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Gut hormonal signaling pathways
There are four types of pathways through which gut hormones signal to exert their regulatory functions (Figure 10): (1) the endocrine pathway via the blood, (2) the paracrine pathway by acting on neighboring cells, (3) the neurocrine pathway, mostly by signaling through afferent nerves (e.g. the vagal nerve), and (4) the neurocrine-like pathway, directly connecting glial cells to the EECs. This latter pathway was suggested recently by the discovery of EEC structures called neuropods, which displays axon-like features (Bohorquez et al., 2014). These structures have so far been described for CCK- and PYY-positive EECs (Bohorquez et al., 2015).
The regulation of enterohormone secretion
A wide range of luminal compounds, such as nutrients (per review (Furness et al., 2013), microbial metabolites (e.g. SCFAs or bile acids) (Christiansen et al., 2018, Kuhre et al., 2018, Lu et al., 2018), and microbial components (e.g. LPS or toxins) (Bogunovic et al., 2007, Lebrun et al., 2017) can stimulate the expression and secretion of gut enterohormones. We will not exhaustively review all activators for all enterohormones. We will first focus on the intestinal endocrine response to acute or chronic exposure to fructose. Then, we will examine the endocrine intestinal response to major changes in nutrient influx into the lower GI tract and discuss the role of microbial metabolites on the regulation of the enterohormones. Finally, the regulation of CCK secretion and its function will be described in more detail.
The impact of fructose on the secretion of gut enterohormones
Sugars, such as fructose and glucose, as well as polysaccharides (fiber and starch), are major components of the diet and play a major role in the regulation of the expression and secretion of gut enterohormones. We will mostly center our review on the acute response of EECs to fructose relative to their response to glucose, as well as the consequences of chronic fructose intake on the intestinal endocrine response.
The intestinal endocrine response to acute fructose exposure
GLP-1 secretion is stimulated in response to oral fructose challenge in healthy humans and type 2 diabetic patients (Ganda et al., 1979, Vozzo et al., 2002, Kuhre et al., 2014, Yau et al., 2017). Similar results have been observed for mice and rats (Kuhre et al., 2014). Fructose also stimulates GLP-1 secretion in GLUTag cells (Gribble et al., 2003, Kuhre et al., 2014). In contrast, fructose does not activate the secretion of the other incretin hormone, GIP, in neither humans, rats, or mice (Vozzo et al., 2002, Kuhre et al., 2014). However, GIP secretion is mildly stimulated in response to 10mM fructose in primary mouse cells in culture (Parker et al., 2009). Over the course of a day, fructose was shown to prolong the postprandial release of GLP-1 relative to glucose when glucose and fructose were consumed in the context of isocaloric meals (Teff et al., 2004). In the same study, the postprandial suppression of ghrelin was lower after ingestion of a meal associated with a fructose-containing beverage than when associated with a glucose-containing beverage (Teff et al., 2004). This confirmed previous data found in rats, in which fasting ghrelin levels increased after two weeks of fructose consumption, whereas they remained unchanged after two weeks of glucose consumption (Lindqvist et al., 2008). In humans, acute fructose intake also stimulates the release of CCK and NTS to a similar extent as glucose, whereas PYY blood levels modestly increase in response to fructose but not glucose (Kuhre et al., 2014). Thus, acute exposure of EECs to fructose stimulates the secretion of most enterohormones.
The intestinal endocrine response to chronic fructose exposure
Numerous studies in rodents and humans have associated the chronic intake of fructose with impairment in insulin sensitivity and glycemic homeostasis (Thorburn et al., 1989, Aeberli et al., 2013). This suggests that chronic exposure to dietary fructose may impair intestinal GLP-1 and GIP secretion in response to nutrients, as GLP-1 and GIP mediate the insulinotropic response to luminal nutrients. This hypothesis was tested, but the measured effects of long-term fructose intake have been largely variable and contradictory (Madani et al., 2015, Maekawa et al., 2017, Matikainen et al., 2017). The differences observed between studies can be explained largely by differences in the duration of exposure to fructose, the mode of administration (liquid or solid), the composition of other nutrients ingested (e.g. in association with a HFD or not), and the concentration of fructose used. This reflects the complexity of the intestinal endocrine response in vivo and may also reflect the contradictory food intake behavior and satiety response to fructose (Soenen and Westerterp-Plantenga, 2007, Lindqvist et al., 2008, Moran, 2009, Page et al., 2013, Purnell and Fair, 2013).
The potential sensor of fructose in enteroendocrine cells
The mechanism by which fructose activates enterohormone secretion is less clear than for that of glucose. In the intestine, sweets exert part of their regulatory action through the sweet taste G-protein coupled receptor (GPCR) heterodimer system, taste receptor type 2 or 3 (T1R2/T1R3) (Shirazi-Beechey et al., 2011). This receptor can detect the large variety of sweet-tasting molecules (e.g. glucose, fructose, sucrose, aspartame, and sucralose) (Li et al., 2002). T1R2/T1R3 has been found along the intestinal tract at the apical membrane of most of EECs (Dyer et al., 2005, Jang et al., 2007, Margolskee et al., 2007). Rodent EEC cell lines, such as STC-1 and GLUTag, also express T1R2/T1R3 (Dyer et al., 2005, Margolskee et al., 2007), as well as the human L-cell line, NCI-H716 (Jang et al., 2007). Among the various EEC types, T1R2/T1R3 is strongly expressed by GLP-1 and PYY-positive EECs (Meyer-Gerspach et al., 2014) and GIP-positive cells (Moran et al., 2010), but is poorly expressed in duodenal I-cells that secrete CCK (Daly et al., 2013). Interestingly, lactitol, a competitive inhibitor of T1R3, reduces glucose-induced GLP-1 and PYY release in vivo and in vitro (Margolskee et al., 2007, Gerspach et al., 2011), but has no effect on CCK secretion (Gerspach et al., 2011), indicating that sweet taste receptors are unlikely to be involved in the regulation of CCK secretion. The activation of GLP-1/2, GIP, and PYY in response to fructose through the T1R2/T1R3 pathway is theoretically possible since fructose also activates T1R2/T1R3 in EECs (Shirazi-Beechey et al., 2014). However, no study has investigated the role of the sweet taste receptor in mediating the effect of fructose in EECs. Another possible mechanism may involve the fructose transporters, GLUT2 and GLUT5. The GLUT5 transcript has been detected by qRT-PCR in isolated K-cells of the upper small intestine and isolated colonic L-cells (Reimann et al., 2008, Parker et al., 2009). GLUT2 is expressed at the apical and basolateral membranes of L-cells in rodents and humans (Parker et al., 2012, Schmitt, 2016).
The impact of change in the nutrient flow on enterohormone expression
Numerous studies have shown that changes in nutrient flow in the intestine can modify endocrine function along the GI tract through modification of the distribution or transcriptional activity of EECs. In a rodent model of Roux-en-Y gastric bypass (RYGB), the number of GLP-1-, GIP- and PYY-positive cells increased in the alimentary and common limbs (intestinal segments in which the nutrient flow increased after the surgery) but not the biliopancreatic limb (intestinal segment without nutrient flow) (Cavin et al., 2016). Similar results have also been observed in humans after RYGB (Nergård et al., Rhee et al., 2015, Cavin et al., 2016). In addition to GLP-1, GIP, and PYY, which are the most extensively studied gut enterohormones in the context of RYGB, a few studies have also investigated changes in CCK and NTS; CCK-positive cell density increased in the alimentary and common limbs after RYGB in humans (Rhee et al., 2015) and rat models (Mumphrey et al., 2013) and postprandial CCK and NTS serum levels were greater in response to a meal in RYGB patients than control subjects (Jacobsen et al., 2012, Dirksen et al., 2013). In rats, interposition of the ileum into the jejunum led to an increased in mRNA levels of the precursor of GLP-1 and the GLP-2, pre-proglucagon (Gcg), in the remnant ileum segments and the colon (Holst, 1997, Brubaker and Anini, 2003). In humans, short bowel syndrome (SBS), a strong malabsorption disorder resulting from resection of the small intestine, is associated with elevated plasma levels of GLP-1, GLP-2, and PYY (Jeppesen et al., 2000, Gillard et al., 2016). SBS animal models also exhibit major endocrine adaptations in the GI tract, including elevated Pyy and Gcg transcript levels in the colon (Gillard et al., 2016).
The role of the gut microbiota and its metabolites on the regulation of enteroendocrine cells
The transfer of SBS patient microbiota into germ-free (GF) rats increases the density of GLP-1-positive cells in the colon of recipient animals relative to that of rats colonized with conventional microbiota, emphasizing the role of the intestinal ecosystem in intestinal EECs proliferation and differentiation (Gillard et al., 2017). Numerous studies have highlighted the ability of microbiota-derived products, such as SCFAs (Zhou et al., 2008, Tolhurst et al., 2012, Psichas et al., 2015, Plovier and Cani, 2017) and bile acids (Thomas et al., 2009, Trabelsi et al., 2015, Fuchs et al., 2018), to regulate Gcg expression and GLP-1 or PYY secretion. Interestingly, GF rodents and rodents treated with antibiotics display higher Gcg expression levels, GLP-1-positive cell density in the colon, and elevated circulating levels of GLP-1 than conventionally raised mice (Wichmann et al., 2013, Arora et al., 2018). The gut microbiota also profoundly impairs the transcriptional responses of the Gcg-positive cells in the ileum and colon (Arora et al., 2018). However, although it is now clearly established that most of EECs secrete more than one enterohormone (Gribble and Reimann, 2016), the ability of the microbiota to specifically modulate the panel of secreted hormones in individual EECs is still unclear. Moreover, the impact of microbiota on enterohormones that have long been assumed to be expressed and secreted in the upper small intestine has not been investigated.
Table of contents :
INTRODUCTION
I-Structures and functions of the gastrointestinal tract
I-1 Structures of the intestinal epithelium
I-2 Cell populations of the intestinal epithelium
I-3 Intestinal epithelium renewal
II-Gut microbiota
II-1 General overview of the gut microbiota composition
II-2 The functions of the gut microbiota
II-3 The stability and dietary-dependent alterations of the microbiota composition .
II-4 The microbial metabolites and components
II-4.1 Short-chain fatty acids
II-4.2 Bile acids
II-4.3 Tryptophan metabolites
II-4.4 Lipopolysaccharides
II-5 The role of gut microbiota in metabolic diseases
III- Enteroendocrine functions of the gastrointestinal tract
III-1 The classification of enteroendocrine cells: from the old to a new dogma
III-2 Gut hormonal signaling pathways
III-3 The regulation of enterohormone secretion
III-3.1 The impact of fructose on the secretion of gut enterohormones
III-3.1.1 The intestinal endocrine response to acute fructose exposure
III-3.1.2 The intestinal endocrine response to chronic fructose exposure.
III-3.1.3 The potential sensor of fructose in enteroendocrine cells
III-3.2 The impact of change in the nutrient flow on enterohormone expression
III-3.3 The role of the gut microbiota and its metabolites on the regulation of enteroendocrine cells
III-4 Cholecystokinin: its regulation and main function
III-4.1 Transcript structure and derived molecular forms of cholecystokinin
III-4.2 Stimulation of cholecystokinin secretion
III-4.2.1 The fatty acids
III-4.2.2 Protein hydrolysates and amino acids
III-4.2.3 Sweet and Bitter stimuli
III-4.2.4 Non-nutrient stimuli
III-4.3 Physiological effects of cholecystokinin
III-4.3.1 Food intake
III-4.3.2 Pancreatic secretion, gut motility and gallbladder contraction
III-4.3.3 Pain
III-4.3.4 The central action of cholecystokinin on various behavior processes .
III-5 Regulation of the other gut peptides: Peptide YY, glucagon-like peptide-1, and neurotensin
III-5.1 Peptide YY
III-5.2 Glucagon-like peptide-1
III-5.3 Neurotensin
IV- Gut permeability and its major role in metabolic disorders
IV-1 Gut permeability: definition and main components
IV-1.1 Transcellular permeability
IV-1.2 Paracellular permeability
IV-1.2.1 Tight junction proteins
IV-1.2.1.1 The claudin family
IV-1.2.1.2 Occludin
IV-1.2.1.3 The family of junctional adhesion molecules
IV-1.2.1.4 The family of zonula occludens
IV-1.2.2 The regulation of paracellular permeability
IV-2 The measurement of gut permeability
IV-2.1 In vivo permeability assays
IV-2.2 Ex vivo Ussing chamber system
IV-2.3 In vitro permeability measurements
IV-3 The effect of nutrients on gut permeability
IV-3.1 Lipids and chronic exposure to a high-fat diet
IV-3.2 Sugars
V-Enteric nervous system
V-1 The basic structure and functions of enteric nervous system
V-2 The regulation of enteric nervous system on intestinal barrier function
V-3 The inflammation induced modification in enteric nervous system
V-4 The effects of gut microbiota on enteric nervous system
V-5 The function of enteric nervous system in nutrients sensing
VI- Fructose consumption, transport and metabolism – health consequences of its excessive consumption
VI-1 The pattern of fructose consumption
VI-2 Intestinal transport of fructose
VI-2.1 The main intestinal fructose transporters GLUT5 and GLUT2
VI-2.2 Other potential transporters
VI-2.3 The regulation of GLUT5 in intestinal tissue
VI-2.4 Developmental Regulation of GLUT5
VI-2.5 The regulation of GLUT5 by luminal fructose
VI-3 Ketohexokinase: the key enzyme in fructose metabolism
VI-4 Health outcome of excessive fructose intake
VI-4.1 Liver: the central target
VI-4.2 Fructose intake and functional alteration of other organs
VI-5 Fructose malabsorption
OBJECTIVES
RESULTS
Fructose malabsorption – Ketohexokinase knockout mice model
Article1: Fructose malabsorption modifies the endocrine response of the lower intestine by Modulating microbiota composition and metabolism
Additional Results for Article 1
Article2: Glucose but not fructose alters the intestinal paracellular permeability in association with inflammation in mice and Caco-2 cells
GENERAL DISCUSSION AND PERSPECTIVES
I-The potential physiological consequence of the increase in CCK in the lower intestine
II-The potential link between the increase in intestinal CCK and the symptoms associated with fructose malabsorption
III-Nature of the stimuli able to activate CCK in the lower intestine
IV-The role of the fructose-induced changes in the microbiota composition in the alteration of gastrointestinal endocrine and barrier functions
V-Impact of fructose on intestinal permeability in normo- and mal-absorptive fructose conditions
GENERAL CONCLUSION
BIBLIOGRAPHY
