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Perfluorooctanesulfonic acid modulates barrier function and systemic T-cell homeostasis during intestinal inflammation.

ABSTRACT: The intestinal epithelium is continuously exposed to deleterious environmental factors that might cause aberrant immune responses leading to inflammatory disorders. However, what environmental factors might contribute to disease are poorly understood. Here, to overcome the lack of in vivo models suitable for screening of environmental factors, we used zebrafish reporters of intestinal inflammation. Using zebrafish, we interrogated the immunomodulatory effects of polyfluoroalkyl substances, which have been positively associated with ulcerative colitis incidence. Exposure to perfluorooctanesulfonic acid (PFOS) during 2,4,6-trinitro-benzene sulfonic acid (TNBS)-induced inflammation enhanced the expression of proinflammatory cytokines as well as neutrophil recruitment to the intestine of zebrafish larvae, which was validated in the TNBS-induced colitis mouse model. Moreover, PFOS exposure in mice undergoing colitis resulted in neutrophil-dependent increased intestinal permeability and enhanced PFOS translocation into the circulation. This was associated with a neutrophil-dependent expansion of systemic CD4+ T cells. Thus, our results indicate that PFOS worsens inflammation-induced intestinal damage with disruption of T-cell homeostasis beyond the gut and provides a novel in vivo toolbox to screen for pollutants affecting intestinal homeostasis.

SUBMITTER: Diaz OE

PROVIDER: S-EPMC8713990 | biostudies-literature | 2021 Dec

REPOSITORIES: biostudies-literature

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Perfluorooctanesulfonic acid modulates barrier function and systemic T-cell homeostasis during intestinal inflammation.

Diaz Oscar E OE Sorini Chiara C Morales Rodrigo A RA Luo Xinxin X Frede Annika A Krais Annette M AM Chávez Myra N MN Wincent Emma E Das Srustidhar S Villablanca Eduardo J EJ

Disease models & mechanisms 20211223 12

The intestinal epithelium is continuously exposed to deleterious environmental factors that might cause aberrant immune responses leading to inflammatory disorders. However, what environmental factors might contribute to disease are poorly understood. Here, to overcome the lack of in vivo models suitable for screening of environmental factors, we used zebrafish reporters of intestinal inflammation. Using zebrafish, we interrogated the immunomodulatory effects of polyfluoroalkyl substances, which ...[more]

PMID: 34792120

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Project description:Background & aimsSenescence has been reported to have differential functions in cholangiocytes and hepatic stellate cells (HSCs) during human and murine cholestatic disease, being detrimental in biliary cells and anti-fibrotic in HSCs. Cholestatic liver disease is associated with loss of intestinal barrier function and changes in the microbiome, the mechanistic cause of which is undetermined.MethodsIntestinal samples were analysed from controls and patients with primary sclerosing cholangitis, as well as wild-type (WT) and p16-3MR transgenic mice. Cholestatic liver disease was induced by bile duct ligation (BDL) and DDC diet feeding. Fexaramine was used as an intestinal-restricted FXR agonist and antibiotics were given to eliminate the intestinal microbiome. Senescent cells were eliminated in p16-3MR mice with ganciclovir and in WT mice with the senolytic drug ABT-263. In vitro studies were done in intestinal CaCo-2 cells and organoids were generated from intestinal crypts isolated from mice.ResultsHerein, we show increased senescence in intestinal epithelial cells (IECs) in patients with primary sclerosing cholangitis and in mice after BDL and DDC diet feeding. Intestinal senescence was increased in response to reduced exposure to bile acids and increased presence of lipopolysaccharide in vitro and in vivo during cholestatic liver disease. Senescence of IECs was associated with lower proliferation but increased intestinal stem cell activation, as supported by increased organoid growth from intestinal stem cells. Elimination of senescent cells with genetic and pharmacological approaches exacerbated liver injury and fibrosis during cholestatic liver disease, which was associated with increased IEC apoptosis and permeability.ConclusionsSenescence occurs in IECs during cholestatic disease and the elimination of senescent cells has a detrimental impact on the gut-liver axis. Our results point to cell-specific rather than systemic targeting of senescence as a therapeutic approach to treat cholestatic liver disease.Impact and implicationsCholestatic liver disease associates with the dysregulation of intestinal barrier function, while the mechanisms mediating the disruption of the gut-liver axis remain largely undefined. Here, we demonstrate that senescence, a cellular response to stress, is activated in intestinal cells during cholestatic liver disease in humans and mice. Mechanistically, we demonstrate that the reduction of bile acids and the increased presence of bacterial products mediate the activation of intestinal senescence during cholestatic liver disease. Importantly, the elimination of these senescent cells promotes further damage to the intestine that aggravates liver disease, with increased tissue damage and fibrosis. Our results provide evidence that therapeutic strategies to treat cholestatic liver disease by eliminating senescent cells may have unwanted effects in the intestine and support the need to develop cell/organ-specific approaches.

Dataset Information

Perfluorooctanesulfonic acid modulates barrier function and systemic T-cell homeostasis during intestinal inflammation.

Publications

Perfluorooctanesulfonic acid modulates barrier function and systemic T-cell homeostasis during intestinal inflammation.

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