edu
Baylor College of Medicine

 

Institutionen för Medicinska Vetenskaper, Uppsala Universitet
http://www.euronanomed.net

 

 

 

Infectious Disease Control