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The Host-Microbiota Interactions in Pediatric Inflammatory Bowel Disease PathogenesisSchramm, Laetitia 21 April 2022 (has links)
The exact mechanism of pathogenesis of inflammatory bowel disease (IBD) is not yet clear. However, a key role for intestinal bacteria in the development and maintenance of IBD is now well-accepted and has led to extensive efforts to characterize IBD patients’ gut microbiota composition. Nonetheless, few studies have examined intestinal microbial composition and host interactions in pediatric treatment-naïve IBD subjects. Using a multi-omic approach, we analyzed the gut microbiota-host interactions at the mucosal- luminal interface from two distinct colonic regions in a pediatric treatment-naïve cohort of Crohn’s disease (CD), ulcerative colitis (UC) and non-IBD control individuals. CD patients displayed a significant decrease in bacterial richness in the distal colon, as compared to controls. Significant changes in the microbial composition at different taxonomic levels were observed in IBD patients relative to controls, especially in the distal colon. IBD patients had an increased abundance of hydrogen sulfide (H2S) producers, including Veillonella (g), Streptococcus (g) and Fusobacterium (g), and a decreased abundance of butyrate producers such as Blautia (g), Lachnospiraceae (f) and Ruminococcus (g). IBD patients showed statistical differences in their metabolomic profile as compared to controls, with the majority of significant metabolites, such as pesticides, amino acids, bacterial-derived molecules and dipeptides, being increased in CD and UC subjects. An alteration of the gut microbiota composition was associated with an alteration of the host and bacteria metabolome in IBD subjects; notably, increase of taurine, mecarbam-f7 and oxazole positively correlated with H2S producers and negatively correlated with butyrate producers. Finally, microbial genes involved in oxidative stress response, virulence, iron uptake, storage and metabolism were upregulated in the proximal colon of IBD patients. Our findings provide information about the host-microbiota interactions in the context of IBD. Understanding the relationships between the host and his intestinal microbes could help to develop therapeutic strategies to treat IBD.
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ENTERIC PARASITE INFECTION-INDUCED ALTERATION OF THE GUT MICROBIOTA REGULATES INTESTINAL GOBLET CELL BIOLOGY AND MUCIN PRODUCTION VIA TLR2 SIGNALLINGYousefi, Yeganeh January 2022 (has links)
In the gastrointestinal (GI) tract, goblet cells are the major source of mucins, the
main structural components of the mucus layer, which functions as the front line of innate
defense. The GI tract contains trillions of commensal microbes, and these microbes can
manipulate mucin production by activating different signalling cascades initiated by
pattern recognition receptors (PRRs), including bacterial sensing Toll-like receptors
(TLRs). In addition, sterile α motif pointed domain-containing ETS transcription factor
(SPDEF) is a transcription factor that modulates goblet cell differentiation and positively
regulates mucin production. During helminth infections, due to the co-existence of
parasites and microbiota in close proximity of goblet cells in the gut, it is likely that
helminth-microbiota interactions play an important role in mucin production. Indeed,
goblet cell hyperplasia and increased mucin production are observed in many enteric
helminth infections, including Trichuris muris, and these processes play key roles in host
infection clearance. However, it should be noted that the role of microbiota within this
axis is not yet understood. Here, we hypothesize T. muris-induced altered microbiota
modulates goblet cell differentiation and mucin production via SPDEF-mediated
transcriptional regulation and TLR2 signalling.
C57BL/6 mice were gavaged with ~300 T. muris eggs. Mice were sacrificed 36
days post-infection. Microbiota from these T. muris-infected and non-infected mice were
transferred into two groups of germ-free (GF) mice. Microbiota analysis revealed that
treatments in both experiments (infection with T. muris and microbiota transfer from T.
muris-infected mice into GF mice) significantly account for the among-sample variations
in the composition of the gut microbiota between groups (p <= 0.001).
In GF mice, transfer of T. muris-infected microbiota significantly increased goblet
cell numbers and TLR2 expression as well as upregulated Muc2 expression compared to
MSc Thesis –Yousefi Y; McMaster University – Medical Sciences
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GF mice with non-infected microbiota. Antibiotic-treated (ABX-treated) TLR2 knockout
(KO) mice after receiving microbiota from T. muris-infected mice showed significantly
decreased expression of Muc2 and Muc5ac compared to ABX-treated wild-type (WT)
mice receiving the same microbiota. To investigate whether SPDEF is a driving factor
for Muc2 production in response to T. muris microbiota stimulation, we next transferred
T. muris-infected microbiota into antibiotic-treated SPDEF KO and WT mice. We
observed a slight, though not significant, the influence of SPDEF on the stimulation of
mucin production by T. muris microbiota. These findings reveal important interactions
among parasites, resident microbiota, and host in relation to goblet cell response in the
gut. In addition, this study provides new information on TLR2-based innate signalling in
the regulation of goblet cell biology and mucin productio / Thesis / Master of Science (MSc)
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