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  • The balance and composition of the gut microflora can be

    2021-09-15

    The balance and composition of the gut microflora can be altered by the use of antibiotics or by colonization of the intestine by pathogens. This change may also induce, or be induced by, modifications in the body’s immune response, ultimately leading to disease. Thus, when intestinal homeostasis is compromised, it can frequently lead to inflammation and invasion of the epithelial layer, diarrhea and poor nutrient DLPC [11], [12]. This review will focus on a member of the receptor guanylyl cyclase family of proteins, GC-C, in regulating intestinal function. While it was realized many years ago that GC-C was the target of a family of bacterial heat-stable enterotoxins that caused watery diarrhea in humans and animals [13], recent information has highlighted the role of GC-C and cGMP in maintaining intestinal homeostasis [14], [15]. Aspects of GC-C structure have been described in a comprehensive review that has been published recently [16], and we will therefore not dwell on this in the current review. Instead, we will highlight recent findings arising from genetic approaches using mice, as well as evidence from human populations, that indicate the important roles that GC-C and cGMP have to play in intestinal physiology.
    Guanylyl cyclase C, intestinal fluid secretion and feeding behavior Diarrhea was initially considered a primitive mechanism by which the host attempts to ‘flush out’ infectious agents, but it is now appreciated that microbes disrupt the host’s secretory and absorptive machinery in an attempt to be successfully transmitted. There are various mechanisms by which microbes and their products cause diarrhea, and include direct lysis of epithelial cells, production of pore forming toxins, or by manipulation of host signaling pathways via second messengers such as cyclic AMP, cyclic GMP and calcium ions [17]. The enterotoxigenic Escherichia coli or ETEC adhere to the intestine and produce two types of toxins, the heat- labile (LT) and the heat-stable enterotoxins (ST). The LT shares 82% amino acid homology to cholera toxin, binds to the GM1 ganglioside and mediates the onset of diarrhea in a manner similar to that of cholera toxin, via elevation of intracellular cAMP [18]. ST is an 18-amino acid long peptide with three disulfide bridges, and causes an increase in chloride ion secretion, leading to secretory diarrhea [13]. The ST receptor is guanylyl cyclase C [19]. GC-C is a multi-domain protein, and a member of the receptor guanylyl cyclase family. GC-C is primarily expressed in intestinal epithelial cells, and binds to the endogenous gastrointestinal hormones guanylin and uroguanylin [20], [21], [22]. Binding of guanylin or uroguanylin to GC-C results in receptor activation, catalyzing the production of cGMP (Fig. 1). Cyclic GMP can activate cGMP-dependent protein kinase II (PKGII), or inhibit the activity of a cAMP-specific phosphodiesterase, PDE3, thereby cross-activating cAMP–dependent protein kinase (PKA). PKGII and PKA phosphorylate the cystic fibrosis transmembrane conductance regulator or CFTR, increasing its chloride-secreting activity [23]. A marked reduction in Na+ absorption, and consequently decreased fluid uptake by the intestinal cell, is also brought about by ST and the guanylin family peptides [24]. This is mediated by inhibition of the sodium-hydrogen exchanger, NHE3, following its interaction with PKGII and the scaffolding protein NHERF2 [25]. In addition, cGMP enhances duodenal bicarbonate secretion through an unknown channel [26]. Cyclic GMP can also directly activate cyclic nucleotide gated channels (CNGs), leading to Ca2+ influx [27] (Fig. 1). GC-C signaling is terminated by hydrolysis of cGMP to GMP by a cGMP-dependent phosphodiesterase, PDE5 [16]. Secretion of water into the intestinal lumen is necessary for the lubrication and breakdown of the bolus of food, and this fluid secretion is regulated by the endogenous ligands of GC-C, guanylin and uroguanylin [21], [28]. ST is a super-agonist of GC-C, and induces abnormally high levels of intracellular cGMP which causes aberrant fluid-ion efflux, leading to diarrhea. This disease is usually self-limiting in adults and symptoms resolve within a few days, therefore no specific treatment is required except oral rehydration. However, the incidence DLPC of mortality in children can be very high [17].