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TMBIM1-dependent TLR4 degradation is a key regulator of NAFLD
Zhao GN, Zhang P, Gong J, et al. TMBIM1 is a multivesicular body regulator that protects against non-alcoholic fatty liver disease in mice and monkeys by targeting the lysosomal degradation of Tlr4. Nat Med 2017;23:742–52.
Toll-like receptor 4 (TLR4) signalling in non-alcoholic fatty liver disease (NAFLD) is associated with liver inflammation, insulin resistance and the metabolic syndrome. However, TLR4 also underpins important immunoregulatory and antimicrobial functions, making global TLR4 inhibition an unappealing long-term therapeutic strategy for patients. In this study, the authors have identified a role for transmembrane BAX inhibitor motif-containing 1 (TMBIM1) in regulating TLR4 degradation in hepatocytes, with resultant effects on NAFLD. TMBIM1 is a membrane protein, which is expressed in late endosomes and lysosomes. Hepatic TMBIM1 expression was reduced in both human and murine models of NAFLD, while knockout of TMBIM1 in hepatocytes exacerbated murine insulin resistance, hepatic steatosis and liver inflammation in response to a high-fat diet. Furthermore, hepatic overexpression of TMBIM1 protected mice against steatosis and liver inflammation. These beneficial effects of TMBIM1 were antagonised by TLR4, and the authors proceeded to demonstrate that TMBIM1 promotes TLR4 degradation via a multivesicular body endosomal-lysosomal pathway. Finally, in a monkey model of non-alcoholic steatohepatitis (NASH), viral overexpression of TMBIM1 in the liver resulted in reduced lipid accumulation, inflammation and fibrosis. Hence, TMBIM1 represents a potential therapeutic target for patients with NAFLD. Importantly, TMBIM1-dependent TLR4 degradation was only active in steatotic livers and not under basal conditions, potentially enabling the targeting of pathogenic TLR4 activity without the adverse effects of global TLR4 blockade.
Cancer stem cells: tracing the evidence
Shimokawa M, Ohta Y, Nishikori S, et al. Visualization and targeting of LGR5+ human colon cancer stem cells. Nature 2017;545:187–92.
The cancer stem cell (CSC) theory is based on a hierarchy of cell types within cancer, with only CSCs being able to self-renew and sustain cancer growth. Xenotransplantation of isolated CSCs and tumour regeneration is the gold standard for proof, but this is not reliable in colorectal cancer (CRC) as CSCs show poor engraftment. This paper provides proof of LGR5+ cells as CSCs based on lineage tracing of human cancers. A library of CRC organoids was established and those with high LGR5 and KRT20 expression were used, as indication of hierarchical preservation. LGR5 was traced using GFP insertion by CRISPR-CAS9. Transplantation of GFP+ cells into a mouse renal capsule produced tumours reflecting the original cancer histology. Rainbow reporter was used to trace LGR5 in vivo and clonal ribbons gave rise to LGR5+ and LGR5− cells, so these cells can both self-renew and differentiate; hallmarks of stem cells. Ablating LGR5 cells with an LGR5-Caspase9 dimeriser initially reduced tumour size, but this was followed by regrowth along with re-emergence of LGR5+ cells, due to plasticity in LGR5− cells. KRT20-labelled cells were also shown to be capable of reacquiring LGR5. Plasticity has previously been shown in progenitor cells after damage but not in fully differentiated cells. To potentiate conventional chemotherapy, short-term LGR5 ablation was given with cetuximab, and caused marked tumour regression. Cetuximab upregulates LGR5 and this effect was not seen with oxaliplatin. This is the first in vivo study of human CRC tracing and gives proof of CSC plasticity and its therapeutic potential.
The paradox of fast gastric empting in hyperglycaemia
Hayashi Y, Toyomasu Y, Saravanaperumal SA, et al. Hyperglycemia increases interstitial cells of Cajal via MAPK1 and MPAK3 signaling to ETV1 and KIT, leading to rapid gastric emptying. Gastroenterology [Epub ahead of print: 21 Apr 2017]
Interstitial cells of Cajal (ICC) play a key role in gastric motility. In type 1 diabetes mellitus (DM), gastroparesis and delayed gastric emptying (GE) through depletion of ICC are more common than nerve loss. It is believed that reduced insulin and insulin-like grow factor 1 (IGF1) as well as oxidative stress play a role in this process. At least 20% of the diabetic population displays accelerated GE and this remains an unexplained phenomenon. Hayashi and colleagues studied female Leprdb/db mice as a model for type 2 DM (high glucose, high insulin, high weight but normal IGF-1). GE in these mice was significantly faster than control mice. When Leprdb/db antral tissue was isolated and stimulated by a cholinergic agonist, slow wave and contractile frequency were increased with a higher number of ICC and raised expression of KIT, ETV1, ANO1 and ERK1,2 (proteins associated with proliferation of ICC). In mice with hypertrophy of ICC, an increased number of ICCs was identified and regardless of aetiology led to rapid GE for solids (measured by [13C] octanoic breath test). In hyperinsulinaemic Leprdb/db mice KIT was reduced but hyperglycaemia stimulated proliferation of ICC through activation of ERK-ETV1-KIT loop. This occurred in a ligand-dependent manner and was mediated by aerobic glycolysis. Moreover, ICCs were not affected by hyperglycaemia-mediated apoptosis in contrast to neurons. These findings could represent a precursor phase prior to loss of function and depletion of ICC in diabetic subjects.
Blocking downstream signalling with tofacitinib: emergence of a novel player in the therapeutic armamentarium of treating UC
Sandborn WJ, Su C, Sands BE, et al. Tofacitinib as induction and maintenance therapy for ulcerative colitis. N Engl J Med 2017;376:1723–36.
Tofacitinib, an oral small molecule that selectively inhibits Janus kinases, was tested in phase 3 trials in patients with moderate-to-severe UC. In two induction trials (n=598 and 541, respectively), clinical remission at week 8 was reached significantly higher in the tofacitinib (10 mg) compared with the placebo group (18.5% vs 8.2% and 16.6% vs 3.6%, respectively). In the maintenance trial (n=593), clinical remission at week 52 occurred in 40.6% (10 mg) and 34.4% (5 mg) in the tofacitinib versus 11.1% in the placebo group (p<0.001). Mucosal healing rates at week 8 (31.3% vs 15.6% and 28.4% vs 11.6%) and week 52 (45.7% vs 37.4% vs 13.1%) were also significantly higher in the tofacitinib groups. There was no difference regarding therapeutic efficacy between anti-tumour necrosis factor experienced and naïve patients. The rates of overall, herpes zoster and serious infections as well as cardiovascular events and non-melanoma skin cancer were higher with tofacitinib than placebo across some of the trials. Small molecule inhibitors represent a new class of therapy in IBD. They offer the advantage of oral intake, short half-life and absence of immunogenicity in comparison to biologicals. Nevertheless, the potential for ‘off target’ effects has to be closely monitored due to the inhibition of multiple signalling pathways. The safety profile of tofacitinib has to be closely observed, especially regarding infections, and herpes zoster vaccination might be recommended in treated patients. As with all other available IBD treatments, characterisations of the molecular mechanism of action and biomarkers for predicting therapeutic efficacy are urgently needed to enable rational treatment with tofacitinib in clinical practice.
Preventing ulcer rebleeding: looking for the sounds of silence
Jensen DM, Kovacs TOG, Ohning GV, et al. Doppler endoscopic probe monitoring of blood flow improves risk stratification and outcomes of patients with severe non-variceal upper gastrointestinal hemorrhage. Gastroenterology 2017;152:1310–18.
Residual blood flow in the target lesion independently predicts rebleeding and endoscopic assessment may guide therapy. Jensen and colleagues performed a study including 148 patients randomised to receive either standard therapy or Doppler probe-guided therapy; if arterial flow was detected further clips or electrocoagulation was deployed. Standard treatment with proton pump inhibitor infusion was used in both groups. Primary outcome was rebleeding at 30 days and secondary outcomes were rates of surgery, angiography, complications, transfusion requirements, length of stay and death. Rebleeding rate at 30 days was significantly lower in the Doppler group (8/72, 11.1% vs 20/76, 26.3%, p=0.0214) compared with the standard group, OR 0.35 (95% CI 0.143 to 0.857), requiring a number needed to treat of 7. The median time to rebleed event was significantly shorter in the standard treatment arm compared with the Doppler arm (median 2 days vs 3 days, p=0.0174). Rates of surgery, complications, transfusion requirements, death and length of stay were all higher in the standard treatment group and the rate of angiography was higher in the Doppler group (all p>0.1). This study has limitations; no information was given on amount of epinephrine used in each group, no scoring systems were used (eg, Blatchford), the trial had been suspended due to slow recruitment, and the rebleeding rates appear high although this was a cohort with severe bleeding at presentation. This technology does not require intensive training and therefore this study provides a potentially new adjunct to managing patients with non-variceal upper intestinal bleeding.
Inhibition of MadCAM-1 in UC
Vermeire S, Sandborn WJ, Danese S, et al. Anti-MAdCAM antibody (PF-00547659) for ulcerative colitis (TURANDOT): a phase 2, randomised, double-blind, placebo-controlled trial. Lancet [Epub ahead of print: 17 May 2017]
Anti-integrin biological therapy to the GI-specific α4β7 integrin is a current treatment choice in inflammatory bowel disease, primarily for those non-responsive or intolerant to anti-tumour necrosis factor treatment. This acts by blocking the migration of immune cells, particularly activated T cells expressing a ‘gut homing’ integrin motif, to the GI mucosa. Here, a new biologic (PF-00547659) is assessed to block leucocyte migration through inhibition of MadCAM-1 (mucosal addressin cell adhesion molecule-1). MabCAM-1 is expressed on the endothelium and interacts with integrin expression on the surface of leucocytes to guide cell migration to inflamed tissue. Therefore, this new biologic inhibits the immune cell migration pathway to the gut from a different angle to the currently available anti-integrin strategy. This paper reports on a global multicentre phase 2 double-blinded randomised controlled trial in 357 patients with UC who received this new drug subcutaneously in a range of doses (7.5–225 mg) or placebo. Considering the primary end point of achieving remission at 12 weeks, there was a significant, although modest, improvement seen with three out of the four treatment doses, with the greatest effect seen with 22.5 and 75 mg (achieved in 2.7% placebo group vs 11.3%, 16.7%, 15.5% and 5.7% in the 7.5, 22.5, 75 and 225 mg treatment groups, respectively). No safety issues were raised and therefore this appears safe and well tolerated. The advantage of this migration-directed inhibitory treatment is its mode of delivery. Further larger studies are required to confirm efficacy. This will likely widen the therapeutic choices for patients with IBD in the future.
Dr Prakash Ramachandran, Dr Sujata Biswas, Dr Francesca Moroni, Prof Raja Atreya, Dr John Leeds, Dr Mairi McLean.
Nature Medicine, Nature, Gastroenterology, New England Journal of Medicine, Lancet.
Competing interests None declared.
Provenance and peer review Not commissioned; internally peer reviewed.
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