The regulation of glucagon-like peptide-1 and peptide YY hormone levels are regulated based on different influential factors, but primarily levels are dependent upon ingested food content. As meals today become more fat-enriched, there is greater requirement for evaluation of these hormones that regulate insulin and satiety levels within the body. We have shown that the gene expression transcript production of glucagon-like peptide-1 and peptide YY are modulated by different concentrations, and times of short-chain fatty acids and long-chain fatty acids. Although the peptide hormone levels have the influential physiological role on effector tissue, the regulation of these hormones begins at the transcript levels. Recent research indicates that glucagon-like peptide-1 and peptide YY hormones are altered in response to different free-fatty acids. The present investigation generally demonstrated an overall decrease in both hormones after chronic exposure to fatty acids. Intestinal secretin tumor cell line (STC-1 cells) was used as a representative for intestinal L-cells. Quantitative real-time PCR analysis was used to determine the changes in RNA transcripts. Overall, there was a decrease in the 3-hour timeline, which continued to decrease in the 16-hour and 24-hour timelines for glucagon-like peptide-1. Peptide YY transcript expression in 3-hours increased significantly after exposure to propionate, a significant decrease after exposure to acetate, and no significant increase or decrease after exposure to butyrate. However, there was a significant decrease in peptide YY once reaching 24-hour exposure. It was determined there is a threshold for different concentrations of free-fatty acids to influence glucagon-like peptide-1 and peptide YY production, which was present in the different concentrations of butyrate. Lastly, exposure to both concentrations of linolenic acid caused a significant decrease in glucagon-like peptide-1 and peptide YY.

L’optimisation de l’utilisation de phosphore reste un enjeu majeur pour assurer la durabilité de nos filières avicoles et porcines. Aujourd’hui, l’utilisation de coproduits, relativement riches en fibres alimentaires, est grandissante. Or, les fibres alimentaires sont reconnues pour moduler les processus de digestion et la digestibilité des nutriments. Ce travail de thèse a permis de progresser sur les mécanismes digestifs engendrés par l’apport de coproduits riches en fibres alimentaires et leurs effets sur la digestion des minéraux, en lien avec la phytase microbienne, spécifiquement chez le porc et le poulet. Leurs conséquences métaboliques en terme de balance minérale et d’équilibre acidobasique ont également été mises en évidence Les connaissances acquises vont contribuer à l’amélioration de l’apport en minéraux, notamment de phosphore et de calcium, dans des formules diversifiées chez le porc et le poulet. A terme, ceci permettra de mieux adapter nos systèmes d’alimentations au regard des enjeux de durabilité. / The optimisation of the use of phosphorus remains a major challenge to ensure the sustainability of poultry and pig industry. Today, the use of co-product, relatively rich in dietary fibre, is increasing. However, dietary fibre is known to modulate digestion processes and digestibility of nutrients. This work contributed to progress on the digestive mechanisms generated by the intake of dietary fibre from coproducts and their effects on the digestion of minerals, in relation with microbial phytase, specifically in pigs and chickens. Their metabolic consequences in terms of mineral and acid-base balance have also been demonstrated. The knowledge gained will contribute to the improvement of the intake of minerals, in particular phosphorus and calcium, in diversified formulas in pigs and the chicken. Finally, this will allow us to better adapt our feeding systems to the challenges of sustainability.

While substantial progress has been made in replacing live prey with artificial diets in the feeding of marine fish larvae, it still remains impossible to successfully rear larvae on artificial diets without some period of co-feeding live prey or algae. This study investigated the presence and role of the gastrointestinal hormone cholecystokinin (CCK) in the red drum (Sciaenops ocellatus) to gain a better understanding of the factors limiting the utilization of artificial diets by red drum larvae. Work with other fish species has shown that CCK is the principal hormone which regulates the release of pancreatic enzymes into the gut lumen and emphasizes the potential importance of CCK in early red drum larvae. This work investigated the hypothesis that some signal present in the live prey or algae stimulates CCK and thereby initiates the digestive process in the larvae. First, the nucleotide and amino acid sequence of the putative red drum cholecystokinin precursor was determined and the development of CCK immunoreactive cells was examined. This work showed that red drum CCK is highly similar to CCK in other vertebrates and can be detected in the digestive tract of larval red drum within three days after the initiation of exogenous feeding. Next; postprandial trypsin, CCK, and CCK mRNA responses were quantified in red drum juveniles and larvae over a three hour period. Both CCK and trypsin were increased within thirty minutes following feeding while CCK mRNA levels were increased within the next two to three hours. Finally, the trypsin, CCK, and CCK mRNA responses of red drum larvae to homogenates of live prey and algae were examined. Homogenized rotifers appeared to be sufficient to induce both the CCK and trypsin responses in larval red drum. These results suggest that in addition to other factors, some component of live prey may initiate the release of CCK and prime the digestive process. Understanding these factors and their effects in early larvae may allow us to formulate and produce a prepared diet which will support growth and survival to metamorphosis equal to that provided by live feeds. / text

Asymmetric cell divisions constitute a basic foundation of animal development, providing a mechanism for placing specific cell types at defined positions in a developing organism. In a 4-cell stage embryo in Caenorhabditis elegansthe EMS cell divides asymmetrically to specify intestinal cells, which requires a polarizing signal from the neighboring P2 cell. Here we describe how the extracellular signal from P2 is transmitted from the membrane to the nucleus during asymmetric EMS cell division, and present the identification of additional components in the pathways that accomplish this signaling. P2/EMS signaling involves multiple inputs, which impinge on the Wnt, MAPK-like, and Src pathways. Transcriptional outputs downstream of these pathways depend on a homolog of β-catenin, WRM-1. Here we analyze the regulation of WRM-1, and show that the MAPK-like pathway maintains WRM-1 at the membrane, while its release and nuclear translocation depend on Wnt/Src signaling and sequential phosphorylation events by the major cell-cycle regulator CDK-1 and by the membrane-bound GSK-3 during EMS cell division. Our results provide novel mechanistic insights into how the signaling events at the cortex are coupled to the asymmetric EMS cell division through WRM-1. To identify additional regulators in the pathways governing gut specification, we performed suppressor genetic screens using temperature-sensitive alleles of the gutless mutant mom-2/Wnt, and extra-gut mutant cks-1. Five intragenic suppressors and three semi-dominant suppressors were isolated in mom-2 suppressor screens. One extragenic suppressor was mapped to the locus ifg-1, eukaryotic translation initiation factor eIF4G. From the suppressor screen using cks-1(ne549), an allele of the self-cleaving nucleopore protein npp-10 was identified as a suppressor of cks-1(ne549)and other extra-gut mutants. Taken together, these results help us better understand how the fate of intestinal cells are specified and regulated in early C. elegans embryos and broaden our knowledge of cell polarity and fate specification.

C1q TNF Related Protein 3 (CTRP3), is a cytokine that is primarily secreted from adipose tissue, which classifies it as an adipokine. Our previous research has shown that CTRP3 prevents alcoholic fatty liver disease (ALD) in male mice. However, even when accounting for confounding factors such as absolute and relative alcohol intake, females are more sensitive to the effects of consumption compared to male mice. Therefore, the goal of this project was to determine whether CTRP3 prevented ALD in female mice. Methods: Female wild type (WT) and female CTRP3 transgenic over expressing (Tg) mice were fed an ethanol containing liquid diet (5% v/v) for 6 weeks. Daily weight and food intake measurements were taken and external heat-pads were placed under a portion of the cage to facilitate thermoregulation. Hepatic steatosis was determined by total triglyceride quantification and lipid droplet quantitation in liver sections. Data were analyzed by repeated measures ANOVA, t-test, or Log-rank (Mantel-Cox) test as appropriate. Results: There was no difference between WT and Tg mice in food intake or body weight. There was no difference in survival between WT and Tg mice, however, Tg mice trended towards a reduced rate of survival compared with WT mice (78% in WT versus 44% in Tg, p=0.13). Stereological analysis indicated no difference in the percent of lipid liver volume between the two groups (WT 7.2±3.6 vs Tg 5.1±4.1%). This finding was consistent with no difference in total hepatic triglyceride accumulation observed between WT and Tg mice (12.7±4.4 vs. 13.1±6.8 mg triglycerides/gram liver protein). Conclusion: Combined these data indicate that unlike previous studies with male mice, CTRP3 is not protective against alcohol-induced hepatic steatosis in female mice. Combined, these data indicate that the adipokines such as CTRP3 contribute to physiology in a sex-specific manner.

INTRODUCTION: The diagnosis of esophageal varices in cirrhotic patients is made by the upper gastrointestinal endoscopy. Multiple non-invasive predictors have been studied for the diag-nosis of esophageal varices. The objective of this study is to testthe FIB4 index as screening of esophageal varices in patients with liver cirrhosis. MATERIALS AND METHODS: A cross-sectional analytic study was developed in four national hospital using hepatic cirrhosis patient's medi-cal files. We assessed the information using univariate and bivariate analysis, sensitivity, speci-ficity, predictive positive and negative value, the positive and negative likelihood ratio calcu-lation of the esophageal varices screening and its size. We built ROC curve for every analysis group. RESULTS: The study included 289 liver cirrhosis patients. Most of the patients were male (54.33%). 77.85% patients had esophageal varices. The distribution of varices was 19.03%, 35.99% and 22.84% for large, medium and small varices, respectively. In the FIB-4 index analysis for the presence of varices, it was found a sensitivity of 81.3%, specificity of 37.5% (AUC: 0.57). The calculation for variceal size showed a sensitivity of 81.8%, specificity of 23.9% (AUC: 0.50). In the analysis of FIB-4 index for prophylaxis groups was found a sensitivity of 81.8% and a specificity of 28.5% (AUC: 0.54). CONCLUSIONS: The FIB-4 index has no good performance in the screening for the presence of esophageal varices and its size in liver cirrhosis patients. / Revisión por pares

Le cancer colorectal (CCR) est le 3ème plus diagnostiqué au Canada. Son traitement implique une résection chirurgicale du côlon ou du rectum, et une reconnexion des deux bouts intestinaux pour rétablir la continuité gastrointestinale. Cette reconnexion, appelée « anastomose », peut ne pas bien guérir chez jusqu’à 30% des patients, ce qui mène à une complication morbide et mortelle appelée « fuite anastomotique ». En plus de diminuer la survie et la qualité de vie, la fuite est possiblement associée à une récidive accrue du cancer pour des raisons qui demeurent obscures. Malgré des progrès techniques importants dans les dernières décennies, les taux de fuite n’ont pas significativement diminué, et sa survenue demeure hautement imprévisible. Des données récentes ont suggéré que le microbiote intestinal, ou la collection de microorganismes dans l’intestin, peut influencer le processus de guérison après la chirurgie, mais l’évidence sur cette relation reste faible. Les études suivantes visaient donc à évaluer le lien causal entre le microbiote, la fuite anastomotique le CCR. En utilisant des échantillons de selles collectés avant la chirurgie de 18 patients avec CCR (9 avec fuite et 9 sans fuite), on a évalué le rôle causal du microbiote humain chez des souris assujetties à une greffe de microbiote fécal (GMF) puis une chirurgie colique. On a trouvé que la GMF avec des échantillons de patients avec fuite a entrainé chez la souris une mauvaise guérison anastomotique, un affaiblissement de la matrice extracellulaire dans la plaie colique, et une inflammation accrue localement. On a identifié 2 souches bactériennes, Parabacteroides goldsteinii kh35 et Alistipes onderdonkii kh33, qui influençaient la guérison anastomotique, la 1ère positivement et la 2ème négativement. Ces souches modulaient l’inflammation dans la muqueuse colique, avec P. goldsteinii exerçant un effet anti-inflammatoire et A. onderdonkii un effet pro-inflammatoire. En utilisant des échantillons de muqueuses collectés de patients avant la complétion de l’anastomose, on a trouvé avec une analyse multiplex que les patients présentant une fuite avaient des niveaux basaux plus élevés des macrophage inflammatory protein-1 alpha, monocyte chemoattractant protein-1, macrophage inflammatory protein 2 et interleukin-17A/F, et que le microbiote de ces patients entraine une augmentation similaire de ces cytokines pro-inflammatoires dans l’intestin des souris. Pour corroborer l’hypothèse que les patients présentant une fuite après la chirurgie avaient des niveaux basaux plus élevés d’inflammation intestinale de bas-grade induite par le microbiote, on a quantifié 9 cytokines dans la muqueuse colorectale de 77 patients avec CCR, pami lesquels 13 ont présenté une fuite après la chirurgie. Les 9 cytokines étaient plus élevées chez les patients ayant développé une fuite. On a exploré des marqueurs inflammatoires potentiels dans les selles, et qui peuvent être utilisés comme des biomarqueurs de dépistage avant la chirurgie, et avons identifié la calprotectine et la lipocaline-2 comme étant significativement différentes entre les patients présentant, ou pas, une fuite anastomotique. Ensuite, on a exploré si des métabolites bactériens peuvent être utilisés pour améliorer la guérison anastomotique. Les acides-gras à courte chaine (AGCCs) sont produits dans le côlon après la fermentation bactérienne de fibres alimentaires. On a ainsi testé si une supplémentation chez la souris avec de l’inuline ou des galacto-oligosaccharides (GOS), deux oligosaccharides fermentables, peut améliorer la guérison. On a trouvé que l’inuline et le GOS ont augmenté les niveaux du bénéfique AGCC butyrate, amélioré la guérison anastomotique, favorisé la réparation épithéliale, la déposition du collagène et la barrière intestinale. Enfin, puisque le butyrate est connu pour son effet anticancérigène via une activation peroxysome proliferator-activated receptor gamma (PPAR-γ), on a investigué la relation entre l’amélioration de la guérison intestinale postopératoire avec l’inuline et le 5-aminosalicylate (5-ASA), un activateur de PPAR-γ, et la récidive du CCR. Une revue de la survie postopératoire de patients avec CCR ayant, ou pas, présenté une fuite a été effectuée. L’effet d’une supplémentation alimentaire avec de l’inuline ou du 5-ASA sur les tumeurs anastomotiques a été évalué chez des souris subissant une chirurgie colique. L’inuline et le 5-ASA ont été aussi évalués dans un modèle murin de métastases hépatiques où les cellules de CCR étaient inoculées chirurgicalement dans la rate. Les patients présentant une fuite présentaient une survie globale et oncologique moindre que les patients sans fuite. Une mauvaise guérison anastomotique chez la souris a entrainé des tumeurs anastomotiques et péritonéales plus volumineuses. L’inuline et le 5-ASA ont renforcé la barrière intestinale et prévenu les tumeurs anastomotiques et dissémination métastatique chez la souris. Ces trouvailles renforcent l’hypothèse que prévenir la fuite améliore les issues oncologiques des patients avec CCR, et ouvre la voie à des essais cliniques où des interventions modifiant le microbiote seraient utilisées pour favoriser la guérison et diminuer la récidive du cancer. En résumé, on a démontré pour la première fois le lien causal entre le microbiote intestinal préopératoire et la guérison anastomotique chez les patients avec CCR. On a aussi identifié des biomarqueurs potentiels qui peuvent être utilisés en pratique pour détecter l’inflammation subclinique de bas-grade induite par le microbiote pour prédire la guérison avant la chirurgie. On a aussi démontré que le microbiote et PPAR-γ peuvent être modulés avec des oligosaccharides fermentables pour améliorer la guérison, renforcer la barrière intestinale et prévenir la récidive du cancer. / Colorectal cancer (CRC) is the third most diagnosed cancer in Canada. Its treatment involves a surgical resection of the colon or rectum, and a reconnection of the remaining bowel segments to re-establish gastrointestinal continuity. This reconnection, termed “anastomosis”, may fail to heal and leak in up to 30% of patients, which leads to a morbid and mortal complication called “anastomotic leak” (AL). In addition to decreasing survival and quality of life, AL may be linked to higher cancer recurrence for reasons that remain unclear. Despite significant technical progress over the last decades, the rates of AL have not significantly decreased, and its occurrence remains highly unpredictable. Recent data have suggested that the gut microbiota, or the collection of microorganisms in the gut, may influence the healing process after surgery, but evidence on this relation remains weak. The following studies aimed therefore at assessing the causal link between the gut microbiota, AL, and CRC in patients undergoing surgery. Using fecal samples collected before surgery from 18 patients with CRC (9 with AL and 9 without AL), we assessed the causal role of the human microbiota in mice subjected to fecal microbiota transplantation (FMT) then colonic surgery. We found that FMT from AL patients led to poor anastomotic healing, a weakened extracellular matrix in the colonic wound, and heightened inflammation locally. We identified 2 bacterial strains, Parabacteroides goldsteinii kh35 and Alistipes onderdonkii kh33, that were found to influence anastomotic healing, the first one positively and the second one negatively. These strains were found to modulate inflammation in the colonic mucosa, with P. goldsteinii exerting an anti-inflammatory effect and A. onderdonkii a pro-inflammatory effect. Using mucosal samples collected from patients before the completion of the anastomosis, we found with a multiplex assay that patients experiencing AL harbor higher basal levels of macrophage inflammatory protein- 1 alpha, monocyte chemoattractant protein-1, macrophage Inflammatory Protein 2 and interleukin-17A/F, and that the microbiota of these patients lead to the same increase in pro-inflammatory cytokines in mice. To corroborate the hypothesis that patients experiencing AL after surgery harbor higher basal levels of microbiota-driven low-grade inflammation in the gut, we quantified 9 cytokines in the colorectal mucosa of 77 patients with CRC, among whom 13 experienced AL after surgery. All 9 cytokines were found to be increased in patients developing AL. We explored potential fecal inflammatory markers that could be used as screening biomarkers before surgery, and identified calprotectin and lipocalin-2 as being significantly different between patients that subsequently developed, or not, AL. 4 Next we explored whether bacterial metabolites may be used to improve anastomotic healing. Short-chain fatty acids are produced in the gut upon bacterial fermentation of dietary fibers. We therefore tested in mice whether dietary supplementation with inulin or galacto-oligosaccharides (GOS), two fermentable oligosaccharides, could improve healing. We found that inulin and GOS increased the levels of the beneficial SCFA butyrate, improved anastomotic healing, promoted epithelial repair, collagen deposition and the gut barrier function. Finally, as butyrate is known to exert anticarcinogenic effect by stimulating the nuclear receptor peroxisome proliferator-activated receptor gamma (PPAR-γ), we further investigated the relationship between promotion of postoperative intestinal healing using inulin and 5-aminosalicylate (5-ASA), a PPAR-γ activator, and CRC recurrence. A review of postoperative survival of CRC patients with and without AL was performed. The effect of dietary supplementation with inulin and 5-ASA on local anastomotic tumors was assessed in mice undergoing colonic surgery. Inulin and 5- ASA were also assessed in a mouse model of liver metastasis where CRC cells are surgically inoculated into the spleen. Patients experiencing AL displayed significantly lower overall and oncological survival than non-AL patients. Poor anastomotic healing in mice led to larger anastomotic and peritoneal tumors. Inulin and 5-ASA reinforced the gut barrier and prevented anastomotic tumors and metastatic spread in mice. These findings reinforce the hypothesis that preventing AL improves oncological outcomes in patients with CRC, and pave the way towards clinical trials in which microbiotatargeted interventions may be used to enhance healing and diminish cancer recurrence. In summary, we demonstrated for the first time the causal link between the preoperative gut microbiota and anastomotic healing in patients with CRC. We also identified potential biomarkers that could be used in practice to detect microbiota-driven subclinical inflammation and predict healing before surgery. We also showed that the gut microbiota and PPAR-g could be modulated using fermentable oligosaccharides to improve healing, reinforce the gut barrier and prevent cancer recurrence.

<p>Parasite infections around the world are a huge economic burden and decrease the quality of life for many people. Probiotic bacteria are being investigated as a possible treatment for many enteric issues due to their beneficial effects by altering the immune system. Goblet cells are the main source of mucins in the gut, and play an important role in host defense. Alterations in goblet cells and mucin have been implicated in a number of gastrointestinal (GI) diseases and infections. The aim of this study is to develop a probiotic based strategy to modulate goblet cell function in relation to host defense in enteric infection. Utilizing a murine model of parasite infection, <em>Trichuris muris</em>,<em> </em>we examined the effect of daily administration with probiotic <em>Lactobacillus reuteri</em> in different strains of mice and investigation of goblet cell alterations, immune and inflammatory responses in gut, and host defense mechanisms.</p> <p>Treatment with<strong> </strong>live <em>L. reuteri</em> significantly enhanced worm expulsion in resistant C57BL/6 mice and this was associated with significant increase in goblet cells numbers and an increase in IL-10. This lead to investigation of the probiotic effects in IL-10 knock out (KO) and Muc2 KO mice during the infection. There was no difference of worm burden or goblet cell amounts in infected IL-10 KO mice infected treated with probiotic or medium. In infected Muc2 KO mice treated with <em>L. reuteri</em>, there was an earlier increase of goblet cells, and a corresponding decrease in worm numbers. Finally, assessment of this probiotic in susceptible ARK mice revealed no alterations in worm burden, but the treatment prevented the increase in IFN-γ and IL-1β and significantly increased goblet cell numbers.</p> <p>These data demonstrate that altering the flora with probiotic <em>L. reuteri</em> treatment can modulate intestinal goblet cell biology and immune responses in gut, and promote worm expulsion, possibly through an IL-10 mediated mechanism. The increases in goblet cell numbers may also play a role in the early expulsion of the parasite. In addition to enhancing our understanding on the beneficial effect of probiotics in host defense in enteric infection, this research provides new information on gut function in the context of goblet cells and mucins.</p> / Master of Science (MSc)

<p>Nonsteroidal anti-inflammatory drugs are among the most commonly used prescription and over-the-counter medications, but they often produce significant gastrointestinal ulceration and bleeding, particularly in elderly patients and patients with certain co-morbidities. Novel anti-inflammatory drugs are seldom tested in animal models that mimic the high-risk human users, leading to an underestimate of the true toxicity of these drugs. In the present study we examined the effects of two novel NSAIDs and two commonly used NSAIDs in models in which mucosal defence was expected to be impaired. Naproxen, celecoxib, ATB-346 (a hydrogen sulfide- and naproxen-releasing compound) and NCX 429 (a nitric oxide- and naproxen-releasing compound) were evaluated in healthy, arthritic, obese, hypertensive rats, and in rats of advanced age (19 months) and rats co-administered low-dose aspirin and/or omeprazole. In all models except hypertension, greater gastric and/or intestinal damage was observed when naproxen was administered in these models than in healthy rats. Celecoxib-induced damage was significantly increased when co-administered with low-dose aspirin and/or omeprazole. In contrast, ATB-346 and NCX 429, when tested at doses that were as effective as naproxen and celecoxib in reducing inflammation and inhibiting cyclooxygenase activity, did not produce significant gastric or intestinal damage in any of the models. These results demonstrate that animal models of human co-morbidities display the same increased susceptibility to NSAID-induced gastrointestinal damage as observed in humans. Moreover, two novel NSAIDs that release mediators of mucosal defence (hydrogen sulfide and nitric oxide) do not induce significant gastrointestinal damage in these models of impaired mucosal defence.</p> / Master of Science (MSc)

<p>Intestinal microbiota are key determinants of gut homeostasis and affect various gut physiological and immune processes. Co-evolution has enabled the host and intestinal microbes to exist in a mutualistic relationship. However, interactions between the host and its intestinal microbiota exist in a delicate balance between mutualism and pathogenicity. Maintenance or disruption of this balance depends on a complex interplay between the microbiota and the host, as well as other gut luminal factors, including diet, that are poorly understood. The main goal of this thesis has been to study the host-gut luminal interactions that regulate gut physiology and immunity. In particular, <strong>Chapter 2</strong> centers on investigating the effect of perturbing the intestinal barrier using a non-steroidal inflammatory drug on host-microbial and dietary interactions in a mouse model of gluten sensitivity. I demonstrated that indomethacin-induced increase in intestinal permeability is associated with altered intestinal microbiota composition, systemic antibody development against intestinal bacteria and a shift in immune responses to the dietary antigen, gluten. <strong>Chapter 3</strong> focuses on investigating whether modulation of the intestinal microbiota can affect the host’s susceptibility to intestinal injury. I used mice with defective intracellular bacterial receptor signaling because discrimination between commensals and pathogens is, in part, achieved by a family of receptors that recognize conserved bacterial components. I demonstrated that the microbiota with which these mice are colonized influences the expression of RegIII-γ, a type of antimicrobial peptide, and susceptibility to intestinal injury. To gain further insight on the effect of microbiota on antimicrobial peptides, in <strong>Chapter 4</strong> we conducted a combination of gnotobiotic and <em>in-vitro</em> experiments where we identified that specific components of the microbiota differentially regulate RegIII expression. Further examination showed that <em>MyD88 a</em>nd <em>Ticam1 </em>genes, which are signaling adaptor proteins of pattern recognition receptors, are essential regulators of microbial–induced RegIII expression by intestinal epithelial cells. Collectively, the work presented in this thesis provides novel insight on the bi-directional interaction between the host and the gut luminal content as well as of potential beneficial effects of microbiota-modulating strategies in maintaining homeostasis and preventing disease.</p> / Doctor of Philosophy (Medical Science)