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Rao JN, Wang JY. Regulation of Gastrointestinal Mucosal Growth. San Rafael (CA): Morgan & Claypool Life Sciences; 2010.

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Regulation of Gastrointestinal Mucosal Growth.

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Luminal Nutrients and Microbes in Gut Mucosal Growth

The GI epithelium is critically located at the interface between the body and environment. This interface acts as a peace keeping force positioned between two opposing armies, and it must placate the local environment to prevent conflict from erupting. As befitting a role requiring a high degree of tact and dexterity, the GI epithelium incorporates an array of strategies to facilitate peaceful communication between luminal contents, including nutrients and microbes and the mucosal renewal system, thereby preserving its tissue homeostasis. During starvation, the small intestinal mucosa atrophies rapidly, with a reduction in cell proliferation being noted within hours of food withdrawal [235]. This inhibition in the GI mucosal growth occurs even when the overall nutritional state of the animals are maintained by total parenteral nutrition (TPN).

There is an increasing body of evidence showing that luminal nutrients stimulate gut mucosal growth by local direct effect at their site of absorption [27,236,237], and this direct action does not result from the use of the nutrients as sources of energy by mucosal cells, since nonmetabolizable absorbed substrates, such as galactose and 3-O-methyl-D-glucose, also promote mucosal cell proliferation [238]. Although the exact mechanism underlying this process remains unclear, it is likely that the workload of absorption determines the gut mucosal growth response. Luminal nutrient also stimulates intestinal mucosal growth indirectly by releasing gut hormones from the distal small intestine, colon and pancreas [239]. In addition, adaptive changes in small intestinal mucosal mass are generally associated with parallel changes in segmental absorptive function [236], but the magnitude of induction of individual transport processes can be selectively affected by the specific nature of the nutrients within the lumen. In rats receiving TPN, for example, infusion of D-glucose into the small intestine increases specific transport capacity for glucose, while substituting protein isocalorically for carbohydrate in the diet increases amino acid transport capacity and reduces the transport capacity for galactose. Recently, interaction between animal and bacterial cells is also shown to play an important role in the regulation of GI mucosal growth [240,241].

LUMINAL FACTORS

Luminal factors include a variety of nutrients, secretions, and other essential components in the diet or produced in the lumen of the GI tract that have been known to function physiologically to stimulate gut mucosal growth (Figure 11). A large body of evidence has accumulated and strongly suggests that luminal factors are the principal stimulus for GI growth [27,242,243]. Initially, Dowling [244] proposed “luminal nutrition” as the underlying regulator of GI mucosal growth which is derived by the absorbing enterocytes from absorbed nutrients. Ricken and Menge [245] later defined it as “the presence of nutrient material in the lumen” and proposed that “this does not imply that nutrients must be absorbed to have effects.” A later definition of luminal nutrition includes direct effects of nutrients, luminal growth factors, and the releasing trophic hormones by the ingested food substances. Almost two decades ago, an excellent review published by Johnson [27] on the regulation of GI mucosal growth emphasized the roles of luminal nutrition in the regulation of gut mucosal growth under physiological conditions and he also named these luminal nutrients and growth factors as “local nutrition” to avoid confusion among scientific community.

FIGURE 11. Nutrient adaptive responses of the intestinal mucosa.

FIGURE 11

Nutrient adaptive responses of the intestinal mucosa. Adaptation to nutrition and luminal factors by developmental aspects and metabolic learning. Used with permission from Horm Metab Res 38: pp. 452–4, 2006.

Stimulation of gut growth by luminal nutrients is verified by infusing a wide variety of nutrient substances into Thiry–Vella (T–V) loops. Jacobs et al. [246] showed that infusion of liquid elemental diets causes hyperplasia of bypassed intestinal mucosa. Clarke [247] proposed the interesting concept of work-load model, based on the experiments in which the morphology and crypt cell metaphase accumulation rates were examined in starved rats with a self-emptying loop that was designed to test when the group of animals had infused with distilled water into the loop and to determine whether or not a noncaloric luminal stimulus would affect the parameters of intestinal growth. He also tested with different isotonic solutions, such as galactose, methylglucoside, or sodium chloride infusion, to stimulate cell production to the same extent as glucose. Philpott et al. [248] examined the role of luminal versus systemic factors in promoting intestinal recovery using the refeeding of previously malnourished infant rabbits using T–V loops. They found that the luminal factors stimulate intestinal repair during the refeeding of malnourished infant rabbits. Studies in the pig as well as in rat have shown the similar results as luminal nutrients stimulate the mucosal cell growth indirectly by releasing enterotrophic hormones from intestine [240,249,250].

The relative potency of various sugar compounds in stimulating mucosal growth had been intensively investigated by several laboratories utilizing parenteral nutrition. The infusion of dextrose intragastrically or into the mid ileal region causes enormous gut hyperplasia [251,252]. There is a linear correlation between the amount of dextrose infused into the gut and mucosal growth. Infusion of 5% glucose, galactose or fructose solution did not elevate intestinal mass compared to saline infusion alone. However, 5% sucrose, maltose, or lactose solution significantly increases intestinal mass content, suggesting that disaccharides are more trophic to the intestinal mucosa than monosaccharides [252]. These trophic responses were abolished when hydrolysis of disaccharides was prevented. Mannitol, a nonabsorbable sugar, is ineffective in promoting growth, while the infusion of nonmetabolizable sugar 3-O-methyl glucose does promote intestinal growth [238]. These findings indicate that the functional work load of the absorbing epithelium, including work of hydrolysis, plays a crucial role in the stimulating effect of nutrients on GI mucosal growth. Another experiment determined how luminal nutrients control the GI mucosal growth by using various supplemental diets. Mice raised on a high-carbohydrate diet exhibited almost 35% greater intestinal mass, primarily in the proximal intestine, compared to those raised on a carbohydrate-free diet. High carbohydrate fed mice had elevated levels of sugar uptake, but switching those mice to carbohydrate-free diet led to a rapid decrease in glucose uptake, which suggests that there is no pre-programming of intestinal function [252]. Furthermore, different hydrolyzable disaccharides are shown to have similar stimulatory effects on small intestinal mucosal mass when fed with a mixture of amino acids [236]. Dietary supplements with ornithine led to an induction in small intestinal mucosal growth, probably due to an increased polyamine production, but other individual amino acids stimulate mucosal cell proliferation through different mechanisms. Ingested food is the major source of polyamines in the lumen of the upper small bowel, and shortly after meal, polyamine concentrations in the duodenal and jejunal lumen reach its peak and it occurs as early as 120 min after meal luminal polyamine content and then gradually returns to the fasting level. Our laboratory investigations show that luminal polyamine content plays a major role in the GI mucosal growth, and we emphasize more on the luminal polyamines in the next chapter.

Epithelial cells of the small intestine are nevertheless capable of incorporating orally administered amino acids into protein [253]. Hirschfield and Kern [254] suggested that luminally derived amino acids are important in the nutrition of the small intestinal mucosa during protein deprivation. Studies in parenterally nourished rats have shown that infusion of relatively low concentrations of amino acids (>5%) stimulates intestinal mucosal growth to a greater degree than isotonic saline or isocaloric dextrose. This process was further delineated when individual amino acids were infused and each amino acid had its specific trophic potential. It appears from the various studies that histidine is a better stimulator of GI mucosal growth than valine or glycine in small intestine [236]. Attention has been recently focused on the role of the amino acid glutamine in small intestinal growth, and we discuss the importance of glutamine in the following section in this chapter.

Dietary lipid content in a mixed nutrition has a moderate trophic effect on the small intestinal mucosal growth. Intragastric infusion of long-chain triglycerides was found to enhance the adaptive response to partial small intestinal resection in the rat compared to carbohydrate, protein, or medium-chain triglycerides administration (Figure 11) [255]. Further studies showed that long-chain free fatty acids have a greater effect than long-chain triglycerides. The nature of ingested fat also influences the absorptive function of the small intestine, perhaps as a result of changes in the nature of lipid incorporated into the cell membrane of the enterocytes. It has been noticed that essential fatty acids have an important role in mucosal proliferative responses, as deficiency of this dietary component attenuates the adaptive response of the small intestinal mucosa [256]. In addition to fat substances, dietary fiber also plays a prominent role in the regulation of small intestinal growth and function. The addition of nonabsorbable kaolin has no trophic effect on the small intestinal hyperplasia, although it increases glucose and water absorption in vitro. Supplementing an elemental diet with α-cellulose increases small intestinal weight and cell proliferation compared with the same elemental diet alone. Dietary fiber can be fermented by lower gut bacteria to release short-chain fatty acids (SCFAs). Goodlad et al. [257] reported that small intestinal and colonic mucosal growth is significantly increased by the most fermentable fibers and that these enterotrophic effects are abolished in germ-free animals.

Various GI secretions, including pancreatic and biliary secretions, are also shown to act as stimulants for the intestinal mucosal growth [258]. Feeding stimulates the stomach, liver, pancreas, and small intestine to secrete the compounds that are able to promote intestinal mucosal growth and are implicated in the pathogenesis of intestinal mucosal hyperplasia. Luminal nutrients also stimulate structural and functional regeneration in the intestine through a process involving IGF-1 and glucagon-like peptide 2 (GLP-2). Nelson et al. [259] investigated the relationship between IGF-1 and GLP-2 responses and mucosal function in rats fasted for 2 days and then refed for 2 or 4 h by continuous intravenous or intragastric infusion or ad libitum feeding. Fasting induced a significant decrease in plasma IGF-1 and GLP-2 levels, body weight, intestinal protein, DNA content, and villous height, but these changes are attenuated by exogenous IGF-1, GLP-2, or refeeding. Parenteral nutrition and the absence of luminal feeding result in impaired intestinal growth and differentiation of enterocytes. In a separate study, administration of GLP-2 is also shown to have trophic effects on the intestine [249,260]. The specific roles of these GI secretions, including gastrin, secretin, CCK, SST, and various growth factors, have been discussed in the previous chapters and have also been discussed in several excellent reviews [84,214,232].

MICROBES IN HEALTH AND MUCOSAL GROWTH

The GI mucosa is in continuous contact with prokaryotic symboints. Until recently, it has been recognized that microbes present in the lumen of gut affect GI health and functions including the regulation of the GI mucosal growth [241,261]. The epithelial cells lining the intestine function to keep bacteria from invading the body, but they also have mutually beneficial relationship with these intestinal flora, collectively termed as “microbiota” or “microflora,” which regulate a wide variety of physiological functions of the gut (Figure 12). Prebiotics are nondigestive foods able to selectively stimulate the growth and/or activity of a limited number of colonic bacteria, where probiotics are defined as living microorganisms which when administered in adequate amounts confer a health benefit on the host [241,261], including gastric bile and pancreatic secretions, attach to epithelial cells and colonize in the intestine, and also they provide the same beneficial functions and activities that have evolved from the normal intestinal microbiota [262].

FIGURE 12. Preferred sites of commensal/probiotic interaction with the gut.

FIGURE 12

Preferred sites of commensal/probiotic interaction with the gut. Cecum/ascending colon is a “bioreactor” with the greatest amounts of bacteria, metabolic activity, and short chain fatty acids (SCFA) fermentation. Concentration of SCFA (more...)

Several recent studies have enhanced our ability to understand the interactions between the host and its intestinal microflora and the importance of microflora in maintaining intestinal homeostasis [237,262,263]. Among the substrates considered as prebiotics are the oligosaccharides, inulin, fructo-oligosaccharides, galacto-oligosaccharides, and lactulose. Studies showed that prebiotics have beneficial effects on various markers of health [261,264]. Roy et al. [265] described that the dietary carbohydrates escaping digestion/absorption in the small bowel and prebiotics undergo fermentation of these substances in the colon, giving rise to SCFAs and use them as a major source of energy for colonocytes (Figure 12). Thus, the dietary supplementation with bacterial fermentation substrates, usually complex carbohydrates, can increase luminal concentration of SCFAs. SCFA, in general, and butyrate, in particular, enhance the growth of lactobacilli and bifidobacteria and play a major role in the physiology and metabolism of colon [262,266]. The effects of prebiotics on cell proliferation, differentiation, apoptosis, immune function, mineral absorption, and GI peptides synthesis have been extensively studied recently [261,263,264,267,268]. Currently, the food industry is also making efforts to commercialize prebiotics and exploit a wide array of application for their potential health benefits [261,263,267].

Several studies also have attempted to identify specific positive health benefits of probiotics using different bacterial strains. Beneficial effects exerted by probiotic bacteria in the treatment of human diseases are broadly classified as those effects which arise due to the activity in the large intestine and are related to colonization of inhibition of pathogen growth [269]. Human milk (colostrum or mature milk) constitutes an excellent source of commensal bacteria for the infant gut [266]. Among the bacteria found in human milk belong to the species Staphylococcus, Lactococcus, Enterococcus, and Lactobacillus, and some of these strains are considered as potentially probiotic species [267,270]. The health promoting properties of probiotics are known to be strain-dependent. Thus, strain identification and characterization are important in developing probiotics for human use. For example, the oral administration of a specific probiotic strain Pediococcus acidilactici (Pa) to piglets exhibited a remarkable increase in intestinal villous height and crypt depth [240]. In this study, authors also investigated the effects of dietary supplementation with the probiotic Pa on the piglet intestine, circulating lymphocytes, and aspects of piglet performance during the first 42 days after weaning. Pa supplementation positively influenced weight and post-weaning average daily weight gain of treated piglets, associated with the larger number of proliferating enterocytes than in control animals. These studies showed that the probiotics supplementation is able to protect the piglet's small intestinal mucosa, improving local resistance to infections in the stressful weaning period.

Another study conducted recently by Awad et al. [271] showed the beneficial effect of probiotic strain Lactobacillus species on the growth of small intestinal mucosal architecture in broiler chickens. The body weight and average daily weight gain are significantly increased by the dietary inclusion of Lactobacillus species, which is associated with increased glucose transport, intestinal villous height and crypt depth ratio compared with control group. Results also showed the improvement of intestinal architecture and epithelial nutrient absorption after administration of probiotic strain Lactobacillus species. Probiotic supplementation not only improves the growth of intestinal mucosa but also augments intestinal host defense by regulating apoptosis and promoting cytoprotective responses [272]. Lin et al. [273] demonstrated that administration of Lactobacillus rhamnosus GG (LGG) reduces chemically induced intestinal epithelial apoptosis in vitro and ex vivo as measured by staining for apoptotic markers in murine models and that LGG also prevents necrotizing enterocolitis (NEC) in preterm infants. Soluble proteins produced by probiotic bacteria LGG are shown to activate Akt, inhibit cytokine-induced epithelial cell apoptosis, and promote cell growth in human and mouse colon epithelial cells and in cultured mouse colon explants [273]. These findings also suggest that probiotic bacterial components are useful for preventing cytokine-mediated GI diseases. Probiotic approaches are and will be confounded by the diversity of the human microbiota and its plasticity in the face of the varied human diets and genetic backgrounds. Based on the data from both in vitro and in vivo models, probiotics offer great potential benefits and might be used to treat intestinal functional and inflammatory disorders, metabolic syndromes as well as intestinal nociception [261,264,267,268,274,275].

DIETARY SUPPLEMENTS

The GI tract is the only part of the body that directly comes in contact with a wide variety of nutrient molecules before they are absorbed. Various nutritional supplements, such as vitamins, amino acids, nucleic acids, and sugars, are shown to have trophic effects on GI mucosal growth, epithelial cell proliferation, and differentiation [276]. It has been widely accepted that the amino acid glutamine plays an important role in the regulation of GI mucosal metabolic functions and growth [277279]. Several studies showed that intestinal glutamine metabolism not only acts as a nutritionally important portion of the energy generation, but also as the precursor or key factor of a number of important metabolic pathways of other amino acids, especially those leading to the synthesis of ornithine, citrulline, arginine, and proline. Among all amino acids, glutamine metabolism has had a greater influence on a variety of aspects of clinical nutrition [277]. There is evidence showing that the removal of glutamine by starvation of cultured intestinal mucosal cells inhibits cell proliferation [277], whereas the glutamine supplementation in rats exhibits a significant increase in the villous heights of small intestine. In contrast, the numbers of villi per unit length of bowel decrease when glutamine synthesis is inhibited by methionine sulphoximine or in the animals fed with glutamine-free diet [280]. In this study, it has been also noticed that there is a breakdown of the epithelial junctions in the glutamine-deprived and glutamine synthetase-inhibited intestines. These findings support the notion that glutamine in diet supplements is necessary for normal intestinal mucosal growth and for maintenance of the intestinal mucosal integrity. Wiren et al. [281] demonstrated the importance of glutamine in the regulation of cell differentiation by using cultured Caco-2 and HT-29 cells.

However, there are some controversial evidences about the role of glutamine supplements in the GI mucosal growth. It has been reported that oral glutamine supplementation alone does not sufficiently induce protein synthesis in the jejunal mucosa of malnourished rats, regardless of the total food intake or the presence or absence of glutamine supplementation [282]. Recently, Shyntum et al. [283] reported that dietary sulfur amino acid supplementation stimulates ileal mucosal growth rate after massive small-bowel resection in rats. In this study, they observed that resected and sulfur amino acid supplemented rats exhibited increased ileal adaptation as indicated by the increase in full-thickness wet weight, DNA, protein content, and mucosal crypt depth and villous height. Despite this negative observation, in particular experimental condition, the emerging results suggest that glutamine supplements are important for maintaining normal mucosal architecture including tight junctions.

Other important diet supplements are water- and fat-soluble vitamins which are essential for intestinal epithelial cell growth and epithelial cell proliferation [284,285]. Among them, vitamin A and its bioactive metabolites (retinoic acid) are well characterized as important agents that modulate a variety of GI physiological functions, including mucosal growth and cell proliferation. Uni et al. [286] found that vitamin A deficiency interferes with the normal growth rate in chickens. Decreased vitamin A alters the functionality of the small intestine by reducing epithelial cell proliferation and maturation. Similar findings were also observed in rats and showed that vitamin A deficiency modifies the maturation and differentiation processes of the small intestinal mucosa [287]. In a study conducted in calves that were supplemented with vitamin A, villous heights in the ileum and villous height to crypt depth ratios in the jejunum are enhanced in comparison with those from control animals. In addition, vitamin D, vitamin C, and Riboflavin in diet supplements also have similar beneficial effects on GI mucosal growth and epithelial tissue homeostasis [284288].

Several studies also show the importance of dietary nucleotides in the regulation of GI mucosal growth and development [289,290]. Exogenous supplementation of nucleotides was found to have a beneficial effect on intestinal growth after parenteral supplementation. The wet weight of the jejunal mucosa and content of total protein and DNA are higher in the rats supplemented with a mixture of nucleotide and nucleosides than those observed in the rats fed with parenteral solution alone. The morphometric analysis showed that there is a significant increase in the villous height after nucleic acid supplementation, supporting the notion that dietary nucleotides are also crucial for normal mucosal cell growth and functions.

Sodium butyrate supplementation is also shown to enhance the GI mucosal growth and improve several indices of gastrointestinal biological functions in piglets after weaning [291]. In addition, various minerals, such as zinc, magnesium, and potassium, in diet supplements also affect physiological functions of the intestine and show the beneficial effects on intestinal mucosal growth [292294].

Copyright © 2011 by Morgan & Claypool Life Sciences.
Bookshelf ID: NBK54100

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