Key Advances in Gastroenterology & Hepatology

Key studies published in 2022 further established the importance of alterations in the gut microenvironment and interactions with the enteric and central nervous systems in symptom generation in irritable bowel syndrome and suggested novel and clinically accessible therapeutic approaches for this large group of patients.

2022 was a proficuous year in both the nonalcoholic fatty liver disease (NAFLD) and obesity fields. Pharmacological treatment for obesity and NAFLD is moving forward, with the possibility of replacing bariatric surgery, artificial intelligence might help us access the histological effects of new drugs, and there were advances in personalized hepatocellular carcinoma screening in patients with NAFLD.

In 2022, we witnessed advances in the field of alcohol-related liver disease. Key developments included the discovery of novel proteomics-based biomarkers and potential therapeutic targets that regulate the recognition of molecules derived from gut microbiota to modulate liver injury. Additionally, there have been significant advances in refining selection for liver transplantation in severe alcohol-associated hepatitis.

Various pathways enable communication between the gut and brain, and this communication influences physiology and behaviour. Studies published in 2022 demonstrate how our understanding of several of these pathways is advancing rapidly.

The year 2022 was notable for substantial research progress related to pancreatic ductal adenocarcinoma (PDAC). The first single-cell and spatial transcriptomic atlases of PDAC were reported, a mechanism for how Schwann cells promote perineural invasion was explored, and, finally, the role of exercise in abrogating immunosuppression was shown.

The gut microbiome field is shifting from association to modulation. Microbiota-based treatments come in many shapes and sizes, ranging from dietary intervention to live bacterial products. Recent methodological advances are instrumental to developing innovative new treatment strategies in microbiome-linked pathologies.

Key studies published in 2022 highlight the emergence of several novel drugs for inflammatory bowel disease. Head-to-head trials and network meta-analyses have also been conducted to identify the sequencing of these treatments, but we still have a long way to go to achieve personalized medicine.

Key studies published in 2021 demonstrated mechanisms that drive macrophage–fibroblast pathogenicity in Crohn’s disease, developed multi-omics profiles to predict response to biological therapy, and suggested potential complementary treatments and new therapeutic agents in inflammatory bowel disease (IBD) therapy. These results represent important progress towards precision medicine for patients with IBD.

In 2021, our understanding of resistance to therapy in primary liver tumours improved drastically. By taking a holistic approach, three independent studies have characterized the tumour cell biodiversity across space, time and aetiologies in primary liver cancer, decoding the crosstalk between different cell types within the tumour ecosystem and their individual contributions to therapy resistance.

In 2021, transcriptome analysis of the mouse and human gut advanced our understanding of the cellular composition, development and surrounding non-neural context of the enteric nervous system (ENS). A role for the ENS in tuning regulatory T cell proportions contributed insights into the dependency between the ENS, immune system and microbiota.

Vaccination is a key intervention for the elimination of hepatitis B virus (HBV) and hepatitis C virus (HCV) infections to fulfil the WHO’s 2030 global elimination goal. Innovations in 2021 promise to curb HBV transmission by reducing mother-to-child transmission and enhancing vaccine immunogenicity in at-risk adult groups. Additionally, an HCV vaccination trial was conducted, and there were also advances in our understanding of the immunology underpinning the lack of protection against HCV reinfection.

Important studies in 2021 demonstrated sophisticated developments in the study of liver fibrosis through omics. Cell-specific mapping, single-cell sequencing and deep-learning systems revealed complex intra-hepatic mechanisms and new computational platforms facilitating the research towards drug discovery in liver disease and in fibrosis.

2021 has been a productive year for fungal research. Key studies focused on intestinal inflammation and inflammatory bowel disease highlight antibody-mediated immunity in control of fungal commensalism, commensal and dietary fungi in intestinal inflammation and wound healing, and the therapeutic potential of transgenic yeast engineered to sense and target factors during intestinal inflammation.

Important colorectal cancer (CRC) studies in 2021, including a new standard of care for first-line treatment of MSI-H–dMMR metastatic CRC, single-cell and spatial analysis of primary tumours and investigations of diet in preclinical models of cancer initiation, have provided novel insights into the CRC immune microenvironment.

In 2020, there have been substantial advances in nonalcoholic fatty liver disease mechanisms, diagnostics and treatment. Key developments include the identification of a cellular and tissue signature to provide new insights into pathophysiology, advancements in non-invasive diagnostics and publication of interim results of the first phase III trial to demonstrate improvement in hepatic fibrosis.

In 2020, major advances to the understanding of gastrointestinal inflammatory and infectious disease have been made using ‘mini-gut’ organoids. Key findings include the discovery of somatic inflammatory gene mutations in ulcerative colitis epithelium, a unique mutational signature in colorectal cancer caused by genotoxic Escherichia coli, and infection of intestinal organoids by SARS-CoV-2.

In 2020, important advances were made across three major frontiers of pancreatic ductal adenocarcinoma (PDAC) research: risk factors, therapeutic resistance and tumour recurrence. Pathophysiology of obesity-mediated PDAC initiation was elucidated, novel stromal mechanisms of therapeutic resistance were unveiled and the genetic evolution of recurrent PDAC under therapeutic pressures was tracked in human samples.

In 2020, studies have used pure cultures of members of the gut microbiota to establish a molecular chain of causation for the role of these key bacteria in aggravating or alleviating cancer and metabolic diseases. These studies highlight the need for microbiome studies to move from associations back to cultures to demonstrate causality.

Key studies published in 2020 demonstrate that an impaired intestinal barrier precedes clinical diagnosis of inflammatory bowel disease (IBD) by years. Furthermore, studies identify novel regulators of the intestinal barrier, including intestinal macrophages and diurnal variations of diet–microbiome interactions, which could be future therapeutic strategies for IBD.

One of the most pleasurable, yet dangerous, activities of our daily life is eating. But once food has been swallowed, all we can do is to trust our gut. Several remarkable studies published in 2020 have expanded our knowledge on how the gut is intertwined with essential behaviours beyond food.

The World Health Organization’s targets for hepatitis C elimination by 2030 are ambitious, but, in 2020, global leadership demonstrated by Egypt, innovative strategies to improve linkage to treatment for marginalized populations and the broadened capacity of direct-acting antiviral therapy have been promising for enhanced global elimination efforts.

Important studies published in 2020 highlight that coeliac disease is a systemic autoimmune-like disorder with the potential to result in serious long-term health consequences that might also occur outside the gastrointestinal tract. Ultimately, the results of these studies will enable the development of better strategies for the management of coeliac disease.

In 2020, combination treatments have pushed the efficacy of systemic therapy for hepatocellular carcinoma (HCC) to an unprecedented high, providing a solid base for the future pursuit of further improved, highly efficacious systemic therapies for HCC.

Primary sclerosing cholangitis (PSC) is closely associated with inflammatory bowel disease (IBD) and potentially provides unique insights into the gut–liver axis. This Review explores these links and provides an overview of the gut microbiome in PSC, including PSC–IBD, exploring related hypotheses of disease mechanisms.

The use of antibiotics affects the gut microbiota. Fenneman and colleagues discuss the role of antibiotics in the epidemiology and pathogenesis of several inflammatory conditions that involve the digestive tract: types 1 and 2 diabetes, eosinophilic oesophagitis, coeliac disease and inflammatory bowel disease.

Global alcohol consumption has increased in the past two decades and is projected to increase further. In this Review, Loomba and colleagues discuss the global epidemiology of alcohol-associated cirrhosis and hepatocellular carcinoma, including risk factors, trends and projections.

There are limited available treatment options for the management of abdominal pain in irritable bowel syndrome (IBS). This Review provides an overview of the gastrointestinal endocannabinoid system and its potential as a therapeutic target for the treatment of pain in IBS.

The influence of nerves on cancer is beginning to be understood. This Review discusses emerging insights into the role of the nervous system in gastrointestinal cancer and of nerves as components of the tumour microenvironment, highlighting underlying mechanisms and its potential as a therapeutic target.

Archaea are an overlooked member of the human gut microbiota. This Perspective discusses key characteristics of archaea, their role in human health and physiology, and the clinical relevance of methanogenic archaea in the human gastrointestinal tract.

Genetic predisposition contributes to disease pathophysiology in irritable bowel syndrome (IBS). This Review provides a comprehensive overview of genetic research in IBS and discusses new concepts in IBS genetics.

Experimental and clinical evidence supports a role of metabolic perturbation in the development of gut inflammation in inflammatory bowel disease (IBD). This Review discusses the role of diet and metabolic inflammation in IBD, outlining key concepts and highlighting the links between metabolism and inflammation in IBD.

In this Review, Jess and colleagues describe the prevalence of depression and anxiety in patients with inflammatory bowel disease, the mechanisms underlying the bidirectional association between these diseases and the effect of treatment on their co-occurrence.

Metabolic (dysfunction)-associated fatty liver disease (MAFLD) is a chronic liver disease typically associated with obesity. This Review discusses the epidemiology and physiology of individuals of normal weight with MAFLD and provides insights into their metabolic health and metabolic adaptation.

This Review covers the discovery of Akkermansia muciniphila and its association with health and disease, including metabolic diseases. Insights into underlying mechanisms for how A. muciniphila improves health are given as are comparisons with other next-generation beneficial microorganisms.

Diet is part of the multidisciplinary management of inflammatory bowel disease (IBD). This Review outlines a step-based approach to the dietary management of IBD, outlining the role of dietary therapy with practical insights for dietitians and clinicians.

In this Review, O’Toole and colleagues discuss the composition and function of the gut microbiome as it relates to ageing and ‘unhealthy’ ageing as well as the potential for microbiome-directed interventions to encourage ‘healthy’ ageing.

Multiomics advance our understanding of disease progression and can facilitate drug discovery. In this Perspective, current knowledge and applications of omics platforms in inflammatory bowel disease diagnosis and in identifying risk factors are discussed.

Mechanosensation — detecting mechanical forces and converting them into physiological responses — is important for normal gastrointestinal tract function. Mechanosensation abnormalities are frequently found in gastrointestinal diseases. This Review describes the physical properties of the gut relevant for mechanosensing, as well as the mechanosensory molecules, cells and circuits involved in gastrointestinal tract mechanosensation.

Intestinal fibrosis is an important feature of inflammatory bowel disease (IBD) that remains poorly understood. Here, D’Alessio and Ungaro et al. review the cellular and molecular mechanisms contributing to intestinal fibrosis and discuss future therapeutic strategies for IBD-related fibrosis.

In this Perspective, Duan, Young and Schnabl explore the effects of bacteriophages on the gut microbiota and the potential applications of phage therapy for treatment of gastrointestinal diseases. Limitations and challenges of phage therapy for gastrointestinal diseases are also discussed.

In this Review, Arab and colleagues discuss management of alcohol use disorder in patients with alcohol-associated liver disease, particularly in the setting of liver transplantation. An integrative, multidisciplinary approach is proposed.

Non-alcoholic fatty liver disease (NAFLD) is a potentially serious liver disease with a substantial burden worldwide. In this Consensus Statement, a global multidisciplinary group of experts develop consensus statements and recommendations addressing a broad range of topics on NAFLD to raise awareness and spur action.

Metabolomics and lipidomics approaches are being used to identify biomarkers for nonalcoholic fatty liver disease (NAFLD). This Review discusses the application of metabolomics and lipidomics in clinical studies and in the identification of key metabolic pathway alterations in NAFLD.

Here, the authors describe the complex role of regulated cell death (RCD) in pancreatic tumorigenesis and treatment. They also discuss how RCD is reshaped in tumours at both molecular and metabolic levels and highlight the challenges and opportunities in this field.

This Review discusses the role of dietary fats and carbohydrates in the pathogenesis of nonalcoholic fatty liver disease (NAFLD). Studies on the dietary habits of patients with NAFLD, and the effect on liver fat accumulation of altering dietary macronutrients, are also reviewed.

Pancreatic cancer is typically diagnosed at a late stage and early detection is a priority. This Review focuses on precancerous lesions of the pancreas, describing their pathological and molecular features and highlighting different DNA-based molecular approaches for early detection and their clinical utility.

Vast developments are being made within the field of pancreatic cancer genomics. This Review discusses the wide-ranging and most current research with the goal of integrating this information into a unifying description of the life history of pancreatic cancer.

Enteric glia regulate homeostasis in the enteric nervous system and influence gastrointestinal function. This Review provides an update on enteric glial biology and the underlying mechanisms by which enteric glia regulate gastrointestinal function and disease, with a focus on neuronal and immune interactions.

The therapeutic pipeline for nonalcoholic steatohepatitis (NASH) is expanding as insights into disease pathophysiology are gained. This Review summarizes progress in the development of NASH therapies, current and ongoing clinical trials, and potential challenges with emerging therapies.

Although the role of the enteric nervous system in congenital enteric neuropathic disorders is well acknowledged, its role in systemic diseases is less understood. Here, the authors focus on diseases in which the enteric nervous system has so far not been considered to have a major role and on its emerging role in neurodegeneration, cancer and diabetes.