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The real ‘reserve’ intestinal stem cells
Murata K, Jadhav U, Madha S, et al. Ascl2-Dependent Cell Dedifferentiation Drives Regeneration of Ablated Intestinal Stem Cells. Cell Stem Cell 2020; 263,: 377-390
In the intestinal crypt, when stem cells are damaged, it was previously thought that a reserve group of stem cells in the +4 position stepped in to replace them. Since then several papers have shown that various postmitotic cell types may be capable of dedifferentiating and replenishing damaged stem cells. This paper definitively shows that a group of differentiated progenitors are responsible for restoring the stem cell compartment. Murata et al used a mouse model in which Lgr5 stem cells were fluorescently labelled and used radiation to ablate stem cells. If either secretory or enterocyte cells were ablated using Notch signalling pathway knockout models, the other cell type dedifferentiated and allowed Lgr5+ stem cell recovery. Ascl2 is a Wnt-responsive transcription factor known to regulate stem cells. Ascl2 knockout mice were healthy in homoeostatic conditions, but after irradiation or diphtheria toxin damage, intestinal crypt cell proliferation was compromised and the mice did not survive. Ascl2 cell labelling showed that cells expressed Ascl2 days before Lgr5 expression, and it was in the upper crypt where this re-expression occurred. Flow cytometry and RNA sequencing revealed these cells to have markers of goblet cells and enterocytes. Ascl2 target genes were found to include interleukin receptor 11 gene, IL11ra1, recognised as a regulator in stem cell renewal. The authors concluded that differentiated secretory and absorptive cell progenitors in the upper crypt dedifferentiate after stem cell damage via Ascl2 re-expression and replace intestinal stem cells.
Enteric nervous system: the protagonist in barrier immune responses?
Jarret A, Jackson R, Duizer C, et al. Enteric Nervous System-Derived IL-18 Orchestrates Mucosal Barrier Immunity Cell 2020; 180(1): 50-63.e12
The interactions between the nervous and immune systems have been shown to maintain the intestinal mucosal barrier function and shape its responses to environmental triggers. Traditionally, the enteric nervous system (ENS) has been considered to have a more central role in regulating gut motility in response to nutrients and the immune system in providing protection against potential pathogens and other dangers. Over the last decade preclinical and clinical work has revealed some of the mechanisms underlying the complimentary role of these two systems. In this elegant study, Jarret et al show for the first time that neurons of the ENS can produce the pleiotropic cytokine IL-18 and non-redundantly protect against the development of intestinal inflammation. While IL-18 is produced in abundance by both epithelial and immune cells, this intriguingly is redundant in this model of acute colitis. By combining elegant mouse experiments with single-cell next-generation sequencing the authors were able to identify a very specific transcriptional programme, characterised by three transcripts coding for antimicrobial peptides, regulated in goblet cells to be the downstream effect of the ENS originating IL-18. Unknowns on the regulation of IL-18 production/excretion by ENS neurons and the functional implications of spatial relationships between the different cellular types in the observed effects of IL-18 still remain. While the relevance of this ‘ENS-immune system’ axis in chronic inflammation requires further exploration, the possibility of hijacking it therapeutically to prevent dysregulation of the mucosal barrier’s immune tone is intriguing.
New insight into alcohol-induced carcinogenesis
Hodskinson MR, Bolner A, Sato K, et al. Alcohol-derived DNA crosslinks are repaired by two distinct mechanisms. Nature 2020; 579: 603–608 DOI: 10.1038/s41586-020-2059-5
Alcohol is associated with cancer in many tissues, including the liver where it also synergises with other liver diseases. Alcohol causes DNA damage leading to cancer directly through the production of acetaldehyde. Protection from aldehyde-related damage is achieved through their clearance by aldehyde dehydrogenase enzymes and repair of damaged DNA. Deficiency of the clearance enzyme (aldehyde dehydrogenase 2 (ALDH2)) is common in Asian populations and is associated with a greater incidence of alcohol-related cancers. Aldehydes, like some chemotherapies (eg, cisplatin), damage DNA by binding the two DNA strands together through crosslink formation. In this study Hodskinson et al created a synthetic DNA molecule with a single site-specific acetaldehyde crosslink and then studied the mechanism by which this DNA crosslink was repaired. They showed that while a common mechanism repairs both cisplatin and acetaldehyde crosslinks, a further mechanism exists specifically for acetaldehyde damage. This new mechanism is both faster and potentially safer. Rather than excising linked nucleotides (unhooking) to create a double strand DNA break, this repair process actually breaks the crosslink itself releasing the DNA strands. The damaged nucleotide can then be repaired in situ. While repairing damaged nucleotide can lead to mismatch mutations, crucially this avoids the creation of a double strand DNA break or a site without a DNA base; both of these are much more damaging to the genome as a whole. Harnessing and improving this repair mechanism may provide insights and translational opportunities to limit harmful mutations occurring with alcohol and other DNA damaging agents.
Baseline colonoscopy findings associate with 10-year surveillance outcomes
Lieberman D, Sullivan BA, Hauser ER et al. Baseline Colonoscopy Findings Associated With 10 Year Outcomes in a Screening Cohort Undergoing Colonoscopy Surveillance. Gastroenterology 2020; 158 (4): 862–874.e8
Benefits of colorectal screening programmes with reductions in colorectal cancer (CRC) incidence and mortality are well established in screening programmes for flexible sigmoidoscopy, faecal occult blood testing and adenomas removed at baseline colonoscopy. Little is known regarding the long-term outcomes of prospective ongoing colonoscopy screening and surveillance to decrease CRC rates. Lieberman et al analysed long-term outcomes following baseline screening colonoscopy during a 10-year period to determine if screening colonoscopy findings would be predictive of advanced neoplasia (adenoma ≥10 mm or with villous histology or high-grade dysplasia or CRC) or CRC alone. Between 1994 and 1997, 3121 veterans aged 50–75 years underwent a screening colonoscopy; those with no neoplasia were randomised to usual care or colonoscopy at 5 years resulting in 1915 undergoing at least one surveillance colonoscopy. Predictive baseline characteristics of an increased risk for advanced neoplasia included baseline CRC, advanced adenomas or three+ small adenomas, when compared with those with no neoplasia at baseline. Participants with one to two adenomas at baseline did not have a significantly increased risk of advanced neoplasia or CRC (6.3%; 95% CI 4.1% to 8.5%) when compared with those without adenomas at baseline (4.1%; 95% CI 2.7% to 5.4%). The first 3 years following baseline colonoscopy was when most advanced neoplasia and CRC were identified. Important aspects of this study limit generalisability to current surveillance populations, including a predominantly male population (97%), the surrogate marker of advanced adenomas for CRC, lack of data on serrated lesions and the historic lack of an organised surveillance programme.
Shielding patients with IBD from COVID-19 infection
Ping A, Mengyao J, Haixia R et al. Protection of 318 Inflammatory Bowel Disease Patients from the Outbreak and Rapid Spread of COVID-19 Infection in Wuhan, China. Lancet http://dx.doi.org/10.2139/ssrn.3543590
The coronavirus disease 2019 (COVID-19) pandemic that emanated from Wuhan, China, threatens to overwhelm healthcare systems and economies across the globe. Based on the earliest warnings from Dr Wenliang Li, Ping et al recognised that immunosuppressed patients with IBD maybe at increased risk of a novel pulmonary infection. On 3 January 2020, 20 days before the Chinese government introduced their lockdown, they acted unilaterally to try and protect their patients with IBD. Outpatients were sent serial instructions to limit time spent outside, to use a face mask and pay attention to hand hygiene, and to avoid New Year parties. IBD clinics were closed and non-emergent medical care was conducted online. Biologics and immunosuppressant drugs were stopped in all patients. Inpatients were arranged in single occupancy side rooms and discharged as soon as possible.
Patients retrospectively completed questionnaires outlining COVID-19 exposures, adherence to, and acceptance of the social restrictions. Overall, 318 patients were included: the median age was 39.2 (15–79) years and comorbidities were observed in a third. Less than 10% patients were deemed to have had a high-risk exposure. In all but one domain, for both alerts, adherence was over 90% and mostly well tolerated. By 20 February 2020, no patients had been diagnosed with COVID-19. Self-isolation effectively protected patients with IBD from COVID-19 in the earliest phases of the outbreak in Wuhan.
The thyroid in the liver: new target for hepatic steatosis
Harrison SA, Bashir MR, Guy CD et al. Resmetirom for the treatment of non-alcoholic steatohepatitis: a multicentre randomised, double-blind, placebo-controlled, phase two trial. Lancet 2019; 394: 2012–24
Non-alcoholic fatty liver disease and non-alcoholic steatohepatitis (NASH) carry significant morbidity and mortality for cardiovascular diseases and cirrhosis, and neither has any effective treatments. Thyroid hormone receptor β (THR-β) is concentrated in the hepatocytes and regulates fat metabolism and regeneration in the liver. THR-β analogues reduce hepatic steatosis, inflammation and fibrosis in animal models with NASH. Harrison et al report the result of a multicentre, double-blind, randomised, placebo-controlled, adaptive-dosing trial of resmetirom (liver-directed, oral THR-β selective agonist). One hundred and twenty-five subjects with 10% of hepatic fat at liver MRI proton density fat fraction (PDFF) and biopsy-proven NASH (with fibrosis grade 1–3) were randomised 2:1 to resmetirom 80 mg/daily or placebo for 36 weeks. At week 4 resmetirom dose was adjusted (range 60–100 mg), according to serum concentration, to target exposure. The treatment group had a higher reduction of absolute and relative fat fraction compared with placebo using MRI-PDFF (respectively −36% vs −10% and −7.1% vs −2.5% at week 12 and −40% vs −14% and −8.5% vs −2.3% at week 36). Subjects with high resmetirom exposure had the best results (−39.7% and −8.5% at week 12; 41.1% and −9.2% at week 36). Lipids, lipoproteins, liver enzymes and fibrosis markers confirmed statistically significant improvement in the treatment group. Interestingly, resmetirom had no effect on body weight. Resmetirom was well tolerated: three subjects withdrew for adverse events from the treatment group and one subject from the placebo group (patients lost to follow-up 10 and 7, respectively). These findings support the phase 3 study on resmetiron, which is currently ongoing.
Dr Sujata Biswas, Translational Gastroenterology Unit, Oxford NIHR Biomedical Research Centre, University of Oxford, Oxford, UK
Dr Polychronis Pavlidis, Clinical Lecturer in Gastroenterology, Guy’s and St Thomas’ NHS Trust & King’s College London, London, UK
Dr Tom G Bird, Honorary Consultant Hepatologist, University of Edinburgh, Royal Infirmary of Edinburgh, Edinburgh, UK
Dr Alenka J Brooks, Consultant Gastroenterologist, Sheffield Teaching Hospitals NHS Foundation Trust, Sheffield, UK
Dr James Goodhand, Consultant Gastroenterologist, Exeter IBD Research Group, Royal Devon and Exeter NHS Foundation Trust, Exeter, UK
Dr Francesca Moroni, Scottish Clinical Research Excellence Development lecturer and Gastroenterology Registrar, Aberdeen Royal Infirmary, Aberdeen, UK
Cell Stem Cell, Cell, Nature, Gastroenterology and Lancet.
Funding The authors have not declared a specific grant for this research from any funding agency in the public, commercial or not-for-profit sectors.
Competing interests None declared.
Patient consent for publication Not required.
Provenance and peer review Not commissioned; internally peer reviewed.
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