Sergey R Konstantinov

Erasmus Universiteit Rotterdam, Rotterdam, South Holland, Netherlands

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Publications (45)114.03 Total impact

  • Hester Eppinga · H.B.Thio · M.P. Peppelenbosch · S.R. Konstantinov
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    ABSTRACT: In past decades, gut microbiome perturbations appeared to play a role in the development of several autoimmune diseases. Microbiome dysbiosis together with genetic, lifestyle and/or diet factors may composedly affect the etiology of autoimmune diseases. Studies about the role of the gut microbiome in psoriatic arthritis (PsA), a chronic autoimmune disease of the joint, are limited. We propose that intestinal dysbiosis-associated microbiota or gut microbiota-derived products might reach the joint by translocation to the circulation leading to T-cell activation and inflammation that underline PsA. Future studies on the intestinal microbiome associated with psoriatic arthritis can provide new targets for diagnostic and treatment strategies. Recognizing the PsA ‘early warning phases’ could offer new windows of opportunities regarding prevention.
    International Journal of Clinical Rheumatology 12/2014;
  • Hester Eppinga · Hok Bing Thio · Maikel P Peppelenbosch · Sergey R Konstantinov
    12/2014; 9(6):559-565. DOI:10.2217/ijr.14.52
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    Vilvapathy Narayanan · Maikel P Peppelenbosch · Sergey R Konstantinov
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    Vilvapathy Narayanan · Maikel P Peppelenbosch · Sergey R Konstantinov
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    ABSTRACT: Colorectal cancer (CRC) may develop slowly over years from precursor lesions, and thus, screening combined with early diagnosis is the key to disease prevention. Recent studies have elucidated specific traits in the gut microbiome associated with CRC and suggested that the microbiome may be useful in screening for CRC purposes but failed to provide protocols that can be applied in a practical situation. A recent study by Zackular and colleagues presented in this issue of Cancer Prevention Research provides an important way forward here in showing that specific analysis of multiple aspects of the microbiome composition in toto provides reliable detection of both precancerous and cancerous lesions. This important achievement when combined with other non-invasive techniques promises to provide highly effective tools for early CRC diagnosis and its prevention.
    Cancer Prevention Research 09/2014; 7(11). DOI:10.1158/1940-6207.CAPR-14-0273 · 5.27 Impact Factor
  • Hester Eppinga · Sergey R Konstantinov · Maikel P Peppelenbosch · H Bing Thio
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    ABSTRACT: Psoriatic arthritis is a chronic inflammatory joint disease, seen in combination with the chronic inflammatory skin disease psoriasis and belonging to the family of spondylarthritides (SpA). A link is recognized between psoriatic arthritis and inflammatory bowel disease (IBD). Environmental factors seem to induce inflammatory disease in individuals with underlying genetic susceptibility. The microbiome is a subject of increasing interest in the etiology of these inflammatory immune-mediated diseases. The intestinal microbiome is able to affect extra-intestinal distant sites, including the joints, through immunomodulation. At this point, evidence regarding a relationship between the microbiome and psoriatic arthritis is scarce. However, we hypothesize that common immune-mediated inflammatory pathways seen in the "skin-joint-gut axis" in psoriatic arthritis are induced or at least mediated by the microbiome. Th17 has a crucial function in this mechanism. Further establishment of this connection may lead to novel therapeutic approaches for psoriatic arthritis.
    Current Rheumatology Reports 03/2014; 16(3):407. DOI:10.1007/s11926-013-0407-2 · 2.45 Impact Factor
  • Sergey R Konstantinov · Ernst J Kuipers · Maikel P Peppelenbosch
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    ABSTRACT: The evidence for a strong correlation between the gut microbiota and colorectal carcinogenesis is quickly gathering pace. This correlation raises important questions, such as whether analysis of the microbiota can be used for screening purposes, and whether targeted intervention can influence the risk of development and progression of neoplasia. The recovery of several pathobionts-such as members of the different bacterial phyla Proteobacteria, Bacteroidetes and Fusobacteria-from the tumour microenvironment of patients with colorectal cancer (CRC) now provides a link between specific microbial colonization and cancer. However, other intestinal bacteria belonging to another major intestinal phylum, Firmicutes, might be effective in the treatment of pathogenic inflammation related to CRC. Future approaches based on the analysis of the gut microbiota of patients with CRC combined with large human cohort studies might open up new possibilities for further prophylactic, screening and treatment strategies.
    Nature Reviews Gastroenterology &#38 Hepatology 09/2013; 10. DOI:10.1038/nrgastro.2013.178 · 10.81 Impact Factor
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    ABSTRACT: Although genome wide association studies have partly uncovered the genetic basis of Crohn's disease (CD), it remains a challenge to link genetic polymorphisms to functional intestinal phenotypes. Paneth cells are specialised antimicrobial epithelial cells localised to the small-intestinal crypt-base. Here, we investigate whether genomic variations in ATG16L1 affect Paneth cell function. Genomic variation of ATG16L1 (T300A, rs2241880) was determined in DNA from 78 patients with CD and 12 healthy controls. Paraffin-embedded ileal biopsies from patients with genotype AA (n=17), GA (n=38) and patients with the GG allele (n=23) were stained for GRP78, phospho-EIF2α, lysozyme, cleaved-caspase 3, phosphohistone H3, phospho-IκB, p65, phospho-p38MAPK and PHLDA1. Microbial composition of biopsies was assessed by PCR. Disease phenotype was scored. In patients with quiescent disease but with an ATG16L1 risk allele, the endoplasmic reticulum (ER) stress markers GRP78 and pEIF2α were highly expressed in Paneth cells. Other CD risk gene variations did not correlate with Paneth cell ER stress. Functionally, patients with ER-stressed Paneth cells showed no changes in intestinal epithelial cells proliferation or apoptosis, Paneth cell or stem cell numbers, p65, phospho-IκB and phospho-p38 staining. However, a significantly increased presence of adherent-invasive Escherichia coli was observed in biopsies from patients with ER-stressed Paneth cells. Phenotypically, patients with GRP78 positive Paneth cells have relatively less colonic disease over ileal disease (-21%, p=0.04), more fistulas (+21%, p=0.05) and an increased need for intestinal surgery (+38%, p=0.002). The ATG16L1 T300A polymorphism defines a specific subtype of patients with CD, characterised by Paneth cell ER stress even during quiescent disease. Paneth cell ER stress correlates with bacterial persistence, and is thus likely to modulate antimicrobial functionality of this cell type in patients with CD.
    Gut 08/2013; 63(7). DOI:10.1136/gutjnl-2012-303527 · 13.32 Impact Factor
  • Sergey R Konstantinov · C Janneke van der Woude · Maikel P Peppelenbosch
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    ABSTRACT: Pregnancy has a beneficial influence on the course of certain autoimmune diseases such as inflammatory bowel disease (IBD). It was recently reported that during pregnancy the microbiome undergoes profound changes that are associated with host physiological and immunological adaptations. Here we propose that microbiome remodeling during pregnancy is an active response of the mother, possibly to alter immune system status, and to facilitate metabolic and immunological adaptations that are needed for a successful pregnancy. Furthermore, these changes in the microbiome may ensure the transfer of specific traits into the neonatal gut. As the underlying mechanisms are not well understood, elucidating how pregnancy-related changes in the microbiome influence IBD would be of obvious value for designing rational therapy.
    Trends in Molecular Medicine 07/2013; 19(8). DOI:10.1016/j.molmed.2013.06.002 · 10.11 Impact Factor
  • Sergey R Konstantinov · Maikel P Peppelenbosch
    Gastroenterology 02/2013; 144(4). DOI:10.1053/j.gastro.2012.12.040 · 13.93 Impact Factor
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    ABSTRACT: Prophylactic probiotic therapy has shown beneficial effects in an experimental rat model for acute pancreatitis on the health status of the animals. Mechanisms by which probiotic therapy interferes with severity of acute pancreatitis and associated sepsis, however, are poorly understood. The aims of this study were to identify the probiotic-induced changes in the gut microbiota and to correlate these changes to disease outcome. Duodenum and ileum samples were obtained from healthy and diseased rats subjected to pancreatitis for 7 days and prophylactically treated with either a multispecies probiotic mixture or a placebo. Intestinal microbiota was characterized by terminal-restriction fragment length polymorphism (T-RFLP) analyses of PCR-amplified 16S rRNA gene fragments. These analyses showed that during acute pancreatitis the host-specific ileal microbiota was replaced by an "acute pancreatitis-associated microbiota." This replacement was not reversed by administration of the probiotic mixture. An increase, however, was observed in the relative abundance of a novel bacterial phylotype most closely related to Clostridium lituseburense and referred to as commensal rat ileum bacterium (CRIB). Specific primers targeting the CRIB 16S rRNA gene sequence were developed to detect this phylotype by quantitative PCR. An ileal abundance of CRIB 16S rRNA genes of more than 7.5% of the total bacterial 16S rRNA gene pool was correlated with reduced duodenal bacterial overgrowth, reduced bacterial translocation to remote organs, improved pancreas pathology, and reduced proinflammatory cytokine levels in plasma. Our current findings and future studies involving this uncharacterized bacterial phylotype will contribute to unraveling one of the potential mechanisms of probiotic therapy.
    Applied and Environmental Microbiology 09/2011; 77(21):7749-56. DOI:10.1128/AEM.05428-11 · 3.95 Impact Factor
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    C F Inman · K Haverson · S R Konstantinov · P H Jones · C Harris · H Smidt · B Miller · M Bailey · C Stokes
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    ABSTRACT: Early-life exposure to appropriate microbial flora drives expansion and development of an efficient immune system. Aberrant development results in increased likelihood of allergic disease or increased susceptibility to infection. Thus, factors affecting microbial colonization may also affect the direction of immune responses in later life. There is a need for a manipulable animal model of environmental influences on the development of microbiota and the immune system during early life. We assessed the effects of rearing under low- (farm, sow) and high-hygiene (isolator, milk formula) conditions on intestinal microbiota and immune development in neonatal piglets, because they can be removed from the mother in the first 24 h for rearing under controlled conditions and, due to placental structure, neither antibody nor antigen is transferred in utero. Microbiota in both groups was similar between 2 and 5 days. However, by 12-28 days, piglets reared on the mother had more diverse flora than siblings reared in isolators. Dendritic cells accumulated in the intestinal mucosa in both groups, but more rapidly in isolator piglets. Importantly, the minority of 2-5-day-old farm piglets whose microbiota resembled that of an older (12-28-day-old) pig also accumulated dendritic cells earlier than the other farm-reared piglets. Consistent with dendritic cell control of T cell function, the effects on T cells occurred at later time-points, and mucosal T cells from high-hygiene, isolator pigs made less interleukin (IL)-4 while systemic T cells made more IL-2. Neonatal piglets may be a valuable model for studies of the effects of interaction between microbiota and immune development on allergy.
    Clinical & Experimental Immunology 02/2010; 160(3):431-9. DOI:10.1111/j.1365-2249.2010.04090.x · 3.28 Impact Factor
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    ABSTRACT: Dendritic cells (DCs) are antigen-presenting cells that play an essential role in mucosal tolerance. They regularly encounter beneficial intestinal bacteria, but the nature of these cellular contacts and the immune responses elicited by the bacteria are not entirely elucidated. Here, we examined the interactions of Lactobacillus acidophilus NCFM and its cell surface compounds with DCs. L. acidophilus NCFM attached to DCs and induced a concentration-dependent production of IL-10, and low IL-12p70. We further demonstrated that the bacterium binds to DC-specific ICAM-3-grabbing nonintegrin (DC-SIGN), a DC- specific receptor. To identify the DC-SIGN ligand present on the bacterium, we took advantage of a generated array of L. acidophilus NCFM mutants. A knockout mutant of L. acidophilus NCFM lacking the surface (S) layer A protein (SlpA) was significantly reduced in binding to DC-SIGN. This mutant incurred a chromosomal inversion leading to dominant expression of a second S layer protein, SlpB. In the SlpB-dominant strain, the nature of the interaction of this bacterium with DCs changed dramatically. Higher concentrations of proinflammatory cytokines such as IL-12p70, TNFalpha, and IL-1beta were produced by DCs interacting with the SlpB-dominant strain compared with the parent NCFM strain. Unlike the SlpA-knockout mutant, T cells primed with L. acidophilus NCFM stimulated DCs produced more IL-4. The SlpA-DC-SIGN interaction was further confirmed as purified SlpA protein ligated directly to the DC-SIGN. In conclusion, the major S layer protein, SlpA, of L. acidophilus NCFM is the first probiotic bacterial DC-SIGN ligand identified that is functionally involved in the modulation of DCs and T cells functions.
    Proceedings of the National Academy of Sciences 01/2009; 105(49):19474-9. DOI:10.1073/pnas.0810305105 · 9.81 Impact Factor
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    ABSTRACT: The microbial community in the guts of mammals is often seen as an important potential target in therapeutic and preventive interventions. The aim of the present study was to determine whether enterotoxigenic Escherichia coli (ETEC) F4 infection in young animals might be counteracted by a probiotic treatment with Lactobacillus sobrius DSM 16698. The experiment was conducted in three randomized consecutive replications, each consisting of 16 piglets, and including a control group and an L. sobrius fed group, both experimentally challenged with ETEC. During the entire trial, the animals' health status, body weight, and microbial parameters were monitored periodically. Probiotic supplementation containing L. sobrius significantly reduced the levels of ETEC in the ileum when fed directly to piglets after weaning. In contrast, the number of days when the piglets had an increased faecal water content was significantly higher in the probiotic group. Nevertheless, an improved daily weight gain was also observed in the animals that received probiotic L. sobrius relative to the control fed group. The data indicate that L. sobrius may be effective in the reduction of the E. coli F4 colonization and may improve the weight gain of infected piglets.
    FEMS Microbiology Ecology 07/2008; 66(3):599-607. DOI:10.1111/j.1574-6941.2008.00517.x · 3.88 Impact Factor
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    ABSTRACT: Lactobacilli have a potential to overcome intestinal disorders; however, the exact mode of action is still largely unknown. In this study, we have used the intestinal porcine intestinal IPEC-1 epithelial cells as a model to investigate a possible protective activity of a new Lactobacillus species, the L. sobrius DSM 16698(T), against intestinal injury induced by enterotoxigenic Escherichia coli (ETEC) K88 infection and the underlying mechanisms. Treatment of infected cells with L. sobrius strongly reduced the pathogen adhesion. L. sobrius was also able to prevent the ETEC-induced membrane damage by inhibiting delocalization of zonula occludens (ZO)-1, reduction of occludin amount, rearrangement of F-actin, and dephosphorylation of occludin caused by ETEC. RT-PCR and ELISA experiments showed that L. sobrius counteracted the ETEC-induced increase of IL-8 and upregulated the IL-10 expression. The involvement of IL-8 in the deleterious effects of ETEC was proven by neutralization of IL-8 with a specific antibody. A crucial role of IL-10 was indicated by blockage of IL-10 production with neutralizing anti-IL-10 antibody that fully abrogated the L. sobrius protection. L. sobrius was also able to inhibit the internalization of ETEC, which was likely favored by the leaking barrier. The protective effects were not found with L. amylovorus DSM 20531(T) treatment, a strain derived from cattle waste but phylogenetically closely related to L. sobrius. Together, the data indicate that L. sobrius exerts protection against the harmful effects of ETEC by different mechanisms, including pathogen adhesion inhibition and maintenance of membrane barrier integrity through IL-10 regulation.
    Journal of Nutrition 01/2008; 137(12):2709-16. · 4.23 Impact Factor
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    ABSTRACT: Infection of pancreatic necrosis by gut bacteria is a major cause of morbidity and mortality in patients with severe acute pancreatitis. Use of prophylactic antibiotics remains controversial. The aim of this experiment was assess if modification of intestinal flora with specifically designed multispecies probiotics reduces bacterial translocation or improves outcome in a rat model of acute pancreatitis. Male Sprague-Dawley rats were allocated into 3 groups: (1) controls (sham-operated, no treatment), (2) pancreatitis and placebo, and (3) pancreatitis and probiotics. Acute pancreatitis was induced by intraductal glycodeoxycholate and intravenous cerulein infusion. Daily probiotics or placebo was administered intragastrically from 5 days prior until 7 days after induction of pancreatitis. Tissue and fluid samples were collected for microbiologic and quantitative real-time PCR analysis of bacterial translocation. Probiotics reduced duodenal bacterial overgrowth of potential pathogens (Log(10) colony-forming units [CFU]/g 5.0 +/- 0.7 [placebo] vs 3.5 +/- 0.3 CFU/g [probiotics], P < .05), resulting in reduced bacterial translocation to extraintestinal sites, including the pancreas (5.38 +/- 1.0 CFU/g [placebo] vs 3.1 +/- 0.5 CFU/g [probiotics], P < .05). Accordingly, health scores were better and late phase mortality was reduced: 27% (4/15, placebo) versus 0% (0/13, probiotics), respectively, P < .05. This experiment supports the hypothesis that modification of intestinal flora with multispecies probiotics results in reduced bacterial translocation, morbidity, and mortality in the course of experimental acute pancreatitis.
    Surgery 05/2007; 141(4):470-80. DOI:10.1016/j.surg.2006.10.007 · 3.11 Impact Factor
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    ABSTRACT: An abstract is unavailable. This article is available as HTML full text and PDF.
    Pancreas 10/2006; 33(4):504. DOI:10.1097/00006676-200611000-00228 · 3.01 Impact Factor
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    ABSTRACT: The current study describes the development of the porcine microbiota and its metabolic activities during the neonatal and weaning period. Using 16S rRNA-based approaches, we first analysed the ileal and colonic microbiota of neonatal piglets at days 2, 5 and 12 after birth. To further investigate the effect of weaning at 3 weeks of age, 19-day-old piglets (n = 64) were randomly allocated into two groups. Half of the piglets remained with their sows throughout the study, while the remaining piglets were weaned. As revealed by sequence analysis of 16S rRNA gene amplicons, the samples of 2-day-old piglets harboured a consortium of bacteria related to Escherichia coli, Shigella flexneri, Lactobacillus sobrius, Lactobacillus reuteri and Lactobacillus acidophilus. Moreover, species-specific real-time polymerase chain reaction assays unveiled that L. sobrius and L. reuteri predominated in the ileal samples of the neonatal and unweaned piglets with population levels up to 7 x 10(8) cells per gram of lumen content. Following weaning, however, these two lactobacilli were detected at significantly lower levels (< 10(3)) in the ileal samples. Furthermore, a shift in composition and metabolic activities of the predominant microbiota, and emergence of clostridia and E. coli, were encountered in the intestinal samples of the piglets after the early post-weaning period.
    Environmental Microbiology 08/2006; 8(7):1191-9. DOI:10.1111/j.1462-2920.2006.01009.x · 6.24 Impact Factor
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    ABSTRACT: To obtain porcine isolates related to Lactobacillus amylovorus, we screened strains from piglet intestine grown on Lactobacillus-specific MRS agar for hybridization to a fluorescent 16S rRNA-targeted DNA probe. Six strains were isolated and further characterized by phenotypic and molecular taxonomic methods. The isolates were Gram-positive, catalase-negative, facultatively anaerobic rods. They had similar phenotypic characteristics and displayed genomic DNA-DNA relatedness values of >78 % to each other, indicating that they belong to a single species. Comparative 16S rRNA gene sequence analysis demonstrated that the novel isolates were members of Lactobacillus rRNA group I, which includes Lactobacillus delbrueckii, the type species of the genus. Based on 16S rRNA gene sequence similarity, Lactobacillus kitasatonis (99 %), Lactobacillus crispatus (98 %) and Lactobacillus amylovorus (97 %) were the nearest relatives of the novel isolates, but their DNA-DNA relatedness was found to be lower than 49 %. One of the isolates, strain OTU171-001T, was further characterized using physiological and biochemical tests. Together, the results enabled genotypic and phenotypic differentiation of strain OTU171-001T from the other species that showed 16S rRNA gene sequence similarity values greater than 97 %. Strain OTU171-001T merits species status and the name Lactobacillus sobrius sp. nov. is proposed. The type strain is OTU171-001T (= DSM 16698T = NCCB 100067T).
    International Journal of Systematic and Evolutionary Microbiology 01/2006; 56(Pt 1):29-32. DOI:10.1099/ijs.0.63508-0 · 2.80 Impact Factor
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  • S.R. Konstantinov · H. Smidt

Publication Stats

990 Citations
114.03 Total Impact Points

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  • 2013–2014
    • Erasmus Universiteit Rotterdam
      • Department of Gastroenterology and Hepatology
      Rotterdam, South Holland, Netherlands
    • Erasmus MC
      Rotterdam, South Holland, Netherlands
  • 2010
    • University Medical Center Utrecht
      • Department of Medical Microbiology
      Utrecht, Utrecht, Netherlands
  • 2009
    • VU University Amsterdam
      Amsterdamo, North Holland, Netherlands
  • 2003–2008
    • Wageningen University
      • Laboratory of Microbiology
      Wageningen, Gelderland, Netherlands
  • 2006
    • University of Granada
      • Faculty of Pharmacy
      Granata, Andalusia, Spain