Reviews & Analysis

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 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.

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.

Although nonalcoholic fatty liver disease is the most prevalent liver disease worldwide, there is a paucity of good-quality data on its natural history and most studies to date have reported on retrospective data. Robust data are required to inform regulatory end points, trial design and models of care.

Fatty pancreas disease reportedly affects approximately 1 in 5 people in general populations. This Review discusses the up-to-date knowledge on the risk factors, diagnosis and pathophysiology of the disease and highlights the approaches to reducing intra-pancreatic fat.

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.

Secretory immunoglobulin A (SIgA) regulates the composition and function of the gut microbiota and modulates its interaction with the host, but how this regulation is achieved is poorly understood. Now, Rollenske and colleagues profile the consequences of SIgA binding to the gut microbiota. They suggest that parallel generic and unique epitope-specific effects of SIgA regulate the intestinal microbiota.

In this Review, Kupiec-Weglinski and colleagues describe the roles of macrophages, neutrophils, and platelets in liver ischaemia–reperfusion injury (LIRI) and discuss potential therapeutic strategies for treating LIRI in transplant recipients.

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.

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 this Review, Chu and Traverso provide an overview of gastrointestinal-based drug delivery, discussing conventional delivery methods and challenges posed by the gastrointestinal tract as a drug delivery environment, as well as emerging technologies.

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 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.

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.

Autoimmune pancreatitis and IgG4-related cholangitis are frequent manifestations of IgG4-related disease (IgG4-RD). Here, Löhr and colleagues present current understanding of the pathophysiology of IgG4-RD and describe all IgG4-RD manifestations in the digestive tract. Diagnosis, prognosis and treatment of IgG4-RD are also discussed.

Cancer development is a dynamic evolutionary process. This Review explores the mechanisms underlying clonal expansion and contraction as well as the evolutionary dynamics in Barrett oesophagus and its progression to dysplasia and oesophageal adenocarcinoma. The implications for patient management (including surveillance, risk stratification and therapy) are also explored.

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.

In this Review, Albillos and colleagues describe cirrhosis-associated immune dysfunction (CAID) and its components — systemic inflammation and immune deficiency — as well as the role of CAID in the pathogenesis of acute-on-chronic liver failure. Therapies that aim to modulate CAID are discussed.

Humans and their microbiota are intrinsically linked. Owing to dynamic interactions within the gut, nutritional science needs to incorporate the microbiome. This Perspective re-examines the history, rationale and future prospects of chemically defined diets (enteral or parenteral) in relation to the burgeoning understanding of the human microbiota.