Dietary aluminum may trigger IBS

In addition to changes in enteroendocrine cells, AlCi-treated rats had greater colonic mast cell degranulation and histamine with upregulation of histidine decarboxylase transcripts, suggesting that aluminum activated mast cells.

To determine the role of mast cell activation in visceral hypersensitivity, rats were given AlCi with cromoglycate, an inhibitor of mast cell degranulation. This treatment reduced mast cell degranulation and visceral pain threshold, compared with AlCi-treated rats not receiving cromoglycate, suggesting that mast cell degranulation is a primary driver of visceral hypersensitivity. This observation was confirmed by a mast cell–deficient mouse strain (Kit W-sh/W-sh), that had a normal number of mast cells incapable of degranulation. Treating the mast cell–deficient mice with AlCi did not induce visceral hypersensitivity, thereby confirming the role of mast cell degranulation.

Along with mast cell degranulation, AlCi treatment led to PAR2 activation. Investigators explored the significance of this finding with PAR2 knockout mice. When treated with AlCi, PAR2 knockout mice showed no increase in visceral hypersensitivity, suggesting that hypersensitivity is dependent on PAR2 activation. Further testing revealed that mast cell–deficient mice (Kit W-sh/W-sh) did not have PAR2 upregulation either, connecting a sequence in which aluminum triggers mast cell degranulation, mast cell degranulation drives PAR2 upregulation, and PAR2 upregulation causes visceral hypersensitivity. The latter two events in this chain – mast cell degranulation and PAR2 upregulation – mirror molecular mechanisms of IBS in humans.

“We speculate that aluminum activates mast cells to release mediators that can increase excitability of nociceptive afferences contributing to the visceral pain phenotype,” the investigators wrote. “Taken together, our results linked aluminum to several mechanisms implicated in IBS pathophysiology, highlighting a possible role for aluminum as a triggering factor in IBS development.”

The investigators suggested that these findings could influence preventive or therapeutic strategies: “Aluminum might be the first identified dietary risk factor for IBS, implying that measures to limit aluminum dietary consumption or to chelate aluminum may represent novel pathways of prevention and treatment of IBS in some susceptible patients,” they wrote.

The study was funded by the European Fund for Regional Economic Development; the Hauts de France Region, Ministère de l’Enseignement Supérieur et de la Recherche (CPER IRENI); and Digestscience (European Research Foundation on Intestinal Diseases and Nutrition).

SOURCE: Esquerre N et al. Cell Mol Gastroenterol Hepatol. 2019 Sep 20. doi: 10.1016/j.jcmgh.2018.09.012.