Adaptations of small intestinal nutrient absorption during pregnancy in mice

Abstract

Mammalian pregnancy represents a natural state of increased maternal nutrient demand due to conceptus nutrient and energy requirements, and to prepare for lactation post parturition. To permit increased nutrient absorption, the maternal small intestine (SI), which is the main site of nutrient absorption, needs to adapt to permit increased nutrient absorption throughout pregnancy. However, the timing, size and regional localisation of SI adaptations are unclear. We therefore investigated how SI nutrient absorption and its determinants adapts during pregnancy in mice. To identify gaps in existing knowledge of maternal gut adaptations during pregnancy in monogastric mammals, a scoping review was undertaken (Chapters 2 and 3) which uncovered gaps in knowledge regarding timing, size and regional localisation of SI adaptations. Furthermore, available evidence was inconsistent across species, strains and pregnancy stages for outcomes including macro- and micro-nutrient absorption, nutrient transporter and digestive enzyme expression and region-specific anatomical changes. Most studies did not investigate SI adaptations at early- and mid- pregnancy. To enable characterisation of active glucose transport during pregnancy, we conducted several experiments to optimise Ussing chamber measures of SI active glucose transport ex vivo (Chapter 4). Once optimised, active glucose transport via sodium-dependent glucose transporter 1 (SGLT1) throughout the jejunum (region of peak nutrient absorption) was characterised across the murine oestrous cycle. Food intake changes during the ovarian cycle in rodents and humans, with a nadir during the pre-ovulatory phase and a peak during the luteal phase. However, whether SI glucose absorption also changes remains unknown. We hypothesised that active glucose transport would decrease at oestrus (equivalent to the follicular phase of the human menstrual cycle) based on blood glucose data following a 50 g glucose preload obtained during the luteal and follicular phases of the menstrual cycle. SGLT1-dependent glucose transport decreased at oestrus, providing the first direct evidence of oestrous-stage dependent changes in SI active glucose transport in mice. Once optimised, the Ussing chamber method was utilised to study changes in SI active glucose transport in late- compared to non-pregnant control mice. In Chapter 5, we characterised concurrent SI anatomical, molecular and functional in C57BL/6 mice at early (gestational day, GD6.5), mid (GD12.5) and late-pregnancy (GD17.5) compared to non-pregnant controls using routine histological methods, quantitative real-time polymerase chain reaction and functional studies using Ussing chambers. Despite greater SI villi length and augmented expression of carbohydrate transporter transcripts at late pregnancy, SGLT1-dependent glucose transport per unit area was similar to non-pregnant mice. This suggests other mechanisms beyond SGLT1-dependent transport may take on a greater role in apical glucose absorption. Data presented in this thesis support the hypothesis that adaptations of SI nutrient uptake occur across the oestrous cycle and pregnancy, the latter possibly in response to altered nutrient demand. Further studies are required to elucidate the role(s) of other mechanisms involved in SI glucose uptake and mechanisms driving SI anatomical and molecular adaptations during pregnancy, such as food intake and hormone abundance. Further studies are also required to address gaps in knowledge regarding adaptations which occur at early- and mid-pregnancy.