Liver fibrosis is a substantial risk factor for liver cancer development. In this issue, we focus on molecular and cellular mechanisms of hepatic fibrogenesis and discuss therapeutic implications.

An international prospective cohort study that included 14,726 individuals from the general population without known liver disease developed the LiverRisk score for cirrhosis-risk identification. The participants (43.2% in the derivation group, 29.7% in the first and 27.2% in the second external validation group) were assessed for fibrosis by transient elastography. The LiverRisk score predicted liver

Investigators developed a proof-of-concept model of long-term ex situ perfusion of human livers under normothermic conditions (36 °C). Ten livers were perfused at 36 °C using a red blood cell-based perfusate, split into 20 partial livers and perfused on separate machines simultaneously. Median ex situ overall viability and survival were 125 (~5 days) and 165 hours (~7 days), respectively — 9 of 20

Researchers developed mice carrying functional human liver tissue composed of human hepatocytes and non-parenchymal cells. Humanized livers mirrored human tissue in physiology, architecture and pathologies, including fibrosis and nonalcoholic fatty liver disease, enabling the in vivo investigation of human metabolic processes and liver-cell interactions.

In a combined case–control and cohort study using a USA-based medical record network, researchers identified 24,624 patients with Parkinson disease and made comparisons with 24,624 individuals as negative controls, 19,046 individuals with Alzheimer disease and 23,942 with cerebrovascular diseases (CVD). Gastrointestinal syndromes were investigated in association with Parkinson disease: functional dyspepsia

The gut–liver axis is known to have a role in nonalcoholic steatohepatitis (NASH) and in NASH-induced fibrosis and hepatocellular carcinoma (HCC), but the precise mechanisms are unknown. In a study published in the Journal of Hepatology, researchers identify mechanisms by which intestinal B cells are implicated in the pathogenesis and progression of NASH and liver fibrosis.

New research demonstrates a key role for PIEZO2 (a mechanically gated ion channel) in somatosensory neurons during mechanosensation in the gut. The studies, published in Cell, examine and characterize dorsal root ganglia (DRG) neuron function in the gastrointestinal tract, highlighting their importance alongside PIEZO2 in the control and regulation of gut sensing and motility.

Treatment strategies that combine therapies have revolutionized management across multiple areas of medicine. In inflammatory bowel disease (IBD), there have been a welcome number of new medication options for patients, but a ‘therapeutic ceiling’ has emerged in which no single treatment seems to be effective in any more than 20–30% of patients. Despite there being more options than ever before, one

Non-industrialized human populations are under-represented in microbiome research. In a new study published in Cell, researchers present ultra-deep metagenomic sequencing data from 351 faecal samples from the Hadza hunter–gatherers of Tanzania. Of the microbial genomes present, 44% had not yet been recorded in existing catalogues. In addition, they pinpointed gut-resident species that are not present

A phase III trial is investigating bulevirtide, which inhibits entry of hepatitis D virus (HDV) into hepatocytes, in patients with chronic HDV infection. Patients were randomly assigned to receive daily bulevirtide subcutaneously (either 2 mg or 10 mg, for 144 weeks; n = 49 and 50, respectively) or to receive no treatment (for 48 weeks, followed by 10 mg of bulevirtide for 96 weeks; n = 51). The primary

Researchers have investigated a salivary extracellular vesicle and particle microRNA (miRNA) signature that could be used as a noninvasive biomarker for early detection and risk stratification of oesophageal squamous cell carcinoma (ESCC). From a panel of six miRNAs that were identified as being able to distinguish patients with ESCC from control individuals, a signature was generated that identified

Two randomized, placebo-controlled phase III trials of mirikizumab, an anti-IL-23p19 antibody, in adults with moderately to severely active ulcerative colitis have been conducted. An induction trial (1,281 patients randomized) was followed by a maintenance trial (544 patients who responded to mirikizumab were randomized). In the induction trial, 24.2% versus 13.3% of patients in the mirikizumab group

Antigen-driven inflammation promotes colorectal neoplasia in primary sclerosing cholangitis (PSC), a study published in Nature Medicine has shown. The insights into inflammatory processes could help to prevent colorectal cancer (CRC) in PSC.

Imaging techniques for assessing liver fibrosis are advancing. This Clinical Outlook article discusses the best practices and reviews emerging options for magnetic resonance and ultrasound-based elastography.

Hepatocellular carcinoma (HCC) is the third leading cause of cancer death worldwide. Surveillance for HCC is critical for early detection and treatment, but fewer than one-quarter of individuals at risk of HCC undergo surveillance. Multiple failures across the screening process contribute to the underutilization of surveillance, including limited disease awareness among patients and health-care providers

Novel technologies that target the gastrointestinal tract could revolutionize diagnosis and therapy of digestive and other disorders. Development of these technologies requires multi-disciplinary teams that include clinicians, engineers, policymakers, bioethicists and patients.

In June 2023, Nature Reviews Gastroenterology & Hepatology attended in person the European Association for the Study of the Liver (EASL) Congress 2023 in Vienna, Austria. This was the second year the international liver conference was in person and virtual, with the session recordings available for 6 months.

A cross-sectional, population-based study assessed via transient elastography 5,757,335 adults from 30 provinces in China for liver steatosis and fibrosis. The prevalence of steatosis (44.39%), severe steatosis (10.57%), advanced fibrosis (2.85%) and cirrhosis (0.87%) was increased in participants with fatty liver and metabolic syndrome.

In a single-arm, open-label, phase II trial, 29 patients (9 were included off-label) with hepatocellular carcinoma (HCC) received PD1 blockade before surgical resection. Analysis of the surgically resected HCC lesions showed that immune checkpoint blockade (ICB) response correlated with the expansion of CXCL13+ T helper (TH) cells and PD1hiCD8+ effector T cells. In patients who responded to ICB, progenitor

In a multicentre, double-blind, placebo-controlled, phase IIb trial, 219 patients with biopsy-proven nonalcoholic steatohepatitis (NASH) and moderate or severe fibrosis were randomly assigned to receive subcutaneous pegozafermin for 24 weeks: 15 mg or 30 mg per week or 44 mg every 2 weeks or placebo. In all three groups, treatment led to ≥1-stage fibrosis reduction with no worsening of NASH (versus

Liver tissue fibrosis is the common outcome of liver diseases characterized by chronic hepatocellular damage, irrespective of disease aetiology. The process leads to an advanced stage defined as cirrhosis with severe complications due to portal hypertension and progressive hepatocellular failure.

Increased keratin 18 and hepatocyte-derived large extracellular vesicle concentrations predicted liver-related events at 2 years in patients with active alcohol consumption at enrolment (n = 81) or without (n = 419), independently of model for end-stage liver disease (MELD) and FibroTest scores. Predictions were improved when those hepatocyte-derived biomarkers were combined with MELD or FibroTest

The enteric nervous system (ENS) has a central role in the exacerbation of inflammatory bowel disease (IBD) by psychological stress, according to research published in Cell. The work provides insight into the cellular and molecular mechanisms that link stress with IBD, highlighting the importance of mental health for patients.

Nature Reviews Gastroenterology & Hepatology was in attendance at Digestive Disease Week (DDW) 2023, which took place in Chicago, USA, as well as virtually from 6 May to 9 May 2023. The conference had >13,000 in-person and virtual attendees, according to the organizers.

Liver fibrosis is the common denominator of chronic liver disease caused by excessive extracellular matrix (ECM) accumulation. A new study published in Gastroenterology describes cathepsin S as an essential factor for hepatic ECM remodelling and a potential marker for early diagnosis of liver fibrosis.

In a multicentre, unblinded, noninferiority trial, 1,128 patients with locally advanced rectal cancer eligible for sphincter-sparing surgery were randomly assigned to receive preoperative neoadjuvant chemotherapy with FOLFOX or chemoradiotherapy. FOLFOX was noninferior to chemoradiotherapy for disease-free survival (median follow-up 58 months; HR for disease recurrence or death 0.92; 90.2% CI 0.74–1

In two phase III induction trials (U-EXCEL and U-EXCEED), 1,021 patients with moderate-to-severe Crohn’s disease were randomly assigned to receive 45 mg of upadacitinib (an oral Janus kinase inhibitor) or placebo for 12 weeks. Overall, 502 patients had a clinical response to upadacitinib induction therapy and were randomly assigned in a maintenance trial (U-ENDURE) to receive 15 or 30 mg of upadacitinib

High-alcohol-producing Klebsiella pneumoniae (HiAlc Kpn) might be one of the causes of nonalcoholic fatty liver disease (NAFLD). Researchers tested the effectiveness of HiAlc Kpn-specific bacteriophage therapy in HiAlc Kpn-NAFLD mice. The treatment reduced hepatic dysfunction, regulated liver inflammation and metabolism and did not affect liver or kidney function.

In a first-in-man trial, 32 patients with alcohol-related acute-on-chronic liver failure (ACLF) were randomly assigned to be treated with DIALIVE, a novel extracorporeal liver dialysis device, or with the current standard of care for up to 5 days. The primary endpoint of safety was met with no serious adverse effects. In the DIALIVE group, a reduction in endotoxaemia severity and an improvement in

Recent randomized controlled trials in acute pancreatitis have provided evidence that challenges current approaches to management, including fluid resuscitation, antibiotic administration, management of infected necrosis and use of early endoscopic retrograde cholangiopancreatography. The evidence means that we need to reassess the current management guidelines.

In this Comment, we provide a strategic framework for what could and should be measured, across four domains, to optimize standards of care for multidisciplinary models of care in nonalcoholic fatty liver disease.

Pancreatic ductal adenocarcinoma (PDAC) is a lethal cancer that is often diagnosed late and is commonly initiated by oncogenic KRAS mutations. However, pancreatic epithelial cells with cancer driver mutations can remain normal until being exposed to inflammatory insults — and cellular responses to these insults vary even in genetically identical cells. To investigate this heterogeneous response, a

Extracellular vesicles produced in fatty liver promote liver metastasis in colorectal cancer (CRC) by creating a pro-metastatic microenvironment, a new study shows. Wang et al. studied a mouse model of CRC liver metastasis in animals with and without fatty liver. In mice with fatty liver, upregulation of RAB27A led to increased production of extracellular vesicles containing microRNAs that promote

The phase III SUNLIGHT trial has shown that treatment of metastatic colorectal cancer with trifluridine–tipiracil (FTD–TPI) combined with bevacizumab is more effective than treatment with FTD–TPI alone. A total of 246 patients were randomly assigned to receive FTD–TPI alone or in combination with bevacizumab. Median overall survival was 10.8 months among those who received the combination treatment

Ingestible sampling devices have enabled profiling of the intestinal environment and the metabolome at multiple locations along the intestinal tract in research published in Nature and Nature Metabolism. The capsules were designed to collect fluid at four different pH levels, enabling collection at sites in the duodenum, ileum and colon. Analysis revealed that the bacteria, phages, host proteins and

Deep learning can help to predict the risk of developing pancreatic cancer on the basis of clinical records, new work has shown. The study was based on data from 6 million people in Denmark and 3 million people in the USA. The deep learning algorithm was trained with a subset of data on the sequence of disease codes in patient histories, then tested on the remaining data for its ability to predict

A new study published in Nature Communications suggests engineered polymeric acid-activated acidifying nanoparticles (acNPs) as a first-in-kind treatment for nonalcoholic fatty liver disease (NAFLD) — a disease whose prevalence is rising worldwide.

Recent clinical trials have demonstrated efficacy and safety of etrasimod, a new sphingosine-1-phosphate receptor modulator, in the treatment of patients with moderately-to-severely active ulcerative colitis. Etrasimod is a promising new oral treatment option for ulcerative colitis, although long-term efficacy and safety data should be accumulated.

A new study has found that a strain of the gut bacterium Lactiplantibacillus plantarum activates a NOD2–type I interferon–insulin-like growth factor 1 pathway in young mice to partially protect against the deleterious growth effects of a diet deficient in protein and fat. Could live biotherapeutic products or their derivatives unlock the full potential of nutritional interventions against childhood

A new study published in Nature has linked clonal haematopoiesis with an increased risk of chronic liver disease (CLD). The study examines clonal haematopoiesis of indeterminate potential (CHIP), which is the presence of somatic mutations in haematopoietic stem cells in individuals without a detectable haematological cancer. “Through advances in population-based genomic sequencing and analysis, we

The health-care sector produces significant amounts of waste and greenhouse gas emissions. In turn, environmental damage can have a negative effect on health, including gastrointestinal health. Two articles in this month’s issue prompt us to reflect upon the connections between gastrointestinal health, the health-care sector and the environment.

Colon capsule endoscopy (CCE) is used for restricted indications only. Growing demand for out-of-hospital treatment combined with technical and clinical improvements in quality has made a wider use plausible. Artificial intelligence-supported footage analysis and quality assessment might further improve quality and reduce the price of CCE to a competitive level.