Moving towards new therapeutic options

Pharmacological inhibition of autophagy was shown to exacerbate intestinal inflammation, fibrosis, and epithelial-mesenchymal transition (EMT) in a murine model [1]. In intestinal resections from Crohn’s disease patients, expression of autophagy markers correlated with expression of pro-fibrotic and pro-EMT genes.

Intestinal fibrosis was induced using the heterotopic transplant model. Segments of 1 cm colon from mice were subcutaneously transplanted into the neck of a recipient mice and collected after 7 days. Recipient mice were treated with a daily injection of autophagy inhibitor 3-MA (10 mg/kg). The results showed a significant increase in the expression of proinflammatory genes such as TNF-α, IL-1β, and IL-6. There was an increase in the expression of profibrotic genes such as Col1a1 and Vimentin. The expression of EMT genes such as Snail1 was significantly increased. Autophagy inhibition by 3-MA was confirmed by western blot, showing an increase of p62 and phospho-mTOR and a reduction in LC3. In intestinal resections from Crohn’s disease patients, the expression of p62 positively correlated with the expression of Col1a1 (P=0.004), α-sma (P=0.041), Snail1 (P=0.0003), and Snail2 (P=0.0009).

Dutch scientists showed that a high dose of mesenchymal stromal cells (MSCs)-derived exosomes is able to counteract epithelial damage in vitro and partially reduce colitis in vivo [2]. They isolated exosomes from the conditioned medium (CM) of MSCs and visualised them using electron microscopy. PKH-labelled exosomes showed fusion with epithelial cells in vitro after 24 hours. MSC–CM and a high-exosome concentration were found to increase epithelial cell survival/proliferation and cell migration, and also enhanced the proliferation of non-damaged epithelial cells compared with non-CM and a low concentration of exosomes. Furthermore, in vivo experiments showed that endoscopic injections with a high dose of exosomes partially reduced dextran sodium sulphate (DSS)-induced colitis, demonstrated by a higher relative body weight and lower endoscopic disease score than PBS-treated mice. These results encourage further exploring cell-free MSC-related therapy in inflammatory bowel disease (IBD) by using MSC-exosomes.

Scientists from London investigated whether selective regulation of human colonic γδ cells by BTNL3+8 is perturbed in IBD, and examined factors that may modulate this. They described an important axis by which epithelial cells maintain homeostasis of the γδ T cell compartment, which is frequently dysregulated in IBD [3]. Their data supports the use of IL-12 blockade in restoring this axis, while IL-23 may be redundant in this setting, with implications for future therapeutic strategies. They also claimed that therapeutic blockade of αΕβ7 has the potential to disrupt an important axis in the human colon which may exacerbate disease given the precociously active, pro-inflammatory nature of αΕβ7-γδ T cells.

1. 
   
   1. Cosin-Roger J, et al. ECCO 2019, OP03.
   2. Barnhoorn M, et al. ECCO 2019, OP22.
   3. Dart RJ, et al. CCO 2019, OP32.

Posted on 9 May, 20199 April, 2024