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  • Sloan, Tim J.; Jalanka, Jonna; Major, Giles A. D.; Krishnasamy, Shanthi; Pritchard, Sue; Abdelrazig, Salah; Korpela, Katri; Singh, Gulzar; Mulvenna, Claire; Hoad, Caroline L.; Marciani, Luca; Barrett, David A.; Lomer, Miranda C. E.; de Vos, Willem M.; Gowland, Penny A.; Spiller, Robin C. (2018)
    Background & aims Ingestion of poorly digested, fermentable carbohydrates (fermentable oligo-, di-, mono-saccharides and polyols; FODMAPs) have been implicated in exacerbating intestinal symptoms and the reduction of intake with symptom alleviation. Restricting FODMAP intake is believed to relieve colonic distension by reducing colonic fermentation but this has not been previously directly assessed. We performed a randomised controlled trial comparing the effect of a low FODMAP diet combined with either maltodextrin or oligofructose on colonic contents, metabolites and microbiota. Methods A parallel randomised controlled trial in healthy adults (n = 37). All subjects followed a low FODMAP diet for a week and supplemented their diet with either maltodextrin (MD) or oligofructose (OF) 7g twice daily. Fasted assessments performed pre- and post-diet included MRI to assess colonic volume, breath testing for hydrogen and methane, and stool collection for microbiota analysis. Results The low FODMAP diet was associated with a reduction in Bifidobacterium and breath hydrogen, which was reversed by oligofructose supplementation. The difference in breath hydrogen between groups post-intervention was 27ppm (95% CI 7 to 50, P Conclusion A low FODMAP diet reduces total bacterial count and gas production with little effect on colonic volume.
  • Kringel, D.; Lippmann, C.; Parnham, M. J.; Kalso, E.; Ultsch, A.; Lötsch, J. (2018)
    Background Human genetic research has implicated functional variants of more than one hundred genes in the modulation of persisting pain. Artificial intelligence and machine-learning techniques may combine this knowledge with results of genetic research gathered in any context, which permits the identification of the key biological processes involved in chronic sensitization to pain. MethodsResultsBased on published evidence, a set of 110 genes carrying variants reported to be associated with modulation of the clinical phenotype of persisting pain in eight different clinical settings was submitted to unsupervised machine-learning aimed at functional clustering. Subsequently, a mathematically supported subset of genes, comprising those most consistently involved in persisting pain, was analysed by means of computational functional genomics in the Gene Ontology knowledgebase. Clustering of genes with evidence for a modulation of persisting pain elucidated a functionally heterogeneous set. The situation cleared when the focus was narrowed to a genetic modulation consistently observed throughout several clinical settings. On this basis, two groups of biological processes, the immune system and nitric oxide signalling, emerged as major players in sensitization to persisting pain, which is biologically highly plausible and in agreement with other lines of pain research. ConclusionsSignificanceThe present computational functional genomics-based approach provided a computational systems-biology perspective on chronic sensitization to pain. Human genetic control of persisting pain points to the immune system as a source of potential future targets for drugs directed against persisting pain. Contemporary machine-learned methods provide innovative approaches to knowledge discovery from previous evidence. We show that knowledge discovery in genetic databases and contemporary machine-learned techniques can identify relevant biological processes involved in Persitent pain.
  • Kekkonen, Riina A.; Holma, Reetta; Hatakka, Katja; Suomalainen, Tarja; Poussa, Tuija; Adlercreutz, Herman; Korpela, Riitta (2011)
  • Geerlings, Sharon Y.; Kostopoulos, Ioannis; de Vos, Willem M.; Belzer, Clara (2018)
    Akkermansia muciniphila is a mucin-degrading bacterium of the phylum Verrucomicrobia. Its abundance in the human intestinal tract is inversely correlated to several disease states. A. muciniphila resides in the mucus layer of the large intestine, where it is involved in maintaining intestinal integrity. We explore the presence of Akkermansia-like spp. based on its 16S rRNA sequence and metagenomic signatures in the human body so as to understand its colonization pattern in time and space. A. muciniphila signatures were detected in colonic samples as early as a few weeks after birth and likely could be maintained throughout life. The sites where Akkermansia-like sequences (including Verrucomicrobia phylum and/or Akkermansia spp. sequences found in the literature) were detected apart from the colon included human milk, the oral cavity, the pancreas, the biliary system, the small intestine, and the appendix. The function of Akkermansia-like spp. in these sites may differ from that in the mucosal layer of the colon. A. muciniphila present in the appendix or in human milk could play a role in the re-colonization of the colon or breast-fed infants, respectively. In conclusion, even though A. muciniphila is most abundantly present in the colon, the presence of Akkermansia-like spp. along the digestive tract indicates that this bacterium might have more functions than those currently known.
  • Biesiekierski, Jessica R.; Jalanka, Jonna; Staudacher, Heidi M. (2019)
    Dietary intervention is a challenge in clinical practice because of inter-individual variability in clinical response. Gut microbiota is mechanistically relevant for a number of disease states and consequently has been incorporated as a key variable in personalised nutrition models within the research context. This paper aims to review the evidence related to the predictive capacity of baseline microbiota for clinical response to dietary intervention in two specific health conditions, namely, obesity and irritable bowel syndrome (IBS). Clinical trials and larger predictive modelling studies were identified and critically evaluated. The findings reveal inconsistent evidence to support baseline microbiota as an accurate predictor of weight loss or glycaemic response in obesity, or as a predictor of symptom improvement in irritable bowel syndrome, in dietary intervention trials. Despite advancement in quantification methodologies, research in this area remains challenging and larger scale studies are needed until personalised nutrition is realistically achievable and can be translated to clinical practice.
  • Koenig, J.; Siebenhaar, A.; Hoegenauer, C.; Arkkila, P.; Nieuwdorp, M.; Noren, T.; Ponsioen, C. Y.; Rosien, U.; Rossen, N. G.; Satokari, R.; Stallmach, A.; de Vos, W.; Keller, J.; Brummer, R. J. (2017)
    Background Faecal microbiota transplantation or transfer (FMT) aims at replacing or reinforcing the gut microbiota of a patient with the microbiota from a healthy donor. Not many controlled or randomised studies have been published evaluating the use of FMT for other diseases than Clostridium difficile infection, making it difficult for clinicians to decide on a suitable indication. Aim To provide an expert consensus on current clinical indications, applications and methodological aspects of FMT. Methods Well-acknowledged experts from various countries in Europe have contributed to this article. After literature review, consensus has been achieved by repetitive circulation of the statements and the full manuscript among all authors with intermittent adaptation to comments (using a modified Delphi process). Levels of evidence and agreement were rated according to the GRADE system. Consensus was defined a priori as agreement by at least 75% of the authors. Results Key recommendations include the use of FMT in recurrent C. difficile infection characterised by at least two previous standard treatments without persistent cure, as well as its consideration in severe and severe-complicated C. difficile infection as an alternative to total colectomy in case of early failure of antimicrobial therapy. FMT in inflammatory bowel diseases (IBD), irritable bowel syndrome (IBS) and metabolic syndrome should only be performed in research settings. Conclusions Faecal microbiota transplantation or transfer is a promising treatment for a variety of diseases in which the intestinal microbiota is disturbed. For indications other than C. difficile infection, more evidence is needed before more concrete recommendations can be made.
  • Lääveri, Tinja; Vilkman, Katri; Pakkanen, Sari; Kirveskari, Juha; Kantele, Anu (2018)
    Background: Among visitors to the (sub)tropics, 20-50% contract travellers' diarrhoea (TD) and 5-30% take antibiotics. While shortening the duration of illness, antimicrobials predispose to acquisition of multi-drug resistant bacteria. Therefore, liberal use is no longer advocated. Although antibiotics kill pathogens, no data support the view that they could prevent post-infectious sequelae. We investigated how antibiotic use for TD abroad impacts the pathogen findings at return. Materials and methods: We revisited 456 travellers' clinical data and stool pathogens examined by qPCR for Salmonella, Yersinia, Campylobacter, Shigella, Vibrio cholerae and enteroaggregative (EAEC), enteropathogenic (EPEC), enterotoxigenic (ETEC), enterohaemorrhagic (EHEC) and enteroinvasive (EIEC) Escherichia coli. Results: Among travellers with TD, antibiotic users had pathogen-positive samples less frequently than non-users (50% versus 83%). The difference was significant for EPEC (23% versus 47%) and EAEC (27% versus 54%), but not ETEC (17% versus 26%) or the other pathogens. Shigella/EIEC was found more often among antibiotic users than non-users (4% versus 1%). Conclusion: Despite antibiotic treatment of TD, half of the users still had stool pathogens at return, reflecting either antibiotic resistance of pathogens or recolonisation/reinfection while abroad. Treatment of TD with antibiotics during travel should not be interpreted to indicate eradication of pathogens.
  • COST Action GENIEURI BM1106 Microb; Vork, Lisa; Penders, John; Jalanka, Jonna; Salonen, Anne; de Vos, Willem M.; Jonkers, Daisy M. A. E. (2021)
    Introduction Stool consistency has been associated with fecal microbial composition. Stool consistency often varies over time, in subjects with and without gastrointestinal disorders, raising the question whether variability in the microbial composition should be considered in microbiota studies. We evaluated within-subject day-to-day variability in stool consistency and the association with the fecal microbiota in irritable bowel syndrome (IBS) and healthy subjects, over seven days. Methods Twelve IBS patients and 12 healthy subjects collected fecal samples during seven consecutive days. Stool consistency was determined by the patient-reported Bristol Stool Scale (BSS) and fecal dry weight percentage. 16S rRNA V4 gene sequencing was performed and microbial richness (alpha diversity; Chao1 index, observed number of species, effective Shannon index) and microbial community structure (beta diversity; Bray-Curtis distance, generalized UniFrac, and taxa abundance on family level) were determined. Results Linear mixed-effects models showed significant associations between stool consistency and microbial richness, but no time effect. This implies that between-subject but not within-subject variation in microbiota over time can partially be explained by variation in stool consistency. Redundancy analysis showed a significant association between stool consistency and microbial community structure, but additional linear mixed-effects models did not demonstrate a time effect on this. Conclusion This study supports an association between stool consistency and fecal microbiota, but no effect of day-to-day fluctuations in stool consistency within seven days. This consolidates the importance of considering stool consistency in gut microbiota research, though confirms the validity of single fecal sampling to represent an individual's microbiota at a given time point. NCT00775060.
  • Cammarota, Giovanni; Ianiro, Gianluca; Tilg, Herbert; Rajilic-Stojanovic, Mirjana; Kump, Patrizia; Satokari, Reetta; Sokol, Harry; Arkkila, Perttu; Pintus, Cristina; Hart, Ailsa; Segal, Jonathan; Aloi, Marina; Masucci, Luca; Molinaro, Antonio; Scaldaferri, Franco; Gasbarrini, Giovanni; Lopez-Sanroman, Antonio; Link, Alexander; De Groot, Pieter; de Vos, Willem M.; Hoegenauer, Christoph; Malfertheiner, Peter; Mattila, Eero; Milosavljevic, Tomica; Nieuwdorp, Max; Sanguinetti, Maurizio; Simren, Magnus; Gasbarrini, Antonio; European FMT Working Grp (2017)
    Faecal microbiota transplantation (FMT) is an important therapeutic option for Clostridium difficile infection. Promising findings suggest that FMT may play a role also in the management of other disorders associated with the alteration of gut microbiota. Although the health community is assessing FMT with renewed interest and patients are becoming more aware, there are technical and logistical issues in establishing such a non-standardised treatment into the clinical practice with safety and proper governance. In view of this, an evidence-based recommendation is needed to drive the practical implementation of FMT. In this European Consensus Conference, 28 experts from 10 countries collaborated, in separate working groups and through an evidence-based process, to provide statements on the following key issues: FMT indications; donor selection; preparation of faecal material; clinical management and faecal delivery and basic requirements for implementing an FMT centre. Statements developed by each working group were evaluated and voted by all members, first through an electronic Delphi process, and then in a plenary consensus conference. The recommendations were released according to best available evidence, in order to act as guidance for physicians who plan to implement FMT, aiming at supporting the broad availability of the procedure, discussing other issues relevant to FMT and promoting future clinical research in the area of gut microbiota manipulation. This consensus report strongly recommends the implementation of FMT centres for the treatment of C. difficile infection as well as traces the guidelines of technicality, regulatory, administrative and laboratory requirements.
  • Jalanka-Tuovinen, Jonna; Salonen, Anne; Nikkila, Janne; Immonen, Outi; Kekkonen, Riina; Lahti, Leo; Palva, Airi; de Vos, Willem M. (2011)
  • Ringel-Kulka, Tamar; Cheng, Jing; Ringel, Yehuda; Salojarvi, Jarkko; Carroll, Ian; Palva, Airi; de Vos, Willem M.; Satokari, Reetta (2013)
  • Hynönen, Ulla; Zoetendal, Erwin G.; Virtala, Anna-Maija K.; Shetty, Sudarshan; Hasan, Shah; Jakava-Viljanen, Miia; de Vos, Willem M.; Palva, Airi (2020)
    In our previous studies on irritable bowel syndrome (IBS) –associated microbiota by molecular methods, we demonstrated that a particular 16S rRNA gene amplicon was more abundant in the feces of healthy subjects or mixed type IBS (IBS-M) –sufferers than in the feces of individuals with diarrhea-type IBS (IBS-D). In the current study, we demonstrated that this, so called Ct85-amplicon, consists of a cluster of very heterogeneous 16S rRNA gene sequences, and defined six 16S rRNA gene types, a to f, within this cluster, each representing a novel species-, genus- or family level taxon. We then designed specific PCR primers for these sequence types, mapped the distribution of the Ct85-cluster sequences and that of the newly defined sequence types in several animal species and compared the sequence types present in the feces of healthy individuals and IBS sufferers using two IBS study cohorts, Finnish and Dutch. Various Ct85-cluster sequence types were detected in the fecal samples of several companion and production animal species with remarkably differing prevalences and abundances. The Ct85 sequence type composition of swine closely resembled that of humans. One of the five types (d) shared between humans and swine was not present in any other animals tested, while one sequence type (b) was found only in human samples. In both IBS study cohorts, one type (e) was more prevalent in healthy individuals than in the IBS-M group. By revealing various sequence types in the widespread Ct85-cluster and their distribution, the results improve our understanding of these uncultured bacteria, which is essential for future efforts to cultivate representatives of the Ct85-cluster and reveal their roles in IBS.
  • Oksaharju, Anna; Kankainen, Matti; Kekkonen, Riina A.; Lindstedt, Ken A.; Kovanen, Petri T.; Korpela, Riitta; Miettinen, Minja (2011)
  • Laatikainen, Reijo; Salmenkari, Hanne; Sibakov, Timo; Vapaatalo, Heikki; Turpeinen, Anu (2020)
    Unspecific gastrointestinal symptoms associated with milk consumption are common. In addition to lactose, also other components of milk may be involved. We studied whether the partial hydrolysation of milk proteins would affect gastrointestinal symptoms in subjects with functional gastrointestinal disorders. In a randomised, placebo-controlled crossover intervention, subjects (n = 41) were given ordinary or hydrolysed high-protein, lactose-free milkshakes (500 mL, 50 g protein) to be consumed daily for ten days. After a washout period of ten days, the other product was consumed for another ten days. Gastrointestinal symptoms were recorded daily during the study periods, and a validated irritable bowel syndrome-symptom severity scale (IBS-SSS) questionnaire was completed at the beginning of the study and at the end of both study periods. Blood and urine samples were analysed for markers of inflammation, intestinal permeability and immune activation. Both the IBS-SSS score (p = 0.001) and total symptom score reported daily (p = 0.002) were significantly reduced when participants consumed the hydrolysed product. Less bloating was reported during both study periods when compared with the baseline (p < 0.01 for both groups). Flatulence (p = 0.01) and heartburn (p = 0.03) decreased when consuming the hydrolysed product but not when drinking the control product. No significant differences in the levels of inflammatory markers (tumor necrosis factor alpha, TNF-α and interleukin 6, IL-6), intestinal permeability (fatty acid binding protein 2, FABP2) or immune activation (1-methylhistamine) were detected between the treatment periods. The results suggest that the partial hydrolysation of milk proteins (mainly casein) reduces subjective symptoms to some extent in subjects with functional gastrointestinal disorders. The mechanism remains to be resolved. © 2020 by the authors. Licensee MDPI, Basel, Switzerland.
  • Laaveri, Tinja; Sterne, Jesper; Rombo, Lars; Kantele, Anu (2016)
    Looking at the worldwide emergency of antimicrobial resistance, international travellers appear to have a central role in spreading the bacteria across the globe. Travellers' diarrhoea (TD) is the most common disease encountered by visitors to the (sub) tropics. Both TD and its treatment with antibiotics have proved significant independent risk factors of colonization by resistant intestinal bacteria while travelling. Travellers should therefore be given preventive advice regarding TD and cautioned about taking antibiotics: mild or moderate TD does not require antibiotics. Logical alternatives are medications with effects on gastrointestinal function, such as loperamide. The present review explores literature on loperamide in treating TD. Adhering to manufacturer's dosage recommendations, loperamide offers a safe and effective alternative for relieving mild and moderate symptoms. Moreover, loperamide taken singly does no predispose to contracting MDR bacteria. Most importantly, we found no proof that would show antibiotics to be significantly more effective than loperamide in treating mild/moderate TD. (C) 2016 The Authors. Published by Elsevier Ltd.
  • Rajilic-Stojanovic, Mirjana; de Vos, Willem M. (2014)