Developmental Biology of Gastrointestinal Hormones

M. Wabitsch, C. Posovszky

• Publisher: S. Karger
• Year: 2017
• ISBN:
  9783318059748
• Topic: Medicine
• Subtopic: Endocrinology & Metabolism

The gut not only represents the largest endocrine organ of the human body but is also profoundly involved in the control of metabolism through peptide hormones. Therefore, gastrointestinal hormones are acting via autocrine, paracrine, and classical endocrine pathways and regulate e.g. digestion, hunger, and satiety. Furthermore, they are important regulators of body weight, growth, and glucose metabolism, as well as of mood and behavior. Physicians and scientists in the field of pediatric endocrinology and diabetes, as well as in pediatric gastroenterology, require an extensive understanding of the origin of enteroendocrine cells, factors controlling their differentiation, hormone gene expression, secretion, function and, finally, the complex interaction with other organs, especially the central nervous system. In order to meet these needs, experts in the field have written up-to-date, comprehensive, and illustrated reviews presenting the current knowledge in the field of gastrointestinal endocrinology with a pediatric view. Those reviews comprise this latest volume of Endocrine Development.

Wabitsch M, Posovszky C (eds): Developmental Biology of Gastrointestinal Hormones.
Endocr Dev. Basel, Karger, 2017, vol 32, pp 139–164 (DOI: 10.1159/000475736)

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Enteroendocrine Cells: Metabolic Relays between Microbes and Their Host

Hubert Plovier^{a, b} · Patrice D. Cani^{a, b}

^aWELBIO – Walloon Excellence in Life Sciences and Biotechnology, and ^bMetabolism and Nutrition Research Group, Louvain Drug Research Institute, Université Catholique de Louvain, Brussels, Belgium

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Abstract

Gut bacteria exert a variety of metabolic functions unavailable to the host and are increasingly seen as a virtual organ located inside our gastrointestinal tract. Scattered in our intestinal epithelium, enteroendocrine cells (EECs) regulate several aspects of the host’s physiology and translate signals coming from the gut microbiota through their hormonal secretions. In this chapter, we will assess the interplay between the gut microbiota and EEC and its consequences for the physiology of the host. We will first describe alterations of different populations of EEC in germ-free animals. The role of mediators of this interaction, such as microbial metabolites and their receptors will also be discussed. Finally, different strategies harnessing host-microbe crosstalk for therapeutic purposes will be presented with an emphasis on obesity and related disorders.

© 2017 S. Karger AG, Basel

The Gastrointestinal Tract by the Numbers

Stretching from the stomach to the rectum, the gastrointestinal (GI) tract is an organ of great numbers. With its combination of circular folds, crypts, villi and microvilli, it represents the biggest absorption surface of our body, as illustrated in the chapter by Posovszky [this vol., pp. 20–37] [1]. It can also be seen as our second brain, as GI neurons follow those of the central nervous system in terms of numbers [2]. The gut-associated lymphoid tissue is the largest compartment of the immune system [3]. Although they only represent 1% of the intestinal epithelium, intestinal endocrine cells (enteroendocrine cells, EECs) constitute our biggest endocrine organ [4].

More than 30 GI hormones have been identified to this day, as represented in the chapter by Rehfeld [this vol., pp. 8–19]. Historically, hormonal secretions have been one of the main classification criteria of EEC. It was originally thought that each type of EEC could secrete one specific hormone derived from a single peptide precursor, with exceptions like the L cells, secreting both proglucagon-derived peptides and peptide tyrosine-tyrosine (PYY) in the ileum and colon [5]. However, the use of modern techniques, such as flow cytometry cell sorting-based purification of fluorescently tagged EEC [6] challenged this paradigm. In 3 different studies, cells isolated on the basis of promoter activity for either proglucagon and cholecystokinin were shown to produce up to 6 different hormones, previously thought to be restricted to different cell types [7–9]. Similar results were also obtained with immunohistochemistry, here again showing coproduction of unrelated hormones [10]. Furthermore, targeted ablation of cells based on the promoter activity of cholecystokinin caused a significant decrease in the abundance of EEC positive for 6 different hormones [8]. This led to the proposal of a new classification based on co-produced hormones and the position of the cells along the GI tract: Pan-GI tract EEC are present from the stomach to the rectum and produce somatostatin and serotonin. Stomach-specific EEC produce gastrin and ghrelin, while intestine-specific EEC produce the majority of enteric hormones including secretin, cholecystokinin, glucose-dependent insulinotropic peptide (GIP), neurotensin, the glucagon-like peptides (GLP) 1 and 2, insulin-like peptide 5 (Insl5) and PYY [11].

The functions exerted by enteroendocrine hormones can be divided into 4 categories: (1) regulation of food intake (e.g., appetite and food behavior); (2) modulation of GI motor functions (e.g., gastric emptying and intestinal motility); (3) regulation of secretion from organs, such as the pancreas or gallbladder as well as from other EEC; and (4) stimulation of glucose-induced insulin secretion, also known as the incretin effect. Altogether, they contribute not only to the physiology of the GI tract as a whole, but also to the fine-tuning of our metabolism [5].

The Gut Microbiota, Our Bacterial Counterpart

The GI tract is home to the most important microbial community of our body, also known as the gut microbiota. Bacteria are the main representatives of our microbiota, far beyond archaea, viruses and eukaryotes [12]. The number of bacteria residing in our GI tract is similar to the total number of cells in our body, even ten times higher if red blood cells are not taken into account [13]. Furthermore, the collective microbial genome, termed the gut microbiome, consists of a hundred times more genes than our own genome [14].

Most gut bacteria belong to 3 major taxonomic phyla: Firmicutes, Bacteroidetes and Actinobacteria. These phyla account for more than 90% of the gut bacterial species, with other phyla, such as Tenericutes, Proteobacteria and Verrucomicrobia sharing the last 10%. Each individual harbors at least 160 distinct bacterial species, some of which are shared among the whole community [14]. Furthermore, while interindividual variation in terms of gut microbial community is important, metabolic pathways are stable across individuals [15]. Gut microbes can exert a tremendous amount of metabolic functions that, as a host, we are unable to perform. They can thus be seen as a virtual external organ taking part in nearly all aspects of our physiology, from nutrient absorption and regulation of food behavior to the maturation of our immune and nervous systems and the regulation of our metabolism and endocrine functions (reviewed in [3, 12, 16–18]).

The composition of the gut microbiota is unstable in infants. Stability and diversity of the gut microbial community concomitantly increase to reach an adult-like diverse consortium by 3 years of age [19, 20]. Interestingly, high microbial diversity is associated with a good metabolic health in adults. People harboring a less diverse microbiota display increases in insulin resistance, proinflammatory tone and alterations of lipid metabolism associated with higher predispositions to body weight gain [21, 22]. Furthermore, changes in the composition of the microbiota have been associated with various pathologies of relevance for pediatricians, including type-1 diabetes [23–25], inflammatory bowel disorders [26] and obesity [27, 28].

Impact of the Gut Microbiota on EEC: Lessons from Germ-Free Mice

The influence of gut microbes on the physiology of their host, including the regulation of EEC, is perhaps best illustrated by the study of germ-free (GF) animal models.

As their name suggests, GF animals are raised in sterile conditions and are free of any microbe [29]. Because of this lack of colonization, their physiology profoundly differs from that of conventionally raised (Conv-R) animals that have been in contact with microbes throughout their life. One of the most striking differences is that GF mice weigh significantly less than Conv-R mice, although their food intake is higher [30, 31]. This is due to drastic alterations of their metabolism, notably including lower lipid absorption and changes in various hormonal systems [32]. GF mice display, for example, lower levels of insulin and leptin, which regulate glucose and lipid metabolism [33]. The activity of their somatotropic axis is also decreased, with lower levels of insulin-like growth factor 1 and lower activity of its downstream effectors [31]. In addition to insulin, leptin and somatotropic hormones, various EEC also differ in terms of functionality and hormonal production between GF and Conv-R mice. Examples will be discussed below.

Intestine-Specific EEC, Glucagon-Derived Peptides and PYY

The earliest reports describing differences in EEC physiology in GF animals focused on intestine-specific EEC, producing glucagon-derived peptides and PYY. In a first study in 1989, circulating levels of enteroglucagon and PYY were compared between GF and Conv-R rats. Levels of both hormones were much higher in animals raised without microbes [34]. Subsequent reports focusing on the caecum and colon showed that this increase could be explained by 2 main factors: increased cell size and intracellular hormonal content on the one hand [35, 36], and increased cell density on the other [37]. Surprisingly, in the proximal small intestine, protein levels of GLP-1 and PYY were found to be significantly lower in GF mice [32]. In the same study, EEC density was decreased in the ileum, while it was increased in the colon of GF mice, which probably reflects differences in the physiology of EEC between the small and large intestines [38]. However, as the dens...