Regulation Of Intestinal Growth Research Articles

Effects of ad libitum milk replacer feeding and butyrate supplementation on the epithelial growth and development of the gastrointestinal tract in Holstein calves

Intensive milk feeding and butyrate supplementation in calves stimulate body growth and affect gastrointestinal development. The aim of the present study was to investigate the synergistic effects of ad libitum milk replacer (MR) feeding and butyrate supplementation of MR on rumen and small intestinal growth and on gene expression in the small intestine related to growth and energy metabolism at weaning. Male Holstein calves (n = 32) received colostrum from birth to d 3 of age and MR either ad libitum (Adl) or restrictively (Res; 6 L of MR/d; 12.5% solids) with (AdlB+, ResB+) or without (AdlB-, ResB-) 0.24% butyrate from d 4 until wk 8 of age. From wk 9 to 10, all calves were weaned and were fed 2 L/d until the end of the trial. Concentrate, hay, and water were freely available. At d 80, calves were slaughtered, volatile fatty acids were measured in rumen fluid, and rumen and small intestine samples were taken for histomorphometric measurements. The expression of mRNA associated with the local insulin-like growth factor (IGF) system and glucose metabolism as well as lactase and maltase activities were measured in the intestinal mucosa. The small intestine was 3 m longer in Adl than in Res. In the atrium ruminis, papilla width was greater in Res than in Adl. Villus circumference, cut surface, and height in the duodenum, proximal jejunum, and ileum were greater in Adl than in Res and in the proximal, mid, and distal jejunum and ileum were greater in calves treated with butyrate. Crypt depth in the duodenum and proximal jejunum was greater in Adl than in Res and in the ileum was smaller in calves treated with butyrate. The villus height:crypt depth ratio was greatest in AdlB+ calves. In the proximal and mid jejunum, IGF1 mRNA abundance was lower in calves treated with butyrate. In the proximal jejunum, INSR mRNA abundance was greater in Res than in Adl. The abundance of PCK2 mRNA was greater in Res than in Adl in the duodenum and was greatest in ResB- in the mid jejunum. Lactase activity tended to be greater in Res than in Adl and after butyrate treatment in the proximal jejunum. The results indicated an elevated growth of the small intestinal mucosa at weaning due to intensive milk feeding and butyrate supplementation, and the local IGF system was involved in intestinal growth regulation. Rumen development was not affected by butyrate supplementation of MR and was slightly delayed due to ad libitum MR feeding.

Regulation of intestinal growth in response to variations in energy supply and demand.

SummaryThe growth of the intestine requires energy, which is known to be met by catabolism of ingested nutrients. Paradoxically, during whole body energy deficit including calorie restriction, the intestine grows in size. To understand how and why this happens, we reviewed data from several animal models of energetic challenge. These were bariatric surgery, cold exposure, lactation, dietary whey protein intake and calorie restriction. Notably, these challenges all reduced the adipose tissue mass, altered hypothalamic neuropeptide expression and increased intestinal size. Based on these data, we propose that the loss of energy in the adipose tissue promotes the growth of the intestine via a signalling mechanism involving the hypothalamus. We discuss possible candidates in this pathway including data showing a correlative change in intestinal (ileal) expression of the cyclin D1 gene with adipose tissue mass, adipose derived‐hormone leptin and hypothalamic expression of leptin receptor and the pro‐opiomelanocortin gene. The ability of the intestine to grow in size during depletion of energy stores provides a mechanism to maximize assimilation of ingested energy and in turn sustain critical functions of tissues important for survival.

Glucagon-like Peptide-2 and the Regulation ofIntestinal Growth and Function.

Glucagon-like peptide-2 (GLP-2) is an intestinally derived hormone that enhances intestinal growth, digestion, absorption, barrier function, and blood flow in healthy animals as well as preventing damage and improving repair in preclinical models of enteritis and colitis and following massive small bowel resection. These beneficial effects of GLP-2 on the intestinal tract are largely recapitulated in humans with intestinal failure. The high-specificity of this peptide for the intestinal tract and the development of degradation-resistant, long-acting GLP-2 receptor agonists have rapidly led to clinical implementation of GLP-2-based therapy for the treatment of patients with short bowel syndrome, with few reported side effects. This comprehensive review covers the biology of GLP-2, from the control of proglucagon gene expression and the posttranslational processing of proglucagon to liberate GLP-2 to the regulation of GLP-2 secretion from the intestinal L cell, and from the mechanism of action of GLP-2 through its highly localized receptor to the biological activities of GLP-2 in the intestine and other restricted locations in the body, under physiological conditions as well as in animal models of intestinal disease and in patients with short bowel syndrome. Collectively, the history of GLP-2 serves as a remarkable bench-to-bedside story of translational medicine. © 2017 American Physiological Society. Compr Physiol 8:1185-1210, 2018.

Functional Ontogeny of the Proglucagon-Derived Peptide Axis in the Premature Human Neonate

The regulation of intestinal growth and development in human neonates is incompletely understood, which hinders the provision of nutrients enterally. The "hindgut" hormones glucagon-like peptides 1 and 2 have been shown to play an important role in the regulation of nutrient assimilation, intestinal growth, and function. Our goal was to investigate the production of glucagon-like peptides 1 and 2 in premature human infants and examine the effects of prematurity and feeding on hormone release. With informed consent, premature infants who were admitted to a tertiary neonatal intensive care nursery (gestational age: 28-32 weeks) were monitored with weekly determinations of postprandial glucagon-like peptide 1 and 2 levels. Comparison studies with groups of normal infants and adults were performed. Hormone levels were obtained by using specific radioimmunoassay for glucagon-like peptide 1 (1-36) and glucagon-like peptide 2 (1-33), modified for small sample volumes; accurate monitoring of enteral intake was performed at all of the sampling time points. Forty-five infants with a mean gestational age of 29.6 +/- 1.9 weeks were studied; fasting levels of both glucagon-like peptides 1 and 2 were elevated. There was no correlation between gestational age and glucagon-like peptide 2 output. However, both glucagon-like peptide 1 and 2 levels were correlated with the caloric value of feeds. The premature human neonate has significantly higher fasting levels of glucagon-like peptides 1 and 2 compared with adults; feeding increases these levels further. These findings suggest that the proglucagon-derived peptides may have a role in normal intestinal development and nutrient handling.

Carbenoxolone accelerates maturation of rat intestine.

The rat undergoes profound maturational changes in the intestinal structure and function during the third week of its life. To investigate the role of peripheral glucocorticoid metabolism in this process, we studied the postnatal maturation of intestinal structure and function. The peripheral metabolism of glucocorticoids depends on enzyme 11beta-hydroxysteroid dehydrogenase (11betaHSD), which is responsible for the interconversion of corticosterone to 11-dehydrocorticosterone and thus for the modulation of glucocorticoid access to corticosteroid receptors. The pups were treated with carbenoxolone (CBX), an inhibitor of 11betaHSD, for 10 d during the suckling (days 8-18) or weaning period (days 14-24 or days 20-30), and we determined the parameters of intestinal growth and activities of sucrase, alkaline phosphatase, and Na,K-ATPase. The CBX treatment increased plasma concentrations of corticosterone as a result of a significant reduction of peripheral degradation of corticosterone catalyzed by 11betaHSD. This also stimulated intestinal growth without changing somatic growth. The mucosal cell mass was significantly higher in CBX-treated suckling rats, whereas the effect of this treatment was less obvious in weanling animals. CBX increased the crypt depth and villus height in 18- and 24-d-old pups but not in 30-d-old animals. The small intestinal activities of sucrase, alkaline phosphatase, and Na,K-ATPase were not influenced by CBX. In contrast, colonic Na,K-ATPase was stimulated by CBX. We conclude that the administration of CBX results in acceleration of intestinal growth and structural maturation without any influence on the developmental pattern of brush-border hydrolases. The results indicate an important role of peripheral glucocorticoid metabolism in the regulation of intestinal growth during early postnatal life.

Growth hormone treatment increases transmural colonic growth in GH-deficient dwarf rats

Growth hormone (GH) has been implicated as an important factor in the growth regulation of several visceral organs including the gastrointestinal tract. Our aim was to study the effects of GH administration on colonic growth in dwarf rats with an isolated GH deficiency. Dwarf rats were treated with recombinant human growth hormone (rhGH; 2.0 mg/kg/day) for four weeks and compared with saline treated dwarf rats and rats with normal pituitary function. The colonic wall composition was measured by means of stereological techniques. RhGH treatment of the dwarf rats increased body weight by 80% and proximal and distal colon weight by 63% and 90%, when compared with placebo treated dwarf rats (P< 0.01). The weight of the proximal colonic mucosa increased by 83% (P< 0.01), submucosa by 78% (P< 0.05), and the muscularis propria by 51% (P< 0.001) in rhGH treated dwarf rats compared with dwarf controls. The weight of the distal colonic mucosa increased by 88% (P< 0.01), submucosa by 88% (P< 0.05) and the muscularis propria by 58% (P< 0.05) compared with dwarf controls. The growth of mucosa involved all mucosal layers, with a 73 and 92% increase in the proximal and distal colon luminal surface area respectively (P< 0.001, P< 0.01). The food consumption, expressed as g/day/100 g BW was 13% higher in dwarf rats receiving rhGH than in placebo treated rats (P< 0.05) and normal control rats (P< 0.05). When weights of the GI tract compartments are corrected for the increase in body weight the effects of GH treatment were small or non-significant. RhGH administration in GH deficient dwarf rats induces visceral growth with a pronounced increase in colonic luminal surface area and growth of all layers of the colonic wall. These findings confirm the important role of GH in the regulation of intestinal growth.

Difluoromethylornithine inhibits crypt fission

Crypt fission is a physiologic mechanism of crypt reproduction. It increases in pathophysiologic situations where intestinal regeneration is required (e.g., radiation injury). Polyamine metabolism is important in the regulation of intestinal growth and recovery from injury in response to a variety of stimuli. Our aim was to determine whether inhibition of polyamine synthesis by difluoromethylornithine (DFMO) influenced crypt fission. Forty-eight rabbits underwent patch enteroplasty in the terminal ileum. One group served as a control group and the other took 2% DFMO orally. Animals (n = 6) from each group were killed at 7, 14, 21, and 28 days. Normal ileum adjacent to the enteroplasty was studied. Crypt dissection was performed 2 hours after vincristine was administered intravenously to determine crypt cell production rate, crypt depth, and proportion of bifurcating crypts (fission). DFMO administration decreased crypt fission (4 ± 2% vs. 11 ± 2% and 13 ± 1% vs. 34 ± 4% at 7 and 14 days) compared to control animals. There was a corresponding increase in crypt depth at 14 and 21 days. Crypt cell production rate was similar in both groups and did not change with time. Mucosal ornithine decarboxylase activity (11.9 ± 2.2 vs. 1.2 ± 0.3 specific activity at 21 days; P <0.05) and polyamine content (323 ± 32 vs. 17 ± 8 and 382 ± 89 vs. 160 ± 47 pmol/mg at 14 and 21 days, control vs. DFMO; P <0.05) were significantly lower in the DFMO group. The following conclusions were drawn: (1) DFMO administration inhibits crypt fission in stimulated intestinal epithelium; (2) this effect correlates temporally with reduced polyamine production; and (3) reduced crypt fission is another potential mechanism of inhibition of intestinal growth by altered polyamine metabolism.

Difluoromethylornithine inhibits crypt fission

Crypt fission is a physiologic mechanism of crypt reproduction. It increases in pathophysiologic situations where intestinal regeneration is required (e.g., radiation injury). Polyamine metabolism is important in the regulation of intestinal growth and recovery from injury in response to a variety of stimuli. Our aim was to determine whether inhibition of polyamine synthesis by difluoromethylornithine (DFMO) influenced crypt fission. Forty-eight rabbits underwent patch enteroplasty in the terminal ileum. One group served as a control group and the other took 2 % DFMO orally. Animals (n = 6) from each group were killed at 7, 14, 21, and 28 days. Normal ileum adjacent to the enteroplasty was studied. Crypt dissection was performed 2 hours after vincristine was administered intravenously to determine crypt cell production rate, crypt depth, and proportion of bifurcating crypts (fission). DFMO administration decreased crypt fission (4 ±2% vs. 11 ± 2% and 13 ±1% vs. 34 ±4% at 7 and 14 days) compared to control animals. There was a corresponding increase in crypt depth at 14 and 21 days. Crypt cell production rate was similar in both groups and did not change with time. Mucosal ornithine decarboxylase activity (11.9 ±2.2 vs. 1.2 ± 0.3 specific activity at 21 days; P <0.05)and polyamine content (323 ±32 vs. 17±8 and 382 ±89 vs. 160 ±47 pmol/mg at 14 and 21 days, control vs. DFMO; P <0.05) were significantly lower in the DFMO group. The following conclusions were drawn: (1) DFMO administration inhibits crypt fission in stimulated intestinal epithelium; (2) this effect correlates temporally with reduced polyamine production; and (3) reduced crypt fission is another potential mechanism of inhibition of intestinal growth by altered polyamine metabolism.

Enhanced growth of small bowel in transgenic mice expressing human insulin-like growth factor 1.

Insulin‐like growth factor 1 (IGF‐1) plays an important role in the regulation of intestinal growth and maturation, whereas the direct effects of growth hormone (GH) on intestinal growth are less clear. In this study the authors utilize a transgenic mouse model to assess the extent to which longterm excess of IGF‐1 in a background of GH deficiency stimulates small bowel growth.IGF‐1 transgenic mice that overexpress an IGF‐1 transgene driven by the mouse metallothionein I promotor were compared with wild‐type littermates and GH transgenic mice. The IGF‐1 transgenics showed elevation of circulating IGF‐1, undetectable levels of plasma GH, and a decrease in pituitary GH messenger RNA (mRNA) caused by negative feedback effects of IGF‐1 excess. Growth of small bowel, abundance and localization of mRNAs for the IGF‐1 transgene, and IGF binding protein 3 (IGFBP‐3) were assayed to determine whether enterotrophic effects of excess IGF‐1 correlate with local overexpression of IGF‐1 in small bowel.Small bowel length and mass were greater in IGF‐1 transgenic than in wild‐type mice. Villus height, crypt depth, and crypt cell mitoses were greater in IGF‐1 transgenics than wild‐type mice. Jejunal dissacharidase activities were not different among the IGF‐1 transgenics and wild‐type mice. The IGF‐1 transgene was expressed strongly in villus epithelial cells and at much lower, but significant levels in crypt epithelial cells, lamina propria, and smooth muscle layers. IGFBP‐3 was strongly expressed and localized in the lamina propria.Regional expression of IGF‐1 and IGFBP‐3 correlated with the increase in mucosal mass in IGF‐I transgenics.Effects of IGF‐I overexpression on intestinal length and mucosal mass were similar to effects of GH overexpression, although IGF‐I transgenics showed greater small bowel growth relative to somatic growth compared with GH transgenics. Excess of IGF‐I increased crypt cell proliferation, whereas excess of GH did not increase crypt cell proliferation but did stimulate jejunal sucrase activity. These observations suggest that GH has greater differentiative actions, whereas IGF‐I exerts primarily mitogenic actions in small bowel.

FATE OF OROGASTRICALLY ADMINISTERED INSULIN-LIKE GROWTH FACTORS I AND II (IGF-I AND -II) TO SUCKLING RATS

IGF's are stimulators of mitosis and may be of importance in the regulation of intestinal growth in the neonate. Since IGF's are present in a variety of milks, we tested the hypothesis that ingested milk-borne IGF's might be available to gastrointestinal (GI) tissues and might also be absorbed to sites distant to the GI tract. Recombinant 125I-IGF-I and -II in rat milk were given via stomach tube to suckling rats. Approximately 40% of IGF-I or-II cpm remained in the GI tract at 30 min post ingestion with < 1 % appearing in most other organs. Gel chromatography demonstrated that much of radioactivity present in GI tract homogenates eluted together with authentic IGF. Significant differences we re noted in amounts of IGF-I vs-II found in GI tissues after 30 min, particularly in stomach and intestinal wall and lumen. Exogenous IGF-I represented twice the amount of IGF-II in these tissues. Competitive binding studies confirmed that binding of radioactivity present in peaks at 7.5K MW were identical to those of native 125I-IGF's. These studies show that milk-borne IGF remains intact in the GI tract of suckling rats for at least 30 min post ingestion.