The effects of polyamines on human colonic mucosal function

Rogers, Ailín C.; McDermott, Frank D.; Mohan, Helen; O’Connell, P. R.; Winter, Desmond C.; Baird, Alan W.

doi:10.1016/j.ejphar.2015.07.006

Cited by 16 publications

(10 citation statements)

References 49 publications

(52 reference statements)

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“…As expected, stimulation of adenylyl cyclase with forskolin or cholera toxin increased cytosolic cAMP, and stimulation of guanylyl cyclase with guanylin or the Escherichia coli heat-stable enterotoxin STa increased cytosolic cGMP; increased

or R568 abolished these effects (Geibel et al, 2006 ). Similar inhibitory effects were seen for spermine in isolated human colonic mucosa (Rogers et al, 2015 ). Interestingly, the CaSR-mediated inhibitory effects on cyclic nucleotides as well as on increased fluid secretion were prevented by the phosphodiesterase (PDE) inhibitor IBMX (Geibel et al, 2006 ).…”

Section: Casr and Intestinal Absorption And Secretionsupporting

confidence: 70%

The Extracellular Calcium-Sensing Receptor in the Intestine: Evidence for Regulation of Colonic Absorption, Secretion, Motility, and Immunity

et al. 2016

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Different from other epithelia, the intestinal epithelium has the complex task of providing a barrier impeding the entry of toxins, food antigens, and microbes, while at the same time allowing for the transfer of nutrients, electrolytes, water, and microbial metabolites. These molecules/organisms are transported either transcellularly, crossing the apical and basolateral membranes of enterocytes, or paracellularly, passing through the space between enterocytes. Accordingly, the intestinal epithelium can affect energy metabolism, fluid balance, as well as immune response and tolerance. To help accomplish these complex tasks, the intestinal epithelium has evolved many sensing receptor mechanisms. Yet, their roles and functions are only now beginning to be elucidated. This article explores one such sensing receptor mechanism, carried out by the extracellular calcium-sensing receptor (CaSR). In addition to its established function as a nutrient sensor, coordinating food digestion, nutrient absorption, and regulating energy metabolism, we present evidence for the emerging role of CaSR in the control of intestinal fluid homeostasis and immune balance. An additional role in the modulation of the enteric nerve activity and motility is also discussed. Clearly, CaSR has profound effects on many aspects of intestinal function. Nevertheless, more work is needed to fully understand all functions of CaSR in the intestine, including detailed mechanisms of action and specific pathways involved. Considering the essential roles CaSR plays in gastrointestinal physiology and immunology, research may lead to a translational opportunity for the development of novel therapies that are based on CaSR's unique property of using simple nutrients such as calcium, polyamines, and certain amino acids/oligopeptides as activators. It is possible that, through targeting of intestinal CaSR with a combination of specific nutrients, oral solutions that are both inexpensive and practical may be developed to help in conditioning the gut microenvironment and in maintaining digestive health.

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Section: Casr and Intestinal Absorption And Secretionsupporting

confidence: 70%

The Extracellular Calcium-Sensing Receptor in the Intestine: Evidence for Regulation of Colonic Absorption, Secretion, Motility, and Immunity

et al. 2016

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“…Pathway-wide modulation of LIC polyamine metabolites ( Figures 2B, 5 ) in Pro+RB can work to reduce diarrhea and interfere with HRV replication. Past investigations support that polyamines in the intestinal lumen act on the enterocyte calcium-sensing receptor to inhibit the intracellular release of calcium and reduce chloride secretion into the intestinal lumen (Rogers et al, 2015), simultaneously interfering with rotavirus replication and altering luminal osmolarity to reduce the onset of diarrhea. Collectively, analysis of entire lipid and amino acid/peptide pathways supports that a more comprehensive understanding of anti-diarrheal activity can be achieved when clusters of closely related metabolites are considered as part of an entire, functioning metabolic system.…”

Section: Discussionmentioning

confidence: 99%

Rice Bran and Probiotics Alter the Porcine Large Intestine and Serum Metabolomes for Protection against Human Rotavirus Diarrhea

et al. 2017

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Human rotavirus (HRV) is a leading cause of severe childhood diarrhea, and there is limited vaccine efficacy in the developing world. Neonatal gnotobiotic pigs consuming a prophylactic synbiotic combination of probiotics and rice bran (Pro+RB) did not exhibit HRV diarrhea after challenge. Multiple immune, gut barrier protective, and anti-diarrheal mechanisms contributed to the prophylactic efficacy of Pro+RB when compared to probiotics (Pro) alone. In order to understand the molecular signature associated with diarrheal protection by Pro+RB, a global non-targeted metabolomics approach was applied to investigate the large intestinal contents and serum of neonatal gnotobiotic pigs. The ultra-high performance liquid chromatography-tandem mass spectrometry platform revealed significantly different metabolites (293 in LIC and 84 in serum) in the pigs fed Pro+RB compared to Pro, and many of these metabolites were lipids and amino acid/peptides. Lipid metabolites included 2-oleoylglycerol (increased 293.40-fold in LIC of Pro+RB, p = 3.04E-10), which can modulate gastric emptying, andhyodeoxycholate (decreased 0.054-fold in the LIC of Pro+RB, p = 0.0040) that can increase colonic mucus production to improve intestinal barrier function. Amino acid metabolites included cysteine (decreased 0.40-fold in LIC, p = 0.033, and 0.62-fold in serum, p = 0.014 of Pro+RB), which has been found to reduce inflammation, lower oxidative stress and modulate mucosal immunity, and histamine (decreased 0.18-fold in LIC, p = 0.00030, of Pro+RB and 1.57-fold in serum, p = 0.043), which modulates local and systemic inflammatory responses as well as influences the enteric nervous system. Alterations to entire LIC and serum metabolic pathways further contributed to the anti-diarrheal and anti-viral activities of Pro+RB such as sphingolipid, mono/diacylglycerol, fatty acid, secondary bile acid, and polyamine metabolism. Sphingolipid and long chain fatty acid profiles influenced the ability of HRV to both infect and replicate within cells, suggesting that Pro+RB created a protective lipid profile that interferes with HRV activity. Polyamines act on enterocyte calcium-sensing receptors to modulate intracellular calcium levels, and may directly interfere with rotavirus replication. These results support that multiple host and probiotic metabolic networks, notably those involving lipid and amino acid/peptide metabolism, are important mechanisms through which Pro+RB protected against HRV diarrhea in neonatal gnotobiotic pigs.

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“…GPR35 is listed (Table 1) as a sensor of aromatic acids and, in particular, the tryptophan metabolite kynurenic acid, although a long list of additional and quite diverse agents, including even a chemokine protein, has been proposed as ligands for GPR35 as well (MacKenzie et al, 2014). Similarly, the calcium-sensing receptor CasR, a primary sensor for Brown et al, 2003;Nøhr et al, 2013;Stoddart et al, 2008;Tan et al, 2014;Tang et al, 2015;Ulven, 2012 SCFAs: acetate, propionate, butyrate Brown et al, 2003;Engelstoft et al, 2013;Ge et al, 2008;Nøhr et al, 2013;Stoddart et al, 2008;Tan et al, 2014;Tang et al, 2015;Tolhurst et al, 2012;Ulven, 2012 HCAs: Taggart et al, 2005;Dobbins et al, 2013;Lauring et al, 2012;Semple et al, 2008;Shen et al, 2010;Hanson et al, 2010;Offermanns et al, 2011 extracellular Ca 2+ in the parathyroid and the kidney, is also able to detect dietary amino acids and oligopeptides (Rogers et al, 2015). Yet, another aspect to consider is, as indicated in Figure 1A, that the selectivity is far from absolute.…”

Section: The Large Family Of Metabolite Gpcrsmentioning

confidence: 99%

GPCR-Mediated Signaling of Metabolites

et al. 2017

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In addition to their bioenergetic intracellular function, several classical metabolites act as extracellular signaling molecules activating cell-surface G-protein-coupled receptors (GPCRs), similar to hormones and neurotransmitters. "Signaling metabolites" generated from nutrients or by gut microbiota target primarily enteroendocrine, neuronal, and immune cells in the lamina propria of the gut mucosa and the liver and, through these tissues, the rest of the body. In contrast, metabolites from the intermediary metabolism act mainly as metabolic stress-induced autocrine and paracrine signals in adipose tissue, the liver, and the endocrine pancreas. Importantly, distinct metabolite GPCRs act as efficient pro- and anti-inflammatory regulators of key immune cells, and signaling metabolites may thus function as important drivers of the low-grade inflammation associated with insulin resistance and obesity. The concept of key metabolites as ligands for specific GPCRs has broadened our understanding of metabolic signaling significantly and provides a number of novel potential drug targets.

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The effects of polyamines on human colonic mucosal function

Cited by 16 publications

References 49 publications

The Extracellular Calcium-Sensing Receptor in the Intestine: Evidence for Regulation of Colonic Absorption, Secretion, Motility, and Immunity

The Extracellular Calcium-Sensing Receptor in the Intestine: Evidence for Regulation of Colonic Absorption, Secretion, Motility, and Immunity

Rice Bran and Probiotics Alter the Porcine Large Intestine and Serum Metabolomes for Protection against Human Rotavirus Diarrhea

GPCR-Mediated Signaling of Metabolites

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