Distinct pathways driving inflammatory bowel disease pathotypes with different response to therapy

Friedrich M, Pohin M, Jackson M et al. IL-1-driven stromal–neutrophil interactions define a subset of patients with inflammatory bowel disease that does not respond to therapies. Nat Med 2021; doi: 10.1038/s41591-021-01520-5

Despite progress in the development of novel therapeutics targeting intestinal inflammation in inflammatory bowel disease (IBD), it appears that a ceiling of treatment has been reached, with a large proportion of patients not achieving mucosal healing. In addition, there is an unmet need for precision medicine approaches such as not giving the right drug to the right person at the right time. Our current methods of phenotyping patients, based on clinical parameters and endoscopic or histological findings do not appear to be fit for this purpose.

Friedrich et al use bulk RNA sequencing (RNAseq) to quantify transcriptional changes in the inflamed mucosa of patients with ulcerative colitis (UC) and Crohn’s disease and associate them with clinical variables including histological findings and response to therapies (corticosteroids, antitumour necrosis factor (TNF) and antiintegrin drugs). Rather than looking at single genes they use an algorithm that can cluster multiple genes based on their coexpression, generating gene modules and associating those with clinically relevant phenotypes. They identify gene modules that associate with the hallmarks of pronounced inflammation, including neutrophil infiltration and ulceration size. By aligning these results with single cell RNAseq and in situ localisation, they associate these findings with activated fibroblasts that drive neutrophil chemoattraction and are dependent on interleukin-1 (IL-1) signalling rather than TNF.

With their experimental approach they are not only able to stratify patients based on treatment response but they also highlight potential key upstream regulators of inflammation that may therapeutically target IL-1 signalling.

Perturbations of cellular glycogen metabolism contribute to the development of hepatocellular carcinoma

Liu Q, Li J, Zhang W, et al. Glycogen accumulation and phase separation drives tumour initiation. Cell 2021; 184:5559–5576. doi: 10.1016/j.cell.2021/10.001

A significant …