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
v
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)
| Identifer | oai:union.ndltd.org:mcmaster.ca/oai:macsphere.mcmaster.ca:11375/27353 |
| Date | January 2022 |
| Creators | Yousefi, Yeganeh |
| Contributors | Khan, Waliul, Medical Sciences |
| Source Sets | McMaster University |
| Language | en_US |
| Detected Language | English |
| Type | Thesis |
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