Journal: Nature reviews. Gastroenterology & hepatology
Over 1 million residents in the USA and 2.5 million in Europe are estimated to have IBD, with substantial costs for health care. These estimates do not factor in the ‘real’ price of IBD, which can impede career aspirations, instil social stigma and impair quality of life in patients. The majority of patients are diagnosed early in life and the incidence continues to rise; therefore, the effect of IBD on health-care systems will rise exponentially. Moreover, IBD has emerged in newly industrialized countries in Asia, South America and Middle East and has evolved into a global disease with rising prevalence in every continent. Understanding the worldwide epidemiological patterns of IBD will prepare us to manage the burden of IBD over time. The goal of this article is to establish the current epidemiology of IBD in the Western world, contrast it with the increase in IBD in newly industrialized countries and forecast the global effects of IBD in 2025.
IBS is a debilitating condition that markedly affects quality of life. The chronic nature, high prevalence and associated comorbidities contribute to the considerable economic burden of IBS. The pathophysiology of IBS is not completely understood and evidence to guide management is variable. Interest in dietary intervention continues to grow rapidly. Ileostomy and MRI studies have demonstrated that some fermentable carbohydrates increase ileal luminal water content and breath hydrogen testing studies have demonstrated that some carbohydrates also increase colonic hydrogen production. The effects of fermentable carbohydrates on gastrointestinal symptoms have also been well described in blinded, controlled trials. Dietary restriction of fermentable carbohydrates (popularly termed the ‘low FODMAP diet’) has received considerable attention. An emerging body of research now demonstrates the efficacy of fermentable carbohydrate restriction in IBS; however, limitations still exist with this approach owing to a limited number of randomized trials, in part due to the fundamental difficulty of placebo control in dietary trials. Evidence also indicates that the diet can influence the gut microbiota and nutrient intake. Fermentable carbohydrate restriction in people with IBS is promising, but the effects on gastrointestinal health require further investigation.
Vitamin B(12) (B(12); also known as cobalamin) is a cofactor in many metabolic processes; deficiency of this vitamin is associated with megaloblastic anaemia and various neurological disorders. In contrast to many prokaryotes, humans and other mammals are unable to synthesize B(12). Instead, a sophisticated pathway for specific uptake and transport of this molecule has evolved. Failure in the gastrointestinal part of this pathway is the most common cause of nondietary-induced B(12) deficiency disease. However, although less frequent, defects in cellular processing and further downstream steps in the transport pathway are also known culprits of functional B(12) deficiency. Biochemical and genetic approaches have identified novel proteins in the B(12) transport pathway–now known to involve more than 15 gene products–delineating a coherent pathway for B(12) trafficking from food to the body’s cells. Some of these gene products are specifically dedicated to B(12) transport, whereas others embrace additional roles, which explains the heterogeneity in the clinical picture of the many genetic disorders causing B(12) deficiency. This Review describes basic and clinical features of this multistep pathway with emphasis on gastrointestinal transport of B(12) and its importance in clinical medicine.
The microbial communities that colonize different regions of the human gut influence many aspects of health. In the healthy state, they contribute nutrients and energy to the host via the fermentation of nondigestible dietary components in the large intestine, and a balance is maintained with the host’s metabolism and immune system. Negative consequences, however, can include acting as sources of inflammation and infection, involvement in gastrointestinal diseases, and possible contributions to diabetes mellitus and obesity. Major progress has been made in defining some of the dominant members of the microbial community in the healthy large intestine, and in identifying their roles in gut metabolism. Furthermore, it has become clear that diet can have a major influence on microbial community composition both in the short and long term, which should open up new possibilities for health manipulation via diet. Achieving better definition of those dominant commensal bacteria, community profiles and system characteristics that produce stable gut communities beneficial to health is important. The extent of interindividual variation in microbiota composition within the population has also become apparent, and probably influences individual responses to drug administration and dietary manipulation. This Review considers the complex interplay between the gut microbiota, diet and health.
Dysphagia is a symptom of swallowing dysfunction that occurs between the mouth and the stomach. Although oropharyngeal dysphagia is a highly prevalent condition (occurring in up to 50% of elderly people and 50% of patients with neurological conditions) and is associated with aspiration, severe nutritional and respiratory complications and even death, most patients are not diagnosed and do not receive any treatment. By contrast, oesophageal dysphagia is less prevalent and less severe, but with better recognized symptoms caused by diseases affecting the enteric nervous system and/or oesophageal muscular layers. Recognition of the clinical relevance and complications of oesophageal and oropharyngeal dysphagia is growing among health-care professionals in many fields. In addition, the emergence of new methods to screen and assess swallow function at both the oropharynx and oesophagus, and marked advances in understanding the pathophysiology of these conditions, is paving the way for a new era of intensive research and active therapeutic strategies for affected patients. Indeed, a unified field of deglutology is developing, with new professional profiles to cover the needs of all patients with dysphagia in a nonfragmented way.
NAFLD affects a large proportion of the US population and its incidence and prevalence are increasing to epidemic proportions around the world. As with other liver diseases that cause cirrhosis, NAFLD increases the risk of liver cancer, a disease with poor outcomes and limited therapeutic options. The incidences of hepatocellular carcinoma (HCC) and intrahepatic cholangiocarcinoma are also rising, and HCC is now the leading cause of obesity-related cancer deaths in middle-aged men in the USA. In this Review, we summarize the correlations between liver cancer and NAFLD-related cirrhosis, and the role of the metabolic syndrome in the development of liver cancer from diverse aetiologies, including HCV-mediated cirrhosis. Recent advances in understanding the progression of NAFLD to HCC from preclinical models will also be discussed. Targeted genetic manipulation of certain metabolic or stress-response pathways, including one-carbon metabolism, NF-κB, PTEN and microRNAs, has been valuable in elucidating the pathways that regulate carcinogenesis in NAFLD. Although tremendous advances have occurred in the identification of diagnostic and therapeutic opportunities to reduce the progression of NAFLD, considerable gaps in our knowledge remain with regard to the mechanisms by which NAFLD and its risk factors promote liver cancer.
Evidence is growing that the gut microbiota modulates the host response to chemotherapeutic drugs, with three main clinical outcomes: facilitation of drug efficacy; abrogation and compromise of anticancer effects; and mediation of toxicity. The implication is that gut microbiota are critical to the development of personalized cancer treatment strategies and, therefore, a greater insight into prokaryotic co-metabolism of chemotherapeutic drugs is now required. This thinking is based on evidence from human, animal and in vitro studies that gut bacteria are intimately linked to the pharmacological effects of chemotherapies (5-fluorouracil, cyclophosphamide, irinotecan, oxaliplatin, gemcitabine, methotrexate) and novel targeted immunotherapies such as anti-PD-L1 and anti-CLTA-4 therapies. The gut microbiota modulate these agents through key mechanisms, structured as the ‘TIMER’ mechanistic framework: Translocation, Immunomodulation, Metabolism, Enzymatic degradation, and Reduced diversity and ecological variation. The gut microbiota can now, therefore, be targeted to improve efficacy and reduce the toxicity of current chemotherapy agents. In this Review, we outline the implications of pharmacomicrobiomics in cancer therapeutics and define how the microbiota might be modified in clinical practice to improve efficacy and reduce the toxic burden of these compounds.
Alcohol consumption is a global phenomenon, as is the resultant health, social and economic harm. The nature of these harms varies with different drinking patterns and with the societal and political responses to the burden of harm; nevertheless, alcohol-related chronic diseases have a major effect on health. Strong evidence exists for the effectiveness of different strategies to minimize this damage and those policies that target price, availability and marketing of alcohol come out best, whereas those using education and information are much less effective. However, these policies can be portrayed as anti-libertarian and so viewing them in the context of alcohol-related harm to those other than the drinker, such as the most vulnerable in society, is important. When this strategy is successful, as in Scotland, it has been possible to pass strong and effective legislation, such as for a minimum unit price for alcohol.
NAFLD is one of the most important causes of liver disease worldwide and will probably emerge as the leading cause of end-stage liver disease in the coming decades, with the disease affecting both adults and children. The epidemiology and demographic characteristics of NAFLD vary worldwide, usually parallel to the prevalence of obesity, but a substantial proportion of patients are lean. The large number of patients with NAFLD with potential for progressive liver disease creates challenges for screening, as the diagnosis of NASH necessitates invasive liver biopsy. Furthermore, individuals with NAFLD have a high frequency of metabolic comorbidities and could place a growing strain on health-care systems from their need for management. While awaiting the development effective therapies, this disease warrants the attention of primary care physicians, specialists and health policy makers.
Colorectal cancer is one of the so-called westernized diseases and the second leading cause of cancer death worldwide. On the basis of global epidemiological and scientific studies, evidence suggests that the risk of colorectal cancer is increased by processed and unprocessed meat consumption but suppressed by fibre, and that food composition affects colonic health and cancer risk via its effects on colonic microbial metabolism. The gut microbiota can ferment complex dietary residues that are resistant to digestion by enteric enzymes. This process provides energy for the microbiota but culminates in the release of short-chain fatty acids including butyrate, which are utilized for the metabolic needs of the colon and the body. Butyrate has a remarkable array of colonic health-promoting and antineoplastic properties: it is the preferred energy source for colonocytes, it maintains mucosal integrity and it suppresses inflammation and carcinogenesis through effects on immunity, gene expression and epigenetic modulation. Protein residues and fat-stimulated bile acids are also metabolized by the microbiota to inflammatory and/or carcinogenic metabolites, which increase the risk of neoplastic progression. This Review will discuss the mechanisms behind these microbial metabolite effects, which could be modified by diet to achieve the objective of preventing colorectal cancer in Western societies.