The increased incidence of inflammatory bowel disease (IBD) has become a global phenomenon that could be related to adoption of a Western lifestyle. Westernization of dietary habits is partly characterized by enrichment with the ω-6 polyunsaturated fatty acid (PUFA) arachidonic acid (AA), which entails risk for developing IBD. Glutathione peroxidase 4 (GPX4) protects against lipid peroxidation (LPO) and cell death termed ferroptosis. We report that small intestinal epithelial cells (IECs) in Crohn's disease (CD) exhibit impaired GPX4 activity and signs of LPO. PUFAs and specifically AA trigger a cytokine response of IECs which is restricted by GPX4. While GPX4 does not control AA metabolism, cytokine production is governed by similar mechanisms as ferroptosis. A PUFA-enriched Western diet triggers focal granuloma-like neutrophilic enteritis in mice that lack one allele of Gpx4 in IECs. Our study identifies dietary PUFAs as a trigger of GPX4-restricted mucosal inflammation phenocopying aspects of human CD.

The intestinal epithelium constitutes an indispensable single-layered barrier to protect the body from invading pathogens, antigens or toxins. At the same time, beneficial nutrients and water have to be absorbed by the epithelium. To prevent development of intestinal inflammation or tumour formation, intestinal homeostasis has to be tightly controlled and therefore a strict balance between cell death and proliferation has to be maintained. The proinflammatory cytokine tumour necrosis factor alpha (TNFα) was shown to play a striking role for the regulation of this balance in the gut. Depending on the cellular conditions, on the one hand TNFα is able to mediate cell survival by activating NFκB signalling. On the other hand, TNFα might trigger cell death, in particular caspase-dependent apoptosis but also caspase-independent programmed necrosis. By regulating these cell death and survival mechanisms, TNFα exerts a variety of beneficial functions in the intestine. However, TNFα signalling is also supposed to play a critical role for the pathogenesis of inflammatory bowel disease (IBD), infectious diseases, intestinal wound healing and tumour formation. Here we review the literature about the physiological and pathophysiological role of TNFα signalling for the maintenance of intestinal homeostasis and the benefits and difficulties of anti-TNFα treatment during IBD.

No abstract

Although induction of host cell death is a pivotal step during bacteria-induced gastroenteritis, the molecular regulation remains to be fully characterized. To expand our knowledge, we investigated the role of the central cell death regulator Caspase-8 in response to Salmonella Typhimurium. Here, we uncovered that intestinal salmonellosis was associated with strong upregulation of members of the host cell death machinery in intestinal epithelial cells (IECs) as an early event, suggesting that elimination of infected IECs represents a host defense strategy. Indeed, Casp8 mice displayed severe tissue damage and high lethality after infection. Additional deletion of Ripk3 or Mlkl rescued epithelial cell death and lethality of Casp8 mice, demonstrating the crucial role of Caspase-8 as a negative regulator of necroptosis. While Casp8Tnfr1 mice showed improved survival after infection, tissue destruction was similar to Casp8 mice, indicating that necroptosis partially depends on TNF-α signaling. Although there was no impairment in antimicrobial peptide secretion during the early phase of infection, functional Caspase-8 seems to be required to control pathogen colonization. Collectively, these results demonstrate that Caspase-8 is essential to prevent Salmonella Typhimurium induced enteritis and to ensure host survival by two different mechanisms: maintenance of intestinal barrier function and restriction of pathogen colonization.

No abstract