The Complex Interplay Between Gut-Brain, Gut-Liver, and Liver-Brain Axes

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The Complex Interplay Between Gut–Brain, Gut–Liver, and Liver–Brain Axes
Copyright Page
Dedication
Contents
List of contributors
Preface
Acknowledgments
Introduction
I. Gut-brain axis
1 The pathophysiology of gut–brain connection
1.1 Introduction
1.2 The anatomical entity
1.3 The functional entity and the role of microbiota
1.4 The pathological entity
1.5 Conclusion
References
2 The interactions between gut and brain in gastrointestinal disorders
2.1 Introduction and anatomo-physiological background
2.2 Clinical presentation of the disorders of the gut–brain interaction
2.2.1 Gastroduodenal motility
2.2.2 Impaired gastric accommodation
2.2.3 Gastroduodenal sensitivity
2.2.4 Gastroduodenal inflammation and mucosal permeability
2.2.5 Visceral hypersensitivity in irritable bowel syndrome
2.2.6 Altered gastrointestinal motility in irritable bowel syndrome
2.2.7 Gut microbiota dysbiosis in irritable bowel syndrome
2.2.8 Immune activation and alteration in mucosal permeability in patients with irritable bowel syndrome
2.2.9 Postinfection irritable bowel syndrome
2.3 Therapy of main disorders of the gut–brain axis
2.3.1 Treatment of functional esophageal disorders
2.3.1.1 Mechanism of action of pain modulators
2.3.1.2 Pain modulators in the treatment of functional esophageal disorders
2.3.1.3 Other pain modulators
2.3.1.4 Psychological interventions in functional esophageal disorders
2.3.2 Treatment of functional dyspepsia
2.3.2.1 General and dietary recommendations
2.3.2.2 Pharmacological treatment of functional dyspepsia
2.3.2.3 Antisecretory drugs and antacids in the treatment of functional dyspepsia
2.3.2.4 Centrally active neuromodulators in the treatment of functional dyspepsia
2.3.2.5 Use of prokinetics in functional dyspepsia
2.3.2.6 Fundus relaxing drugs
2.3.2.7 Alternative and nonpharmacological treatment
2.3.3 Treatment of irritable bowel syndrome
2.3.3.1 Diet and physical activity in irritable bowel syndrome
2.3.3.2 Modulators of gut microbiota in irritable bowel syndrome
2.3.3.3 Treatment of irritable bowel syndrome with predominant constipation
2.3.3.4 Treatment of irritable bowel syndrome with predominant diarrhea
2.3.3.5 Treatment of abdominal pain in irritable bowel syndrome
2.3.3.6 Treatment of bloating
2.3.4 Alternative therapies and psychological interventions
References
3 The interactions between gut and brain in psychiatric and neurological disorders
3.1 Introduction
3.2 Development of gut microbiota
3.3 Pathways of brain–gut–microbiota interaction
3.3.1 Immune pathway
3.3.2 Vagus nerve
3.3.3 Microbial metabolites
3.4 Tryptophan metabolism
3.5 Endocrinologic pathway
3.6 Microbial neural substrates
3.7 Neuropsychiatric disorders affected by brain–gut interplay
3.7.1 Autism spectrum disorder
3.7.2 Schizophrenia
3.7.3 Depression
3.7.4 Parkinson’s disease
3.7.5 Alzheimer’s disease
3.8 Psychiatric disorders in gastrointestinal diseases
3.9 Conclusion
References
4 The role of serotonin and its pathways in gastrointestinal disorders
4.1 Role of serotonin in the physiology of digestive and extradigestive systems
4.1.1 Main functions of 5-HT in extradigestive systems
4.1.1.1 Central nervous system
4.1.1.2 Platelets
4.1.1.3 Blood vessels
4.1.2 Serotonin in gut physiology
4.1.2.1 Secretory functions
4.1.2.2 Emesis
4.1.2.3 Gut motility
4.1.2.4 Immune system
4.2 5-HT receptors, serotonin transporter, and their polymorphisms
4.2.1 5-HT receptors and serotonin transporter
4.2.1.1 5HT1 receptor
4.2.1.2 5-HT2 receptor
4.2.1.3 5-HT3 receptor
4.2.1.4 5-HT4 receptor
4.2.1.5 5-HT5 receptor
4.2.1.6 5-HT6 receptor
4.2.1.7 5-HT7 receptors
4.2.2 Serotonergic system, polymorphic variants and functional gastrointestinal diseases
4.3 Serotonin in functional gastrointestinal disorders and the brain–gut axis
4.3.1 Serotonin in functional gastrointestinal disorders
4.3.2 Serotonin in the brain–gut axis
4.4 Serotonin, psychological/psychiatric and extra-gastrointestinal comorbidities
4.5 Serotonin and microbiota, the brain–gut axis and the psychobiota
4.5.1 Serotonin and microbiota
4.5.2 Serotonin in the brain–gut axis and the psychobiota
4.6 Conclusion
References
II. Gut-liver axis
5 The pathophysiology of gut–liver connection
5.1 Regulation of intestinal permeability
5.1.1 The intestinal mucosa structure
5.1.2 The “leaky gut”
5.1.3 Assessment of epithelial barrier dysfunction
5.1.4 Therapeutic potential of intestinal mucosa regulation
5.1.5 Regulation of intestinal permeability by inflammatory cytokines
5.1.6 Regulation of intestinal permeability by gut microbiota
5.1.7 Regulation of intestinal permeability by diet
5.2 Role of altered intestinal permeability in the pathogenesis of NAFLD
5.2.1 Gut microbiota and NAFLD
5.2.2 Role of the leaky gut in the progression of NAFLD
5.2.3 Influence of liver homeostasis on intestinal barrier function
5.3 Role of incretins in NAFLD
5.3.1 Physiological effects of incretins
5.3.2 Effects of incretins on hepatic glucose and lipid metabolism
5.3.3 Effects of incretins on NAFLD and NASH
5.3.4 The role of inhibitors of dipeptidyl peptidase-4 activity
5.3.5 The role of incretin co-agonists
5.4 Alteration of bile acid pathways in NAFLD
5.4.1 Bile acid synthesis and metabolism
5.4.2 Effects of the FXR/FGF-19 pathway on NAFLD and glucose and lipid metabolism
5.4.3 Bile acid receptors as therapeutic targets in NAFLD
References
6 The role of gut microbiota in chronic liver diseases
6.1 Introduction
6.2 Metabolic liver disease
6.3 Primary sclerosing cholangitis
References
7 Gut-liver The role of serotonin and its pathways in hepatic fibrogenesis
7.1 The state of the art
7.2 Serotonin synthesis and metabolism
7.3 Serotonin receptors
7.3.1 5-HT1A
7.3.2 5-HT1B
7.3.3 5-HT1D
7.3.4 5-HT2A
7.3.5 5-HT2B
7.3.6 5-HT2C
7.3.7 5-HT3
7.3.8 5-HT5
7.3.9 5-HT7
7.4 The natural course of chronic liver disease
7.5 Serotonin and liver fibrogenesis
7.6 Serotonin and hepatocellular carcinoma
7.7 Gut microbiota
7.8 Serotonin and gut microbiota
7.9 Conclusions
Acknowledgment
References
III. Liver-brain axis
8 Gut–liver–brain axis in chronic liver disease with a focus on hepatic encephalopathy
8.1 Introduction
8.2 Gut–brain axis in health and liver disease
8.2.1 Changes of gut–liver–brain axis in progression of liver disease
8.3 Pathogenesis of hepatic encephalopathy
8.3.1 Dysbiosis
8.3.2 Neurotoxins
8.3.3 Impairment of neurotransmission
8.3.4 Systemic response to infections and neuroinflammation: proinflammatory mechanisms
8.3.5 Shunting
8.3.6 Sarcopenia
8.4 Clinical relevance and presentation of hepatic encephalopathy
8.4.1 Classification
8.4.2 Diagnostic tests
8.4.3 Relevance of hepatic encephalopathy
8.4.3.1 Hepatic encephalopathy and fitness to drive
8.4.3.2 Hepatic encephalopathy and quality of life
8.4.3.3 Hepatic encephalopathy and sleep disorders
8.4.3.4 Hepatic encephalopathy in clinical scoring systems
8.5 Treatment options
8.5.1 General management
8.5.2 Diet
8.5.3 Treatment of precipitating factors of hepatic encephalopathy
8.5.4 Shunting
8.5.5 Differentiated step-by-step pharmacotherapy
8.5.5.1 Lactulose (nonabsorbable disaccharides)
8.5.5.2 Rifaximin
8.5.5.3 Branched-chain amino acids
8.5.5.4 L-ornithine L-aspartate
8.5.6 Intensive care aspects of hepatic encephalopathy
8.5.7 Treatment of posttransjugular intrahepatic portosystemic shunts hepatic encephalopathy
8.5.8 Prevention of overt hepatic encephalopathy
8.6 Recent advances
8.6.1 Medications in cirrhosis and microbial changes
8.6.1.1 Probiotics
8.6.1.2 Fecal or intestinal microbiota transplantation
8.7 Outlook
References
9 The gut microbiota in hepatic encephalopathy
9.1 Introduction
9.2 Defining hepatic encephalopathy
9.3 Ammonia as a driver of hepatic encephalopathy
9.4 Classifying HE by cause of hyperammonemia
9.4.1 Hyperammonaemia in the brain
9.5 The role of inflammation
9.6 The gut microbiome in health and disease
9.7 Gut dysbiosis in cirrhosis
9.8 Drug use in cirrhosis contributes to dysbiosis
9.9 How dysbiosis drives systemic inflammation and HE
9.10 Directly altering the gut microbiome improves outcomes in HE
9.11 Conclusion and future directions
References
10 The gut–liver–brain axis: dietary and therapeutic interventions
10.1 Introduction
10.2 Routes of communication between periphery and brain
10.3 Gut–brain axis dysregulation in liver disease
10.4 Changes in brain function and behavior in liver disease
10.5 Therapeutics targeting gut–liver–brain axis
10.5.1 Therapeutics targeting the gut microbiome
10.5.1.1 Diet
10.5.1.1.1 Polyunsaturated fatty acids
10.5.1.1.2 Polyphenols
10.5.1.1.3 Dietary patterns
10.5.1.1.4 Prebiotics
10.5.1.2 Probiotics
10.5.1.3 Fecal microbial transplantation
10.5.2 Therapeutics targeting antiadhesion molecules and cytokines
10.5.2.1 Antiadhesion therapies
10.5.2.2 Anticytokine therapies
10.5.3 Therapeutics targeting neural transmission
10.5.3.1 Antidepressants
10.6 Concluding remarks
References
Index
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