COVID-19 and the digestive system: A comprehensive review

The coronavirus disease 2019 (COVID-19) pandemic caused by severe acute respiratory syndrome coronavirus-2 (SARS-CoV-2) is spreading at an alarming rate, and it has created an unprecedented health emergency threatening tens of millions of people worldwide. Previous studies have indicated that SARS-CoV-2 ribonucleic acid could be detected in the feces of patients even after smear-negative respiratory samples. However, demonstration of confirmed fecal-oral transmission has been difficult. Clinical studies have shown an incidence rate of gastrointestinal (GI) symptoms ranging from 2% to 79.1% in patients with COVID-19. They may precede or accompany respiratory symptoms. The most common GI symptoms included nausea, diarrhea, and abdominal pain. In addition, some patients also had liver injury, pancreatic damage, and even acute mesenteric ischemia/thrombosis. Although the incidence rates reported in different centers were quite different, the digestive system was the clinical component of the COVID-19 section. Studies have shown that angiotensin-converting enzyme 2, the receptor of SARS-CoV-2, was not only expressed in the lungs, but also in the upper esophagus, small intestine, liver, and colon. The possible mechanism of GI symptoms in COVID-19 patients may include direct viral invasion into target cells, dysregulation of angiotensin-converting enzyme 2, immune-mediated tissue injury, and gut dysbiosis caused by microbiota. Additionally, numerous experiences, guidelines, recommendations, and position statements were published or released by different organizations and societies worldwide to optimize the management practice of outpatients, inpatients, and endoscopy in the era of COVID-19. In this review, based on our previous work and relevant literature, we mainly discuss potential fecal-oral transmission, GI manifestations, abdominal imaging findings, relevant pathophysiological mechanisms, and infection control and prevention measures in the time of COVID-19.     

Influence of gut microbiota on eye diseases: an overview

The microbiota is a dynamic ecosystem that plays a major role in the host health. Numerous studies have reported that alterations in the intestinal microbiota (dysbiosis) may contribute to the pathogenesis of various common diseases such as diabetes, neuropsychiatric diseases, and cancer. However, emerging findings also suggest the existence of a gut-eye axis, wherein gut dysbiosis may be a crucial factor influencing the onset and progression of multiple ocular diseases, including uveitis, dry eye, macular degeneration, and glaucoma. Currently, supplementation with pre- and probiotics appears is the most feasible and cost-effective approach to restore the gut microbiota to a eubiotic state and prevent eye pathologies. In this review, we discuss the current knowledge on how gut microbiota may be linked to the pathogenesis of common eye diseases, providing therapeutic perspectives for future translational investigations within this promising research field.     

肠道菌群代谢产物在自身免疫性疾病中的作用

肠道菌群及其代谢产物在维持宿主免疫稳态方面具有重要作用,肠道菌群紊乱及代谢产物异常与多种自身免疫疾病的发生发展密切相关。肠道菌群代谢产物中,短链脂肪酸、色氨酸及其衍生物、胆汁酸的研究最为广泛。本文将重点阐述肠道菌群代谢产物的形成途径、对免疫应答的影响及与自身免疫性疾病的关联等,解析其在自身免疫疾病中的作用。     

Brain-gut axis dysfunction in the pathogenesis of traumatic brain injury

Traumatic brain injury (TBI) is a chronic and progressive disease, and management requires an understanding of both the primary neurological injury and the secondary sequelae that affect peripheral organs, including the gastrointestinal (GI) tract. The brain-gut axis is composed of bidirectional pathways through which TBI-induced neuroinflammation and neurodegeneration impact gut function. The resulting TBI-induced dysautonomia and systemic inflammation contribute to the secondary GI events, including dysmotility and increased mucosal permeability. These effects shape, and are shaped by, changes in microbiota composition and activation of resident and recruited immune cells. Microbial products and immune cell mediators in turn modulate brain-gut activity. Importantly, secondary enteric inflammatory challenges prolong systemic inflammation and worsen TBI-induced neuropathology and neurobehavioral deficits. The importance of brain-gut communication in maintaining GI homeostasis highlights it as a viable therapeutic target for TBI. Currently, treatments directed toward dysautonomia, dysbiosis, and/or systemic inflammation offer the most promise.     

Gut microbiome interventions in human health and diseases

Ongoing studies have determined that the gut microbiota is a major factor influencing both health and disease. Host genetic factors and environmental factors contribute to differences in gut microbiota composition and function. Intestinal dysbiosis is a cause or a contributory cause for diseases in multiple body systems, ranging from the digestive system to the immune, cardiovascular, respiratory, and even nervous system. Investigation of pathogenesis has identified specific species or strains, bacterial genes, and metabolites that play roles in certain diseases and represent potential drug targets. As research progresses, gut microbiome–based diagnosis and therapy are proposed and applied, which might lead to considerable progress in precision medicine. We further discuss the limitations of current studies and potential solutions.     

Gut-liver axis in cirrhosis: Are hemodynamic changes a missing link?

Recent evidence suggests that the condition of the gut and its microbiota greatly influence the course of liver disease, especially cirrhosis. This introduces the concept of the gut–liver axis, which can be imagined as a chain connected by several links. Gut dysbiosis, small intestinal bacterial overgrowth, and intestinal barrier alteration lead to bacterial translocation, resulting in systemic inflammation. Systemic inflammation further causes vasodilation, arterial hypotension, and hyperdynamic circulation, leading to the aggravation of portal hypertension, which contributes to the development of complications of cirrhosis, resulting in a poorer prognosis. The majority of the data underlying this model were obtained initially from animal experiments, and most of these correlations were further reproduced in studies including patients with cirrhosis. However, despite the published data on the relationship of the disorders of the gut microbiota with the complications of cirrhosis and the proposed pathogenetic role of hemodynamic disorders in their development, the direct relations between gut dysbiosis and hemodynamic changes in this disease are poorly studied. They remain a missing link in the gut–liver axis and a challenge for future research.     

NOD2-mediated dysbiosis predisposes mice to transmissible colitis and colorectal cancer

Instability in the composition of gut bacterial communities (dysbiosis) has been linked to common human intestinal disorders, such as Crohn’s disease and colorectal cancer. Here, we show that dysbiosis caused by Nod2 deficiency gives rise to a reversible, communicable risk of colitis and colitis-associated carcinogenesis in mice. Loss of either Nod2 or RIP2 resulted in a proinflammatory microenvironment that enhanced epithelial dysplasia following chemically induced injury. The condition could be improved by treatment with antibiotics or an anti–interleukin-6 receptor–neutralizing antibody. Genotype-dependent disease risk was communicable via maternally transmitted microbiota in both Nod2-deficient and WT hosts. Furthermore, reciprocal microbiota transplantation reduced disease risk in Nod2-deficient mice and led to long-term changes in intestinal microbial communities. Conversely, disease risk was enhanced in WT hosts that were recolonized with dysbiotic fecal microbiota from Nod2-deficient mice. Thus, we demonstrated that licensing of dysbiotic microbiota is a critical component of disease risk. Our results demonstrate that NOD2 has an unexpected role in shaping a protective assembly of gut bacterial communities and suggest that manipulation of dysbiosis is a potential therapeutic approach in the treatment of human intestinal disorders.     

Gastroenterology and liver disease during COVID-19 and in anticipation of post-COVID-19 era: Current practice and future directions

Severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) has emerged as a major threat to global public health. The virus causes the clinical syndrome known as coronavirus disease 2019 (COVID-19), in which multiple organs can get affected. Apart from manifestations of the respiratory system, which predominate, its clinical presentation is frequently accompanied by symptoms of the gastro-intestinal (GI) tract and liver abnormalities. The correlation of symptoms and abnormalities with disease severity is discussed, leading to ambiguous results from international literature. Moreover, the disease infects patients with co-existing liver and GI disorders affecting both their health status and the availability of healthcare services provided to them. The risk of transmission of the disease during aerosol-generating procedures has changed the diagnostic approach and follow-up algorithms for liver and GI diseases. For the safety of both doctors and patients, telemedicine and distant evaluation have become everyday practice, whereas several routines and emergency visits at outpatient and emergency departments have been postponed or delayed. Vaccination against SARS-CoV-2 is underway, providing hope to humanity and the expectation that the post-COVID-19 era is near. This review aims to update knowledge about the manifestations of COVID-19 related to liver and GI diseases and the effect of the pandemic on the diagnostic and therapeutic procedures for these diseases with a special focus on how current practices have changed and what changes will possibly remain in the future.     

Expert insights: The potential role of the gut microbiome-bile acid-brain axis in the development and progression of Alzheimer's disease and hepatic encephalopathy

Recent epidemiological and molecular studies have linked the disruption of cholesterol homeostasis to increased risk for developing Alzheimer's disease (AD). Emerging evidence also suggests that brain cholesterol accumulation contributes to the progression of hepatic encephalopathy (HE) via bile acid (BA)-mediated effects on the farnesoid X receptor. In this perspective paper, we reviewed several recently published studies that suggested a role for the gut microbiota transformation of BAs as a factor in AD and HE development/progression. We hypothesize that in addition to cholesterol elimination pathways, alteration of the gut microbiota and subsequent changes in both the serum and brain BA profiles are mechanistically involved in the development of both AD and HE, and thus, are a potential target for the prevention and treatment of the two diseases. Our understanding of the microbiome-BAs-brain axis in central nervous system disease is still evolving, and critical questions regarding the emerging links among central, peripheral, and intestinal metabolic failures contributing to brain health and disease during aging have yet to be addressed.     

肺-肠轴：儿童呼吸道感染与肠道微生态的相关性

肠道菌群是作为维持器官微环境的重要调节剂,由肠道-重要器官轴发挥作用。多项研究表明,肠道菌群及其代谢产物可有效预防和治疗呼吸系统疾病。然而,由于儿童肠道菌群的组成与成年人不同,并且其免疫系统正处于发育过程中,因此关于儿童肠道菌群与呼吸道感染之间相互作用的研究仍然很少。该文从“肺-肠轴”角度介绍了呼吸道感染儿童肠道菌群的变化,并分析了儿童肠道菌群与免疫功能和呼吸道感染之间的相关性,期望能为临床从肠道菌群入手治疗儿童呼吸道感染提供参考。     

Depletion of gut microbiota induces skeletal muscle atrophy by FXR-FGF15/19 signalling

Background: Recent evidence indicates that host-gut microbiota crosstalk has nonnegligible effects on host skeletal muscle, yet gut microbiota-regulating mechanisms remain obscure.Methods: C57BL/6 mice were treated with a cocktail of antibiotics (Abx) to depress gut microbiota for 4 weeks. The profiles of gut microbiota and microbial bile acids were measured by 16S rRNA sequencing and ultra-performance liquid chromatography (UPLC), respectively. We performed qPCR, western blot and ELISA assays in different tissue samples to evaluate FXR-FGF15/19 signaling.Results: Abx treatment induced skeletal muscle atrophy in mice. These effects were associated with microbial dysbiosis and aberrant bile acid (BA) metabolism in intestine. Ileal farnesoid X receptor (FXR)-fibroblast growth factor 15 (FGF15) signaling was inhibited in response to microbial BA disturbance. Mechanistically, circulating FGF15 was decreased, which downregulated skeletal muscle protein synthesis through the extracellular-signal-regulated protein kinase 1/2 (ERK1/2) signaling pathway. Treating Abx mice with FGF19 (human FGF15 ortholog) partly reversed skeletal muscle loss.Conclusions: These findings indicate that the BA-FXR-FGF15/19 axis acts as a regulator of gut microbiota to mediate host skeletal muscle.     

结直肠癌患者肠道微生物多样性的研究进展

结直肠癌是最常见的消化道恶性肿瘤之一,其发病原因除了饮食、环境以及遗传因素外,越来越多的证据指向肠道菌群失调与结直肠癌发生发展有密切的关系。许多元基因组学的研究为揭示肠道微生物在结直肠癌发生发展中起到的作用提供了大量科学依据。在这篇综述中,我们会介绍结直肠癌患者肠道微生物多样性的研究进展,并总结结直肠癌发生发展相关的细菌及其研究现状。     

Intestinal microecology-based treatment for inflammatory bowel disease: Progress and prospects

Inflammatory bowel disease (IBD) is a chronic, recurrent, and debilitating disorder, and includes Crohn’s disease and ulcerative colitis. The pathogenesis of IBD is closely associated with intestinal dysbiosis, but has not yet been fully clarified. Genetic and environmental factors can influence IBD patients’ gut microbiota and metabolism, disrupt intestinal barriers, and trigger abnormal immune responses. Studies have reported the alteration of gut microbiota and metabolites in IBD, providing the basis for potential therapeutic options. Intestinal microbiota-based treatments such as pre/probiotics, metabolite supplementation, and fecal microbiota transplantation have been extensively studied, but their clinical efficacy remains controversial. Repairing the intestinal barrier and promoting mucosal healing have also been proposed. We here review the current clinical trials on intestinal microecology and discuss the prospect of research and practice in this field.     

Impact of gut–brain interaction in emerging neurological disorders

The central nervous system(CNS) is a reservoir of immune privilege. Specialized immune glial cells are responsible for maintenance and defense against foreign invaders. The blood–brain barrier(BBB) prevents detrimental pathogens and potentially overreactive immune cells from entering the periphery. When the double-edged neuroinflammatory response is overloaded, it no longer has the protective function of promoting neuroregeneration. Notably, microbiota and its derivatives may emerge as pathogen-...     

Gut permeability and osteoarthritis,towards a mechanistic understanding of the pathogenesis: a systematic review

Osteoarthritis (OA) is the most common condition affecting human joints. Along with mechanical and genetic factors, low-grade inflammation is increasingly supported as a causal factor in the development of OA. Gut microbiota and intestinal permeability, via the disruption of tight junction competency, are proposed to explain a gut-joint axis through the interaction with the host immune system. Since previous studies and methods have underestimated the role of the gut-joint axis in OA and have only focussed on the characterisation of microbiota phenotypes, this systematic review aims to appraise the current evidence concerning the influence of gut permeability in the pathogenesis of OA. We propose that the tight junction disruption may be due to an increase in zonulin activity as already demonstrated for many other chronic inflammatory disorders. After years of unreliable quantification, one study optimised the methodology, showing a positive validated correlation between plasma lipopolysaccharide (LPS), obesity, joint inflammation, and OA severity. Chemokines show a prominent role in pain development. Our systematic review confirms preliminary evidence supporting a gut-joint axis in OA pathogenesis and progression. Being modifiable by several factors, the gut microbiota is a promising target for treatment. We propose a pathogenetic model in which dysbiosis is correlated to the bipartite graph of tight junctions and bacterially-produced products, aiming to direct future studies in the search of other bacterial products and tight junction disassembly regulators.

KEY MESSAGES

• Previous studies and methods have underestimated the impact of the gut-joint axis in osteoarthritis and have focussed on the characterisation of microbiota phenotypes rather than clear molecular mediators of disease.
• Gut dysbiosis is related to higher levels of bacterial toxins that elicit cartilage and synovium inflammatory pathways.
• Future research may benefit from focussing on both tight junctions and bacterially-produced products.

     

Update on gut microbiota in gastrointestinal diseases

The human gut is a complex microbial ecosystem comprising approximately 100 trillion microbes collectively known as the “gut microbiota”. At a rough estimate, the human gut microbiome contains almost 3.3 million genes, which are about 150 times more than the total human genes present in the human genome. The vast amount of genetic information produces various enzymes and physiologically active substances. Thus, the gut microbiota contributes to the maintenance of host health; however, when healthy microbial composition is perturbed, a condition termed “dysbiosis”, the altered gut microbiota can trigger the development of various gastrointestinal diseases. The gut microbiota has consequently become an extremely important research area in gastroenterology. It is also expected that the results of research into the gut microbiota will be applied to the prevention and treatment of human gastrointestinal diseases. A randomized controlled trial conducted by a Dutch research group in 2013 showed the positive effect of fecal microbiota transplantation (FMT) on recurrent Clostridioides difficile infection (CDI). These findings have led to the development of treatments targeting the gut microbiota, such as probiotics and FMT for inflammatory bowel diseases (IBD) and other diseases. This review focuses on the association of the gut microbiota with human gastrointestinal diseases, including CDI, IBD, and irritable bowel syndrome. We also summarize the therapeutic options for targeting the altered gut microbiota, such as probiotics and FMT.     

COVID-19 in gastroenterology and hepatology: Lessons learned and questions to be answered

BACKGROUNDAlthough coronavirus disease 2019 (COVID-19) presents primarily as a lower respiratory tract infection, increasing data suggests multiorgan, including the gastrointestinal (GI) tract and liver, involvement in patients who are infected by severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2).AIMTo provide a comprehensive overview of COVID-19 in gastroenterology and hepatology.METHODSRelevant studies on COVID-19 related to the study aim were undertaken through a literature search to synthesize the extracted data.RESULTSWe found that digestive symptoms and liver injury are not uncommon in patients with COVID-19 and varies in different individuals. The most common GI symptoms reported are diarrhea, nausea, vomiting, and abdominal discomfort. Other atypical GI symptoms, such as loss of smell and taste and GI bleeding, have also been reported along with the evolvement of COVID-19. Liver chemistry abnormalities mainly include elevation of aspartate transferase, alanine transferase, and total bilirubin. It is postulated to be related to the binding of severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) virus to the angiotensin converting enzyme-2 receptor located on several different human cells. CONCLUSIONStandardized criteria should be established for diagnosis and grading of the severity of GI symptoms in COVID-19 patients. Gastroenterology and hepatology in special populations, such as children and elderly, should be the focus of further research. Future long-term data regarding GI symptoms should not be overlooked.