Research Highlights

in brief

NONALCOHOLIC STEATOHEPATITIS IBD No anti-fibrotic​ effect of selonsertib in NASH Marshall/ Laura Credit: Limited Nature Springer Two randomized, double-blind,​ placebo-controlled​ phase III trials have evaluated the safety and anti-fibrotic​ efficacy Mitochondrial dysfunction in of the selective ASK1 inhibitor, selonsertib, in patients with nonalcoholic steatohepatitis (NASH) with bridging fibrosis Crohn’s disease (STELLAR-3 trial) or compensated cirrhosis (STELLAR-4 trial). Patients were randomly assigned to groups receiving 6 mg Two new studies published in Gut induction of mitochondrial dys­ or 18 mg of selonsertib or placebo daily for 48 weeks, with provide more evidence for the function via specific deletion liver biopsies performed at the start and end of the trials and noninvasive fibrosis tests also evaluated. Although selonsertib role of mitochondrial impairment of Hsp60 in ISCs in mice led to had dose-dependent​ effects indicating pharmacodynamic and Paneth cell dysfunction in reduced Lgr5 expression and activity, and statistically non-significant​ improvements inflammatory bowel disease (IBD). differentiation of Lgr5+ cells into were seen in noninvasive tests, both trials failed to reach the “Many studies have revealed aberrant Paneth cells. “We demons­ primary efficacy endpoint of fibrosis improvement without the involvement of mitochondrial trate that impaired mitochondrial worsening of NASH at week 48. Adverse events were similar stress in the pathophysiology of respiration not only antagonizes between groups. IBD but whether this is a cause or intestinal stemness, but forces Original article Harrison, S. A. et al. Selonsertib for patients with bridging fibrosis or compensated cirrhosis due to NASH: results from randomized Ph III STELLAR trials. consequence of the disease is not ISCs to acquire a Paneth cell-like J. Hepatol. https://doi.org/10.1016/j.jhep.2020.02.027 (2020) known,” explains the corresponding phenotype and provide evidence author of the first study, Arianne that inflammation-associated LIVER CANCER Theiss. The researchers observed mito­chondrial dysfunction in Aspirin associated with lower risk of liver cancer that mice lacking prohibitin 1 the intestinal epithelium triggers A Swedish nationwide registry-based​ study has examined (PHB1, a major component of the a metab­olic imbalance, causing the risk of hepatocellular carcinoma (HCC) and liver-related​ inner mitochondrial membrane) reduced stemness and acquisition mortality associated with low-dose​ aspirin use in patients in intestinal epithelial cells (IECs) of a dysfunctional Paneth cell infected with hepatitis B or hepatitis C viruses. A total of developed spontaneous ileal phenotype,” notes Haller. 50,275 patients who received a diagnosis of chronic hepatitis B or hepatitis C between 2005 and 2015 were inflammation that was preceded by Further work is needed to identified, 14,205 of whom were established as low-dose​ mitochondrial dysfunction in IECs examine the key mechanisms aspirin users according to prescription data. On the basis and early abnormalities in Paneth underlying mitochondrial of a median 7.9 years follow-up,​ the estimated cumulative cells. Crucially, treatment with a dysfunction in IBD and their incidence of HCC was shown to be significantly lower among mitochondrial-targeted antioxidant potential as therapeutic targets. aspirin users than nonusers (4.0% versus 8.3%; P < 0.001), to suppress mitochondrial reactive “Ongoing studies will elucidate an association that was also found to be dependent on the oxygen species alleviated mitochon­ whether abnormal Paneth cells duration of aspirin use. The 10-year​ liver-​related mortality was also significantly lower among aspirin users than drial dysfunction, Paneth cell abnor­ in patients with Crohn’s disease nonusers (11.0% versus 17.9%; P <0.001), but importantly, malities and ileitis in these mice. also exhibit mitochondrial there was no significant difference in the 10-year​ risk of Paneth cells were found to be dysfunction or altered PHB1 gastrointestinal bleeding between the groups. critical and highly susceptible to expression,” says Theiss, adding Original article Simon, T. G. et al. Association of aspirin with hepatocellular mitochondrial dysfunction; deletion that the role of mitophagy will carcinoma and liver-related​ mortality. N. Engl. J. Med. 382, 1018–1028 (2020) of Phb1 in Paneth cells specifically also be explored. “We provide GERD was sufficient to cause ileitis in the proof-of-concept that metabolic mice. Moreover, Phb1 deficiency in injury is a putative drug target to Increasing global burden of gastro-oesophageal intestinal organoids induced loss of prevent inflammation-associated reflux disease viability of the intestinal stem cell damage of the ISC niche,” remarks A systematic review has used data from the Global Burden (ISC) niche and Paneth cell defects. Haller, adding that restoration of of Diseases, Injuries and Risk Factors Study to report the In the second study, Dirk Haller mitochondrial metabolism could burden of gastro-oesophageal reflux disease (GERD) in 195 countries between 1990 and 2017. From 144 location-years and colleagues investigated the have potential as an adjuvant therapy of prevalence data, a mean estimate of age-standardized influence of intestinal inflammation to prevent recurrence. prevalence for all locations in 2017 was determined, ranging on Paneth cell function and the ISC Katrina Ray between 4,408–14,035 cases per 100,000 population. The niche. In patients with Crohn’s dis­ease highest values were in the USA, Italy, Greece and New Zealand, and mice with Crohn’s disease-like Original articles Jackson, D. N. et al. Mitochondrial dysfunction during loss of and the lowest were in high-income Asia Pacific regions, east ileitis, inflammation correlated with Asia and European countries including France, Iceland, Denmark prohibitin 1 triggers Paneth cell defects and ileitis. and Switzerland. Although global age-standardized prevalence decreased gene expression of the ISC Gut https://doi.org/10.1136/gutjnl-2019-319523 marker LGR5 and reduced Paneth (2020) | Khaloian, S. et al. Mitochondrial impairment was stable between 1990 and 2017, the all-age prevalence drives intestinal stem cell transition into increased by 18.1%, suggesting that the epidemiology of GERD cell granularity. This aberrant dysfunctional Paneth cells predicting Crohn’s has not changed but that the burden of disease is increasing as a Paneth cell phenotype and LGR5 disease recurrence. Gut https://doi.org/10.1136/ result of ageing and population growth. gutjnl-2019-319514 (2020) expression correlated with active Related articles Rath, E. et al. Mitochondrial Original article GBD 2017 Gastro-oesophageal Reflux Disease Collaborators. The ileal Crohn’s disease and predicted function — gatekeeper of intestinal epithelial cell global, regional, and national burden of gastro-oesophageal reflux disease in 195 countries homeostasis. Nat. Rev. Gastroenterol. Hepatol. 15, and territories, 1990–2017: a systematic analysis for the Global Burden of Disease Study risk of recurrence in patients 497–516 (2018) 2017. Lancet Gastroenterol. Hepatol. https://doi.org/10.1016/S2468-1253(19)30408-X (2020) after surgical resection. Crucially,

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