Intracellular accumulation of misfolded proteins causes toxic proteinopathies, diseases without targeted therapies. Mucin 1 kidney disease (MKD) results from a frameshift mutation in the MUC1 gene (MUC1-fs). Here, we show that MKD is a toxic proteinopathy. Intracellular MUC1-fs accumulation activated the ATF6 unfolded protein response (UPR) branch. We identified BRD4780, a small molecule that clears MUC1-fs from patient cells, from kidneys of knockin mice and from patient kidney organoids. MUC1-fs is trapped in TMED9 cargo receptor-containing vesicles of the early secretory pathway. BRD4780 binds TMED9, releases MUC1-fs, and reroutes it for lysosomal degradation, an effect phenocopied by TMED9 deletion. Our findings reveal BRD4780 as a promising lead for the treatment of MKD and other toxic proteinopathies. Generally, we elucidate a novel mechanism for the entrapment of misfolded proteins by cargo receptors and a strategy for their release and anterograde trafficking to the lysosome.(F) IF co-staining of distal tubule in MKD patient kidney organoid for MUC1-wt (red), MUC1-fs (green), E-cadherin (blue), and Na + /K + -ATPase (yellow). MUC1-fs localized intracellularly (middle) compared to apical MUC1-wt (left). (G) IF co-staining in P cells for MUC1-fs (green), MUC1-wt (red), and Hoechst (gray). MUC1-fs localized intracellularly (middle) compared to MUC1-wt on the plasma membrane (left). See also Figures S1, S2, and S3 and Table S1.

An essential role of the gut microbiota in health and disease is strongly suggested by recent research. The composition of the gut microbiota is modified by multiple internal and external factors, such as diet. A vegan diet is known to show beneficial health effects, yet the role of the gut microbiota is unclear. Within a 4-week, monocentric, randomized, controlled trial with a parallel group design (vegan (VD) vs. meat-rich (MD)) with 53 healthy, omnivore, normal-weight participants (62% female, mean 31 years of age), fecal samples were collected at the beginning and at the end of the trial and were analyzed using 16S rRNA gene amplicon sequencing (Clinical Trial register: DRKS00011963). Alpha diversity as well as beta diversity did not differ significantly between MD and VD. Plotting of baseline and end samples emphasized a highly intra-individual microbial composition. Overall, the gut microbiota was not remarkably altered between VD and MD after the trial. Coprococcus was found to be increased in VD while being decreased in MD. Roseburia and Faecalibacterium were increased in MD while being decreased in VD. Importantly, changes in genera Coprococcus, Roseburia and Faecalibacterium should be subjected to intense investigation as markers for physical and mental health.

Postoperative complications are a major problem occurring in up to 50% of patients undergoing major abdominal surgery. Occurrence of postoperative complications is associated with a significantly higher morbidity and mortality in affected patients. The most common postoperative complications are caused by an infectious genesis and include anastomotic leakage in case of gastrointestinal anastomosis and surgical site infections. Recent research highlighted the importance of gut microbiota in health and disease. It is plausible that the gut microbiota also plays a pivotal role in the development of postoperative complications. This narrative review critically summarizes results of recent research in this particular field. The review evaluates the role of gut microbiota alteration in postoperative complications, including postoperative ileus, anastomotic leakage, and surgical site infections in visceral surgery. We tried to put a special focus on a potential diagnostic value of pre- and post-operative gut microbiota sampling showing that recent data are inhomogeneous to identify a high-risk microbial profile for development of postoperative complications.