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Gut-brain axis

It is becoming increasingly evident that bidirectional signalling exists between the gastrointestinal tract and the brain, often involving the gut microbiota. This relationship, commonly dubbed the gut–brain axis (or the microbiota–gut–brain axis), involves various afferent and efferent pathways such as the vagus nerve and the hypothalamic-pituitary-adrenal pathway to regulate aspects of homeostasis such as satiety and hunger, and inflammation. Disruption of the gut–brain axis has been shown to be involved in the pathogenesis of a diverse range of diseases, including Parkinson disease and irritable bowel syndrome. This emerging area of research is evolving quickly.

This collection brings together Research, Reviews and News from across the Nature Research journals covering key aspects of the gut–brain axis including immune, neuroendocrine and neural factors. The selected content has been published within the past 2 years in Nature Reviews Gastroenterology & Hepatology, Nature, Nature CommunicationsNature Immunology, Nature Medicine, Nature Microbiology, Nature Neuroscience, Nature Outlook, Nature Reviews Disease Primers, Nature Reviews Endocrinology, Nature Reviews Microbiology, Nature Reviews NeurologyNature Reviews Neuroscience, Nature Reviews Urology and Scientific Reports.

Articles in the core collection have been made freely available for 6 months (until 11th July 2018), thanks to support from Abbott. The collection content is editorially independent and the sole responsibility of Springer Nature.

Image credit: Laura Marshall

This Collection is editorially independent, produced with financial support from a third party. About this content.

Core collection

In this study, the authors show that host microbiota play a key role in modulating microglia homeostasis. Germ-free mice or mice with only limited microbiota complexity displayed defects in microglial cell proportions and maturation, leading to impaired innate immune responses. The authors find that short-chain fatty acid signaling regulates these effects in vivo.

Article | | Nature Neuroscience

Changes to gut microbiota, and altered faecal short-chain fatty acid concentrations, have been associated with obesity, insulin resistance and the metabolic syndrome, but no causal links have been established. Gerald Shulman and colleagues show that a gut microbiota–nutrient interaction increases acetate production in rodents on a high-fat diet. This leads to activation of the parasympathetic nervous system — the part of the nervous system that controls 'subconscious' operations such as heart rate and digestion — which in turn promotes increased glucose-stimulated insulin secretion, ghrelin secretion, hyperphagia and obesity.

Article | | Nature

The enteric nervous system is vital for life, and its dysfunction participates not only in digestive disorders, but also in diseases of the central nervous system (CNS). Here, Rao and Gershon discuss the gastrointestinal consequences of neurological disorders, the acquisition of CNS disease in the gut and the spread of pathology along the gut–brain axis.

Review Article | | Nature Reviews Gastroenterology & Hepatology

Increasing evidence suggests that Alzheimer disease (AD) is not simply a CNS disorder, but involves interactions between systemic and brain-related factors. Wang and colleagues review the role of amyloid-β (Aβ) in AD, highlighting systemic abnormalities linked to Aβ metabolism and discussing how these abnormalities might influence central pathways of Aβ production and clearance.

Review Article | | Nature Reviews Neurology

Functional urological disorders, like their gastrointestinal counterparts, are interrelated and characterized by a chronic course and treatment resistance. Poor outcomes might be attributable to underlying psychological and psychiatric disorders, as the co-occurrence of functional disorders with mood and anxiety disorders is common. In this Review, the authors describe the hypothetical bladder–gut–brain axis, and explain how it is a useful framework under which this interaction can be studied.

Review Article | | Nature Reviews Urology

Here, Patrice Cani and colleagues discuss interactions between gut microorganisms, the endocannabinoid system and host metabolism, in the context of both physiology and pathophysiology. The authors highlight the importance of gut barrier function by discussing the role of specific factors involved in intestinal permeability and their role in the gut microbiota–endocannabinoid system axis. The therapeutic potential of targeting the endocannabinoid system to treat cardiometabolic disorders and intestinal inflammation is also discussed.

Review Article | | Nature Reviews Endocrinology

Functional dyspepsia is a functional gastrointestinal disorder characterized by discomfort or pain in the upper abdomen (generally associated with food intake) with no apparent underlying organic cause. The three subtypes of functional dyspepsia are postprandial distress syndrome, epigastric pain syndrome and a subtype with mixed features.

Primer | | Nature Reviews Disease Primers

Research

Recent evidence supports a functional connection between gut microbiota and the nervous system. Here the authors show that gut microbiota plays a critical role in the development of chemotherapy-induced pain. This role of the microbiota is likely mediated, in part, by Tlr4 expressed on hematopoietic cells, including macrophages.

Brief Communication | | Nature Neuroscience

There is concern about potential long-term effects of antibiotics on children’s health. Here Leclercqet al. show, in mice, that low doses of penicillin during late pregnancy and early life induce lasting effects on the offspring, including alterations in gut microbiota, brain cytokine levels and behaviour.

Article | Open Access | | Nature Communications

Cerebral cavernous malformations (CCMs) are malformations of the vascular system, seen mainly in the brain where they can cause haemorrhagic stroke and seizures. CCMs arise from loss-of-function mutations in components of a complex that negatively regulates MEKK3–KLF2/4 signalling and Rho/ROCK signalling in brain endothelial cells. Mark Kahn and colleagues now identify upstream regulators that activate this pathway in brain endothelial cells. They find that lipopolysaccharide derived from gut bacteria can accelerate CCM formation by activating TLR4 on endothelial cells. The authors further show that polymorphisms in the TLR4 gene or CD14, the gene encoding its co-receptor, are associated with higher CCM lesion burden in humans. These findings suggest that the gut microbiome and TLR4 are important drivers of CCMs and represent potential therapeutic targets.

Article | | Nature

Experimental autoimmune encephalomyelitis (EAE) involves inflammatory cell infiltration into the central nervous system (CNS) and models the human disease multiple sclerosis. Here the authors show that transferred CD4+ gut intraepithelial lymphocytes can migrate into the CNS and inhibit inflammation in recipient mice with EAE.

Article | Open Access | | Nature Communications

Serotonin is a potent stimulator of fat loss and energy expenditure in several species, includingC. elegans. Here, Palamiuc et al. identify the neuropeptide, FP-7, and its receptor in the intestine, NRP-22 as mediators of serotonergic body fat loss in worms.

Article | Open Access | | Nature Communications

Reviews & Comment

Parkinson disease is defined by its motor symptoms, but onset of nonmotor symptoms, including constipation, can start much earlier. In this Review, Klingelhoefer and Reichmann present the evidence that the pathogenesis of Parkinson disease starts in the gut and is transferred to the CNS via trans-synaptic cell-to-cell transport that initiates a cascade of α-synuclein aggregation. They also consider how this process might be triggered by environmental factors, and how these earliest stages of pathogenesis might be targeted to delay or prevent disease progression.

Review Article | | Nature Reviews Neurology

Here, Patrice Cani and colleagues discuss interactions between gut microorganisms, the endocannabinoid system and host metabolism, in the context of both physiology and pathophysiology. The authors highlight the importance of gut barrier function by discussing the role of specific factors involved in intestinal permeability and their role in the gut microbiota–endocannabinoid system axis. The therapeutic potential of targeting the endocannabinoid system to treat cardiometabolic disorders and intestinal inflammation is also discussed.

Review Article | | Nature Reviews Endocrinology

Irritable bowel syndrome (IBS) is a functional gastrointestinal disease with a high prevalence. Enck et al. describe the association between IBS and other gastrointestinal, somatic and psychiatric conditions, as well as the current view on the pathophysiology, and diagnostic and management options.

Primer | | Nature Reviews Disease Primers

IBS is the most common brain–gut disorder and a major cause of chronic abdominal pain. Here, Mayer and colleagues describe the key components of the gut–brain–microbiota axis in IBS and present a systems-based view of how these components interact to integrate the central, peripheral and behavioural IBS-related alterations.

Review Article | | Nature Reviews Gastroenterology & Hepatology

In contemporary society, the ready availability of calorie-dense, highly palatable foods has contributed to the global obesity epidemic. Individuals with obesity often consume an excess of food, despite knowledge of the associated adverse consequences. In this Review, Santa-Cruz Calvo and Egan explore the physiology of taste perception with regard to taste receptors, neuronal signalling and hormonal control of food intake.

Review Article | | Nature Reviews Endocrinology

The gastrointestinal hormones ghrelin and motilin are released during hunger to stimulate appetite and interdigestive movement of the stomach, respectively. Ghrelin and motilin receptor agonists also increase gastric emptying of meals and emerging data shows previously unknown effects on nausea and constipation. In this Review, Sanger and Furness describe the complex interactions of ghrelin and motilin with their receptors and the pathways influencing gastrointestinal functions. Finally, they describe the potential of receptor agonists to treat various gastrointestinal disorders.

Review Article | | Nature Reviews Gastroenterology & Hepatology

Neuroendocrine networks were previously perceived mainly as transcriptionally controlled, neural regulatory pathways that are centred at the hypothalamus. However, multisystemic circuits encompassing the brain and peripheral tissues have now been uncovered that involve nonneuronal cells and nontranscriptional regulatory mechanisms, with previously unidentified functions, such as reward and behaviour. Several developments in 2016 have helped to consolidate these new advances.

Year in Review | | Nature Reviews Endocrinology

In 2016, key studies have increased our understanding of the part played by the brain–gut–microbiota axis in disorders as diverse as depression, obesity and autism spectrum disorder. The data indicate that alterations in gut-microbial composition can substantially affect central physiology, and that transplantation of the gut microbiota can transfer a behavioural or physiological phenotype.

Year in Review | | Nature Reviews Gastroenterology & Hepatology

In the field of movement disorders, areas that have seen important advances in 2016 include the pathogenesis of Parkinson disease involving extra-CNS α-synuclein pathology, treatment of hyperkinetic disorders with novel dopamine-depleting drugs, and MRI-guided ultrasound surgery for the treatment of essential tremor.

Year in Review | | Nature Reviews Neurology

In 2015, four studies demonstrated that hepatic glucose metabolism is altered by targeting the farnesoid X-activated receptor in the gut, the insulin receptor in extrahepatic tissues such as the brain and an S-nitrosylation–endoplasmic reticulum-stress-dependent pathway in the liver. Targeting nutrient-dependent and hormone-dependent signalling pathways in these organs could help regulate hepatic glucose production in patients with diabetes mellitus and obesity.

Year in Review | | Nature Reviews Endocrinology

Discovering the environmental factors that control microglia is key to understanding and managing brain health. A new study finds that microbiota in the gut are essential to the regulation of microglial maturation and activation.

News & Views | | Nature Neuroscience

Bacterial residents of the human body often provide beneficial effects, but some can be harmful. The action of gut bacteria has been found to be tightly linked to neurodegeneration in a mouse model of Parkinson's disease.

News & Views | | Nature

A new study provides clues to the physiological function of amyloid-β (Aβ), the plaque-forming peptide associated with Alzheimer's disease and finds a role for Aβ in fighting infection in the brain, by entangling pathogens in a web of amyloid fibrils. These data add to a growing appreciation of the role of microorganisms in neurodegenerative disease.

News & Views | | Nature Microbiology

Metformin is currently the first-line treatment option for patients with type 2 diabetes mellitus, yet its mechanism of action remains uncertain. A new study reveals the important role for the activation of a duodenal AMPK-dependent neuronal pathway in the acute antihyperglycaemic effect of metformin and the inhibition of hepatic glucose production.

News & Views | | Nature Reviews Endocrinology

Maternal obesity has been linked to neurodevelopmental disorders in offspring but the underlying mechanisms are unclear. Buffington and colleagues now provide causal evidence linking maternal diet, gut microbiota and the central nervous system, highlighting key components of gut–brain signalling and indicating that a probiotic might relieve behavioural abnormalities.

News & Views | | Nature Reviews Gastroenterology & Hepatology

News & Research Highlights

The involvement of intestinal bacteria in gut-brain communication could help to explain the mysteries of irritable bowel syndrome, but the search continues for definitive evidence.

Outlook | | Nature

Enterochromaffin cells in the gut epithelium act as chemosensors and can modulate neural function in response to intestinal signals.

Research Highlight | | Nature Reviews Neuroscience