environmental factors; intestinal barrier function; inflammasome; nanoparticles; ulcerative colitis; extraintestinal manifestations; NLRP3
Ruiz Pedro A, Morón Belen, Becker Helen M, Lang Silvia, Atrott Kirstin, Spalinger Marianne R, Scharl Michael, Wojtal Kacper A, Fischbeck-Terhalle Anne, Frey-Wagner Isabelle, Hausmann Martin, Kraemer Thomas, Rogler Gerhard (2017), Titanium dioxide nanoparticles exacerbate DSS-induced colitis: role of the NLRP3 inflammasome, in Gut
, 66(7), 1216-1224.
SummaryMicro/nano-particles are widely used as food additives or in pharmaceutical formulations and are consumed by millions of people. The most commonly used microparticles are sub-micron sized (0.1-1 µm diameter), inorganic compounds of titanium dioxide (TiO2, E171) aluminum silicate (AlSi, Kaolin, E559), silicon dioxide (SiO2, E551) and iron oxide (E172).The total daily intake of TiO2 in the Western world is estimated to be up to 76 mg. To date, no restrictions for the use of TiO2 and AlSi in dietary products are enforced by food safety authorities. Indicators that TiO2 may have hazardous potential were found in animal and in vitro studies. In intestinal biopsies, aggregates of titanium were detected in M-cells of Peyer’s patches and in underlying macrophages. Crohn's diseased (CD) and ulcerative colitis (UC) are inflammatory bowel diseases (IBD) which represent a chronic, relapsing inflammation of the intestine characterized by an altered pro-inflammatory cytokine pattern, defective mucosal barrier and increased intestinal permeability, the so-called “leaky gut”. Both environmental and genetic factors are associated with an increased risk to develop IBD. Rising incidences of CD in industrialized countries are attributed to Western nutrition. Whereas many (>190) genetic risk factors for IBD are known, insight into environmental factors is scarce.Together with two other proteins (ASC and caspase-1) NLRP3 forms the inflammasome, an intracellular signalling platform that is activated upon a number of stimuli, such as peptidoglycans, ATP, asbestos, silica, and uric acid crystals. Nonbacterial inflammasome activators such as ATP and small inorganic substances are summarized as “danger signals” or danger associated molecular patterns (DAMPs). TiO2 was found to be another inorganic compound that may activate the inflammasome. Since the intestinal epithelium forms the first barrier against food derived TiO2, we investigated whether TiO2 is also recognized as “danger signal” by human IEC. During our recent SNF project of the role of dietary TiO2 particles we could show that TiO2 in concentrations taken up by humans aggravate experimental colitis in mice. TiO2 aggregates can be found in the spleen of these aninals. In addition, in patients with active UC we found significantly increased TiO2 serum levels as copared to patients in remission of the disaese and healthy controls indicating that mainly during active colitis TiO2 may play a disease modifiying role. In a collaboration with colleagues from Lille we coud show that aluminum similarly is able to aggravate experimental colitis. During active colonic inflammation many CD and UC patients also experience extraintestinal manifestations (EIM). So far ist the pathophysiology of EIM is completely unclear. Based on our recent findings we aim to further analyze whether 1) The amount of penetrations of dietary micro/nano-particles (titanium dioxide) in patients with active IBD depends on the extent of involved (inflamed) mucosa.2) Dietary micro/nano-particles (TiO2) are able to penetrate the mucosal barrier and may accumulate in extraintestinal tissues leading to extraintestinal manifestations of IBD 3) Dietary micro/nano-particles (titanium dioxide) may cause indirect impact on mucosal inflammation via microbiota changes and epigenetic alterations in mucosal cells 4) Physical properties of dietary micro/nano-particles allow penetration into the mucosa which are not specific for and restricted to TiO2.5) Modulation of PTPN22 activity will impact the TiO2 effect The long term goal will be a better understanding of environmental factors that contribute to chronic intestinal inflammation and a chance to modify the disease course by diets avoiding these factors.