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Contains fulltext : 244566.pdf (Publisher’s version ) (Closed access) BACKGROUND AND AIMS: The case-mix of patients with intestinal failure due to short bowel syndrome (SBS-IF) can differ among centres and may also be affected by the timeframe of data collection. Therefore, the ESPEN international multicenter cross-sectional survey was analyzed to compare the characteristics of SBS-IF cohorts collected within the same timeframe in different countries. METHODS: The study included 1880 adult SBS-IF patients collected in 2015 by 65 centres from 22 countries. The demographic, nutritional, SBS type (end jejunostomy, SBS-J; jejuno-colic anastomosis, SBS-JC; jejunoileal anastomosis with an intact colon and ileocecal valve, SBS-JIC), underlying disease and intravenous supplementation (IVS) characteristics were analyzed. IVS was classified as fluid and electrolyte alone (FE) or parenteral nutrition admixture (PN). The mean daily IVS volume, calculated on a weekly basis, was categorized as 3 L/day. RESULTS: In the entire group: 60.7% were females and SBS-J comprised 60% of cases, while mesenteric ischaemia (MI) and Crohn' disease (CD) were the main underlying diseases. IVS dependency was longer than 3 years in around 50% of cases; IVS was infused ≥5 days/week in 75% and FE in 10% of cases. Within the SBS-IF cohort: CD was twice and thrice more frequent in SBS-J than SBS-JC and SBS-JIC, respectively, while MI was more frequent in SBS-JC and SBS-JIC. Within countries: SBS-J represented 75% or more of patients in UK and Denmark and 50-60% in the other countries, except Poland where SBS-JC prevailed. CD was the main underlying disease in UK, USA, Denmark and The Netherlands, while MI prevailed in France, Italy and Poland. CONCLUSIONS: SBS-IF type is primarily determined by the underlying disease, with significant variation between countries. These novel data will be useful for planning and managing both clinical activity and research studies on SBS.

Lawsonia intracellularis is a Gram-negative obligate intracellular bacterium that is the aetiological agent of proliferative enteropathy (PE), a common intestinal disease of major economic importance in pigs and other animal species. To date, progress in understanding the biology of L. intracellularis for improved disease control has been hampered by the inability to culture the organism in vitro. In particular, our understanding of the genomic diversity and population structure of clinical L. intercellularis is very limited. Here, we utilized a metagenomic shotgun approach to directly sequence and assemble 21 L. intracellularis genomes from faecal and ileum samples of infected pigs and horses across three continents. Phylogenetic analysis revealed a genetically monomorphic clonal lineage responsible for infections in pigs, with distinct subtypes associated with infections in horses. The genome was highly conserved, with 94 % of genes shared by all isolates and a very small accessory genome made up of only 84 genes across all sequenced strains. In part, the accessory genome was represented by regions with a high density of SNPs, indicative of recombination events importing novel gene alleles. In summary, our analysis provides the first view of the population structure for L. intracellularis, revealing a single major lineage associated with disease of pigs. The limited diversity and broad geographical distribution suggest the recent emergence and clonal expansion of an important livestock pathogen. ispartof: MICROBIAL GENOMICS vol:6 issue:4 ispartof: location:England status: published

International audience; Bacteriophages were discovered in the early 20th century and rapidly used to treat bacterial infections in humans. As the first specific antibacterial agents, they were used worldwide until antibiotics ramped up. Thereafter, rapidly forgotten, they be- came the favorite toolbox for researchers that used them to elucidate some of the most fundamental aspects of the cellular life at the molecular level. Today, facing the threat of antibiotic resistant bacteria, bacteriophages are being reconsidered for their use in medicine. During the past century, knowledge on bacteriophages has improved considerably, nevertheless phage therapy is still in its infancy. Taking two examples of recently published experimental phage therapy results, this article summarizes the hopes but also the challenges that surround the future development of human phage therapy.; -Découverts au début du XX e siècle, les bactériophages ont rapidementété utilisés pour traiter des infections bactériennes, devenant ainsi les premiers antibactériens spécifiquesàêtre employés en médecine. Cependant, l'arrivée des antibiotiques a brutalement réduit leur utilisation, les confinant au rayon ((boîteà outils)) du chercheur. Celui-ci en fît bon usage permettant de dévoiler une très grande partie des secrets moléculaires de la cellule. Aujourd'hui, faceà la menace que représentent les pathogènes bactériens résistants aux antibiotiques, les bactériophages tentent de faire leur retour dans le domaine médical. Bien que la connaissance de ces virus bactériens ait considérablement progressé après presque un siècle d'études, leur utilisation thérapeutique est loin d'être maîtrisée. Cet article relate,à l'aide de deux exemples récents de l'utilisation expérimentale des bactériophages, les espoirs mais aussi les challenges qui entourent la mise en place de la phagothérapie appliquéeà l'Homme. Mots clés : Bactériophages thérapeutiques / infections bactériennes / résistance aux antibiotiques / pneumonie / diarrhée Abstract-Phagotherapy: a nightmare for bacteria, a dream for physicians? Bacteriophages were discovered in the early 20th century and rapidly used to treat bacterial infections in humans. As the first specific antibacterial agents, they were used worldwide until antibiotics ramped up. Thereafter, rapidly forgotten, they became the favorite toolbox for researchers that used them to elucidate some of the most fundamental aspects of the cellular life at the molecular level. Today, facing the threat of antibiotic resistant bacteria, bacteriophages are being reconsidered for their use in medicine. During the past century, knowledge on bacteriophages has improved considerably, nevertheless phage therapy is still in its infancy. Taking two examples of recently published experimental phage therapy results, this article summarizes the hopes but also the challenges that surround the future development of human phage therapy.

International audience; Bacteriophages were discovered in the early 20th century and rapidly used to treat bacterial infections in humans. As the first specific antibacterial agents, they were used worldwide until antibiotics ramped up. Thereafter, rapidly forgotten, they be- came the favorite toolbox for researchers that used them to elucidate some of the most fundamental aspects of the cellular life at the molecular level. Today, facing the threat of antibiotic resistant bacteria, bacteriophages are being reconsidered for their use in medicine. During the past century, knowledge on bacteriophages has improved considerably, nevertheless phage therapy is still in its infancy. Taking two examples of recently published experimental phage therapy results, this article summarizes the hopes but also the challenges that surround the future development of human phage therapy.; -Découverts au début du XX e siècle, les bactériophages ont rapidementété utilisés pour traiter des infections bactériennes, devenant ainsi les premiers antibactériens spécifiquesàêtre employés en médecine. Cependant, l'arrivée des antibiotiques a brutalement réduit leur utilisation, les confinant au rayon ((boîteà outils)) du chercheur. Celui-ci en fît bon usage permettant de dévoiler une très grande partie des secrets moléculaires de la cellule. Aujourd'hui, faceà la menace que représentent les pathogènes bactériens résistants aux antibiotiques, les bactériophages tentent de faire leur retour dans le domaine médical. Bien que la connaissance de ces virus bactériens ait considérablement progressé après presque un siècle d'études, leur utilisation thérapeutique est loin d'être maîtrisée. Cet article relate,à l'aide de deux exemples récents de l'utilisation expérimentale des bactériophages, les espoirs mais aussi les challenges qui entourent la mise en place de la phagothérapie appliquéeà l'Homme. Mots clés : Bactériophages thérapeutiques / infections bactériennes / résistance aux antibiotiques / pneumonie / diarrhée Abstract-Phagotherapy: a nightmare for bacteria, a dream for physicians? Bacteriophages were discovered in the early 20th century and rapidly used to treat bacterial infections in humans. As the first specific antibacterial agents, they were used worldwide until antibiotics ramped up. Thereafter, rapidly forgotten, they became the favorite toolbox for researchers that used them to elucidate some of the most fundamental aspects of the cellular life at the molecular level. Today, facing the threat of antibiotic resistant bacteria, bacteriophages are being reconsidered for their use in medicine. During the past century, knowledge on bacteriophages has improved considerably, nevertheless phage therapy is still in its infancy. Taking two examples of recently published experimental phage therapy results, this article summarizes the hopes but also the challenges that surround the future development of human phage therapy.

In vivo bacteriophage targeting of enteroaggregative Escherichia coli (EAEC) was assessed using a mouse intestinal model of colonization with the O104:H4 55989Str strain and a cocktail of three virulent bacteriophages. The colonization model was shown to mimic asymptomatic intestinal carriage found in humans. The addition of the cocktail to drinking water for 24 h strongly decreased ileal and weakly decreased fecal 55989Str concentrations in a dose-dependent manner. These decreases in ileal and fecal bacterial concentrations were only transient, since 55989Str concentrations returned to their original levels 3 days later. These transient decreases were independent of the mouse microbiota, as similar results were obtained with axenic mice. We studied the infectivity of each bacteriophage in the ileal and fecal environments and found that 55989Str bacteria in the mouse ileum were permissive to all three bacteriophages, whereas those in the feces were permissive to only one bacteriophage. Our results provide the first demonstration that bacterial permissivity to infection with virulent bacteriophages is not uniform throughout the gut; this highlights the need for a detailed characterization of the interactions between bacteria and bacteriophages in vivo for the further development of phage therapy targeting intestinal pathogens found in the gut of asymptomatic human carriers.

International audience; Yeasts and their glycan components can have a beneficial or adverse effect on intestinal inflammation. Previous research has shown that the presence of Saccharomyces cerevisiae var. boulardii (Sb) reduces intestinal inflammation and colonization by Candida albicans. The aim of this study was to identify dietary yeasts, which have comparable effects to the anti-C. albicans and anti-inflammatory properties of Sb and to assess the capabilities of yeast cell wall components to modulate intestinal inflammation. Mice received a single oral challenge of C. albicans and were then given 1.5% dextran-sulphate-sodium (DSS) for 2 weeks followed by a 3-day restitution period. S. cerevisiae strains (Sb, Sc1 to Sc4), as well as mannoprotein (MP) and β-glucan crude fractions prepared from Sc2 and highly purified β-glucans prepared from C. albicans were used in this curative model, starting 3 days after C. albicans challenge. Mice were assessed for the clinical, histological and inflammatory responses related to DSS administration. Strain Sc1-1 gave the same level of protection against C. albicans as Sb when assessed by mortality, clinical scores, colonization levels, reduction of TNFα and increase in IL-10 transcription. When Sc1-1 was compared with the other S. cerevisiae strains, the preparation process had a strong influence on biological activity. Interestingly, some S. cerevisiae strains dramatically increased mortality and clinical scores. Strain Sc4 and MP fraction favoured C. albicans colonization and inflammation, whereas β-glucan fraction was protective against both. Surprisingly, purified β-glucans from C. albicans had the same protective effect. Thus, some yeasts appear to be strong modulators of intestinal inflammation. These effects are dependent on the strain, species, preparation process and cell wall fraction. It was striking that β-glucan fractions or pure β-glucans from C. albicans displayed the most potent anti-inflammatory effect in the DSS model.

International audience; Circulating citrulline is emerging as an innovating biomarker candidate for assessment of intestinal function. Amino acid synthesized by enterocytes of intestinal mucosal, citrulline is not included in proteins or nutrition products and is a precursor for production of arginine by the kidney. Plasma citrulline is, in clinical situation, an established biomarker of enterocyte functional metabolic mass (trophicity) in children and in adult patients due to its high relation to active functional small bowel remnant length in intestinal diseases (short bowel, extensive enteropathies, intestinal toxicity of chemotherapy and radiotherapy. Plasma citrulline concentration (30-50 μmol/L), independent of nutritional status, if less than 10 μmol/L can give an objective threshold for nutrition parenteral use in case of intestinal failure due to enterocyte abnormalities or lack. Its regular dosage allows the monitoring of intestinal function except in case of significant renal failure.

Objective Molecular diagnosis and prenatal care of two pregnant women at risk of transmitting immunodysregulation, polyendocrinopathy, enteropathy X-linked (IPEX) syndrome. Methods FOXP3 coding sequence and exon boundaries were analyzed in the two consultants and family members. Non-invasive sex determination and specific prenatal diagnosis was realized. Results Following sequence analysis a new FOXP3 mutation was identified in each consultant. Sex diagnosis realized by amplification of Y sequences from the plasma of the two mothers revealed a male and a female fetus, respectively. Prenatal diagnosis showed that the male fetus was unaffected. The baby is now born and healthy. Subsequent ultrasound examinations confirmed the sex in the second pregnancy but unfortunately led to the diagnosis of a 69,XXX triploidy. The pregnancy was thus interrupted. Conclusion Two new FOXP3 mutations were identified and prenatal diagnosis could be proposed. Due to the rarity of the disease, clinical diagnosis is often considered with delay. Both patients reported here were already pregnant at the beginning of the genetic investigation and one had previously interrupted a male pregnancy for lack of diagnosis. When faced with children with severe refractory diarrhea, clinicians should entertain the possibility of IPEX. Copyright © 2010 John Wiley & Sons, Ltd.

International audience; Our digestive tract has an autonomous functioning but also has a bidirectional relation with our brain known as brain-gut interactions. This communication is mediated by the autonomous nervous system, i.e., the sympathetic and parasympathetic nervous systems, with a mixed afferent and efferent component, and the circumventricular organs located outside the blood-brain barrier. The vagus nerve, known as the principal component of the parasympathetic nervous system, is a mixed nerve composed of 90% afferent fibers, which has physiological roles due to its putative vegetative functions. The vagus nerve has also anti-inflammatory properties both through the hypothalamic pituitary adrenal axis (through its afferents) and the cholinergic anti-inflammatory pathway (through its efferents). The sympathetic nervous system has a classical antagonist effect on the parasympathetic nervous system at the origin of an equilibrated sympathovagal balance in normal conditions. The brain is able to integrate inputs coming from the digestive tract inside a central autonomic network organized around the hypothalamus, limbic system and cerebral cortex (insula, prefrontal, cingulate) and in return to modify the autonomic nervous system and the hypothalamic pituitary adrenal axis in the frame of physiological loops. A dysfunction of these brain-gut interactions, favoured by stress, is most likely involved in the pathophysiology of digestive diseases such as irritable bowel syndrome or even inflammatory bowel diseases. A better knowledge of these brain-gut interactions has therapeutic implications in the domain of pharmacology, neurophysiology, behavioural and cognitive management.

Background elicobacter pylori infection is associated with several gastro-duodenal inflammatory diseases of various levels of severity. To determine whether certain combinations of genetic markers can be used to predict the clinical source of the infection, we analyzed well documented and geographically homogenous clinical isolates using a comparative genomics approach. Results A set of 254 H. pylori genes was used to perform array-based comparative genomic hybridization among 120 French H. pylori strains associated with chronic gastritis (n = 33), duodenal ulcers (n = 27), intestinal metaplasia (n = 17) or gastric extra-nodal marginal zone B-cell MALT lymphoma (n = 43). Hierarchical cluster analyses of the DNA hybridization values allowed us to identify a homogeneous subpopulation of strains that clustered exclusively with cag PAI minus MALT lymphoma isolates. The genome sequence of B38, a representative of this MALT lymphoma strain-cluster, was completed, fully annotated, and compared with the six previously released H. pylori genomes (i.e. J99, 26695, HPAG1, P12, G27 and Shi470). B38 has the smallest H. pylori genome described thus far (1,576,758 base pairs containing 1,528 CDSs); it contains the vacA s2m2 allele and lacks the genes encoding the major virulence factors (absence of cag PAI, bab B, bab C, sab B, and hom B). Comparative genomics led to the identification of very few sequences that are unique to the B38 strain (9 intact CDSs and 7 pseudogenes). Pair-wise genomic synteny comparisons between B38 and the 6 H. pylori sequenced genomes revealed an almost complete co-linearity, never seen before between the genomes of strain Shi470 (a Peruvian isolate) and B38. Conclusion These isolates are deprived of the main H. pylori virulence factors characterized previously, but are nonetheless associated with gastric neoplasia.

Victoni, Tatiana Coelho, Fernando Rodrigues Soares, Alexandre Learth de Freitas, Andressa Secher, Thomas Guabiraba, Rodrigo Erard, Francois de Oliveira-Filho, Ricardo Martins Vargaftig, B Boris Lauvaux, Gregoire Kamal, Mamdouh A Ryffel, Bernhard Moser, Rene Tavares-de-Lima, Wothan Germany Med Microbiol Immunol. 2010 Feb;199(1):35-42. doi: 10.1007/s00430-009-0134-5. Epub 2009 Nov 26.; International audience; Innate immune responses against microorganisms may be mediated by Toll-like receptors (TLRs). Intestinal ischemia-reperfusion (i-I/R) leads to the translocation of bacteria and/or bacterial products such as endotoxin, which activate TLRs leading to acute intestinal and lung injury and inflammation observed upon gut trauma. Here, we investigated the role of TLR activation by using mice deficient for the common TLR adaptor protein myeloid differentiation factor 88 (MyD88) on local and remote inflammation following intestinal ischemia. Balb/c and MyD88(-/-) mice were subjected to occlusion of the superior mesenteric artery (45 min) followed by intestinal reperfusion (4 h). Acute neutrophil recruitment into the intestinal wall and the lung was significantly diminished in MyD88(-/-) after i-I/R, which was confirmed microscopically. Diminished neutrophil recruitment was accompanied with reduced concentration of TNF-alpha and IL-1beta level. Furthermore, diminished microvascular leak and bacteremia were associated with enhanced survival of MyD88(-/-) mice. However, neither TNF-alpha nor IL-1beta neutralization prevented neutrophil recruitment into the lung but attenuated intestinal inflammation upon i-I/R. In conclusion, our data demonstrate that disruption of the TLR/MyD88 pathway in mice attenuates acute intestinal and lung injury, inflammation, and endothelial damage allowing enhanced survival.

OBJECTIVE The response of ventromedial hypothalamic (VMH) glucose-inhibited neurons to decreased glucose is impaired under conditions where the counterregulatory response (CRR) to hypoglycemia is impaired (e.g., recurrent hypoglycemia). This suggests a role for glucose-inhibited neurons in the CRR. We recently showed that decreased glucose increases nitric oxide (NO) production in cultured VMH glucose-inhibited neurons. These in vitro data led us to hypothesize that NO release from VMH glucose-inhibited neurons is critical for the CRR. RESEARCH DESIGN AND METHODS The CRR was evaluated in rats and mice in response to acute insulin-induced hypoglycemia and hypoglycemic clamps after modulation of brain NO signaling. The glucose sensitivity of ventromedial nucleus glucose-inhibited neurons was also assessed. RESULTS Hypoglycemia increased hypothalamic constitutive NO synthase (NOS) activity and neuronal NOS (nNOS) but not endothelial NOS (eNOS) phosphorylation in rats. Intracerebroventricular and VMH injection of the nonselective NOS inhibitor NG-monomethyl-l-arginine (l-NMMA) slowed the recovery to euglycemia after hypoglycemia. VMH l-NMMA injection also increased the glucose infusion rate (GIR) and decreased epinephrine secretion during hyperinsulinemic/hypoglycemic clamp in rats. The GIR required to maintain the hypoglycemic plateau was higher in nNOS knockout than wild-type or eNOS knockout mice. Finally, VMH glucose-inhibited neurons were virtually absent in nNOS knockout mice. CONCLUSIONS We conclude that VMH NO production is necessary for glucose sensing in glucose-inhibited neurons and full generation of the CRR to hypoglycemia. These data suggest that potentiating NO signaling may improve the defective CRR resulting from recurrent hypoglycemia in patients using intensive insulin therapy.

International audience; OBJECTIVE: Molecular diagnosis and prenatal care of two pregnant women at risk of transmitting immunodysregulation, polyendocrinopathy, enteropathy X-linked (IPEX) syndrome. METHODS: FOXP3 coding sequence and exon boundaries were analyzed in the two consultants and family members. Non-invasive sex determination and specific prenatal diagnosis was realized. RESULTS: Following sequence analysis a new FOXP3 mutation was identified in each consultant. Sex diagnosis realized by amplification of Y sequences from the plasma of the two mothers revealed a male and a female fetus, respectively. Prenatal diagnosis showed that the male fetus was unaffected. The baby is now born and healthy. Subsequent ultrasound examinations confirmed the sex in the second pregnancy but unfortunately led to the diagnosis of a 69,XXX triploidy. The pregnancy was thus interrupted. CONCLUSION: Two new FOXP3 mutations were identified and prenatal diagnosis could be proposed. Due to the rarity of the disease, clinical diagnosis is often considered with delay. Both patients reported here were already pregnant at the beginning of the genetic investigation and one had previously interrupted a male pregnancy for lack of diagnosis. When faced with children with severe refractory diarrhea, clinicians should entertain the possibility of IPEX.

National audience; Small and large bowels are dose-limiting structures for acute and late toxicity of abdominopelvic radiotherapy. Minor or moderate toxicities are underestimated. Major toxicities may occur years from treatment. Current optimal radiotherapy planning may predict precisely toxicities and new technologies for treatment delivery may prevent and/or reduce the frequency and severity of radiation enteropathy.

SUMMARYThe intestinal tract is a complex ecosystem that combines resident microbiota and the cells of various phenotypes with complex metabolic activities that line the epithelial wall. The intestinal cells that make up the epithelium provide physical and chemical barriers that protect the host against the unwanted intrusion of microorganisms that hijack the cellular molecules and signaling pathways of the host and become pathogenic. Some of the organisms making up the intestinal microbiota also have microbicidal effects that contribute to the barrier against enteric pathogens. This review describes the two cell lineages present in the intestinal epithelium: the goblet cells and the Paneth cells, both of which play a pivotal role in the first line of enteric defense by producing mucus and antimicrobial peptides, respectively. We also analyze recent insights into the intestinal microbiota and the mechanisms by which some resident species act as a barrier to enteric pathogens. Moreover, this review examines whether the cells producing mucins or antimicrobial peptides and the resident microbiota act in partnership and whether they function individually and/or synergistically to provide the host with an effective front line of defense against harmful enteric pathogens.