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Abstract
Background:
In the small intestine, dietary carbohydrate is hydrolysed ultimately by
intestinal brush border membrane disaccharidases, sucrase, maltase and lactase,
to glucose, galactose and fructose. Glucose and galactose are transported across
the brush border membrane of enterocytes by the Na+/glucose cotransporter 1,
SGLT1. Expression of SGLT1 is upregulated by lumenal sugars via the
intestinal sweet receptor, the T1R2 + T1R3 heterodimer, expressed in
enteroendocrine cells. Fructose is transported across the luminal membrane of
enterocytes by Na+-independent transporter, GLUT5. All three monosaccharides
exit the cell across the basolateral membrane of enterocytes into the systemic
circulation via the Na+-independent monosaccharide transporter, GLUT2. In
response to dietary CHO, enteroendocrine cells secrete gut hormones such as
glucose-dependent insulinotrophic peptide (GIP), glucagon like peptide 1 (GLP1), glucagon like peptide 2 (GLP-2) and serotonin (5HT). Systemic infusion of
GLP-2 leads to SGLT1 upregulation. Dietary carbohydrates that are not
hydrolysed in the small intestine, reach the large intestine. They are fermented
by colonic microflora to short chain fatty acids, SCFAs, acetate, propionate and
butyrate. In response to dietary fibre the large intestine secretes gut hormones
such as GLP-1 and peptide YY (PYY) which control appetite and food intake.
Aims of this project
The major objectives of the work presented in this thesis were to determine the
effect of i) naturally occurring dietary selectivity, ii) increasing levels of dietary
carbohydrate and iii) pre- and post-natal development of the gut on the
expression of intestinal monosaccharide transporters, brush border membrane
disaccharidases and sweet receptor components.
Another objective of the work presented in this thesis was to determine i) the
precise cellular location of short-chain fatty acid sensors, FFA3 and FFA2 in the
large intestine and ii) to determine their co-expression with the satiety-inducing
gut hormones.
Summary of work carried out in this thesis:
In the small intestine of animals naturally consuming diets containing
different levels of CHO such as horse (a non-ruminant herbivore), pig and
mouse (omnivores), cat (a carnivore) and dog (a carno-omnivore), Na+/glucose
cotransporter 1, SGLT1, labelling is localised on the brush border membrane of
cells on the entire villus. There is negligible SGLT1 expression observed in the
crypt. Furthermore, Na+-independent monosaccharide transporter, GLUT2, is
exclusively expressed on the basolateral membrane of enterocytes in all these
species.
Expression of SGLT1 remains constant when piglets are fed up to 40%
CHO containing diets. However, there is a significant increase in SGLT1
expression when the CHO content of the diet is > 50%. Furthermore,
supplementation of piglets’ feed with a combination of artificial sweeteners
saccharin and neohesperidin dihydrochalcone (NHDC) enhance the expression
of SGLT1 and intestinal glucose transport function.
The intestinal sweet receptor T1R2 + T1R3 and the transducer Gprotein
gustducin are only expressed in a subpopulation of intestinal cells along
crypt villus axes in pig, horse, dog and mouse. However, T1R2 protein is not
expressed in the intestines of cat and the chicken. T1R2 + T1R3 and gustducin
are co-expressed in the intestinal enteroendocrine cells of pig, horse, dog, and
mouse. In addition, GIP, GLP-1 and GLP-2 are co-expressed with T1R2, T1R3
and gustducin, indicating that K- and L-enteroendocrine cells express these taste
elements. In a few endocrine cells, T1R are also co-localised with 5HT. GLP-2
and GIP receptors, but not GLP-1 receptor, are expressed in enteric neurons.
GLP-1, GLP-2 and GIP receptors were not expressed in any surface epithelial
cells.
There is a difference in the levels of disaccharidases, sucrase, lactase
and maltase in the intestine of animals studied. They are low in the cat’s
intestine compared to levels of these enzymes measured in intestines of horse,
pig and the dog. Intestinal villi are long and slender in cats and dogs, shorter and
wider in pigs and shortest and widest in horses. Crypt depth decreased in the
rank order pig > horse > cat > dog. There are no changes in villus height and
crypt depth between piglets maintained on a low or a high CHO diet. There was
a 2.6- and 2.4- fold increase in maltase activity in brush border membrane
vesicles (BBMV) isolated from the intestine of piglets fed isoenergetic 35.9%
and 60.3% carbohydrate (CHO) diets, respectively, compared with those fed the
7.0% CHO diet. There were no statistically significant differences in the activity
of sucrase between the groups fed the 7.0%, 35.9% or 60.3% CHO diets.
SGLT1, GLUT2, lactase, T1R2, T1R3 and gustducin are expressed in
foetal small intestine. Sucrase, maltase and GLUT5 are induced when the
animals are weaned. After weaning, there is a significant difference in the villus
height and the crypt depth in the intestine of weaned piglets compared with
foetal, full term and suckling piglets.
SCFA receptors, free fatty acid receptor 3, FFA3, and free fatty acid
receptor 2, FFA2, proteins, are expressed in human and pig colon. Colocalisation
of chromogranin A with FFA3 and FFA2 indicates that these
receptors are localised in enteroendocrine cells of the colon. FFA3 and FFA2
are expressed in enteroendocrine cells containing GLP-1, PYY and 5HT,
indicating that they are expressed in L-endocrine, and enterochromaffin cells.
There is no FFAs expressed either on the luminal membrane or cytoplasm of
colonic absorptive epithelial cells. SCFA act as ligands for FFA2.
The work presented in this thesis has significant implication for the
control of obesity, the optimisation of animal feeds used to rear livestock and
the treatment of intestinal disease in livestock.