Growth differentiation factor 15 alters intestinal barrier and increases permeability: A new molecular target in inflammatory bowel disease

Abstract

BACKGROUND

Inflammatory bowel disease (IBD) is a group of chronic, inflammatory disorders that include Crohn’s disease and ulcerative colitis. IBD arises from the interaction of various environmental and genetic factors. Altered gut permeability and mitochondrial stress in the colonic mucosa are two mechanisms previously implicated in IBD pathogenesis. We have previously demonstrated activation of the mitochondrial unfolded protein response (UPR^mt) in the colonic mucosa of IBD patients and linked this activation to pro-inflammatory signaling. Growth differentiation factor 15 (GDF15) is an important downstream mediator of the UPR^mt.

AIM

To investigate whether GDF15 has a role in IBD and how GDF15 impacts colonic epithelium.

METHODS

Circulating levels of GDF15 were assessed in plasma samples from IBD patients and healthy controls using an enzyme-linked immunosorbent assay. To study the effects of GDF15 on the colonic mucosa, we employed two different in vitro culture models: Colonic organoids and T84 cells.

RESULTS

We found that circulating GDF15 Levels were elevated in IBD patients and correlated with markers of inflammation (C-reactive protein) and intestinal permeability [haptoglobin and lipopolysaccharide-binding protein (LBP)]. Additionally, we demonstrated that GDF15 alters the intestinal barrier and increases permeability by decreasing the levels of zonula occludens 1 and claudin 1, critical components of tight junctions. Thus, our findings confirm previous reports of increased circulating GDF15 levels in IBD patients and the activation of UPR^mt.

CONCLUSION

In the present study, we describe a novel mechanism in IBD pathophysiology, linking mitochondrial stress to the disruption of the intestinal barrier and increased intestinal permeability.

Keywords: Growth differentiation factor 15; Inflammatory bowel disease; Crohn's disease; Ulcerative colitis; Mitochondrial stress; Intestinal permeability; Tight junctions

Core Tip: Mitochondrial dysfunction in intestinal mucosa is emerging as a novel mechanism in inflammatory bowel disease pathogenesis. In the present study, we show that growth differentiation factor 15 (GDF15), a marker of mitochondrial stress, is elevated in plasma from both ulcerative colitis and Crohn’s disease patients. Furthermore, levels of GDF15 correlate with markers of inflammation and intestinal permeability. In vitro assays using colonic organoids further showed that GDF15 alters the intestinal barrier, reducing the levels of zonula occludens 1 and claudin 1, and subsequently increases intestinal permeability. Targeting GDF15 may offer a promising strategy to prevent disruption of the intestinal barrier, potentially reducing immune overactivation.