Physiological Anti-Reflux Defense Mechanisms of the Esophagus
During physiological swallowing, the lower esophageal sphincter (LES) relaxes, allowing food to enter the stomach. Outside of swallowing, transient LES relaxation can occur, leading to minor and brief episodes of gastroesophageal reflux. However, the following anti-reflux mechanisms prevent the occurrence of significant gastroesophageal reflux:
Esophagogastric Anti-Reflux Barrier
This barrier is formed by the anatomical structures at the junction of the esophagus and stomach, including the LES, the diaphragmatic crura, the phrenoesophageal ligament, and the acute angle between the esophagus and gastric fundus. The LES, a 3-4 cm long circular muscle bundle at the distal end of the esophagus, generates a high-pressure zone at the esophagogastric junction, preventing gastric contents from refluxing into the esophagus.
Esophageal Clearance Mechanisms
Under normal conditions, when gastroesophageal reflux occurs, most of the refluxed material is returned to the stomach through 1-2 spontaneous or secondary peristaltic contractions of the esophagus, a process known as esophageal clearance. Any remaining reflux material is neutralized and washed away by saliva.
Esophageal Mucosal Barrier
When refluxed material enters the esophagus, the esophageal mucosal barrier, consisting of saliva, stratified squamous epithelium, and a rich submucosal blood supply, protects the esophageal mucosa from damage.
Gastric Mucosal Barrier
The gastric mucosal epithelium is invaginated to form gastric glands. The pyloric glands, located in the gastric antrum and pyloric region, are highly branched and coiled tubular mucus glands containing numerous endocrine cells. These glands are the primary source of mucus and gastrin (also known as gastric acid-stimulating hormone). The oxyntic glands, found in the gastric fundus and body, are less branched and consist of chief cells, parietal cells, neck mucus cells, and endocrine cells. These glands, also known as acid-secreting glands, are the primary source of gastric acid, pepsinogen, and intrinsic factor. The cardiac glands, located near the gastric cardia, are simple tubular glands that primarily secrete mucus.
Gastric juice has a pH of approximately 0.9-1.5, with a normal secretion volume of 1.5-2.5 L/day. In this acidic environment, pepsinogen is activated. Despite frequent exposure to pathogenic microorganisms and irritants, the gastric mucosa remains intact, maintaining a steep pH gradient of 1,000-fold between the gastric lumen and the mucosa. This integrity is attributed to three levels of the gastric mucosal barrier:
Pre-Epithelial Layer
This layer consists of a 0.5 mm-thick mucus gel and bicarbonate layer covering the gastric epithelial cells. It protects the epithelium from concentrated hydrochloric acid, pepsin, pathogens, and other irritants or damaging substances, maintaining a high pH gradient between the acidic gastric juice and the neutral mucosa.
Epithelial Cells
The apical membranes of epithelial cells and their tight junctions act as a barrier against acid back-diffusion and harmful factors in the gastric lumen. These cells regenerate rapidly, replacing themselves every 2-3 days, and can quickly repair damage. Epithelial cells produce inflammatory mediators and contain intraepithelial lymphocytes, which are vital components of mucosal immunity.
Sub-Epithelial Layer
Gastric mucosal cells have limited glycogen reserves and low energy production capacity under hypoxic conditions. Therefore, adequate oxygen and nutrient supply are essential for maintaining mucosal integrity. A rich capillary network in the gastric mucosa supports the high secretory activity and constant renewal of epithelial cells. It also removes local metabolic byproducts and reabsorbed hydrochloric acid, ensuring mucosal health. Prostaglandin E plays a protective role in gastric mucosal cells by promoting blood circulation, mucus secretion, and bicarbonate production. It is currently recognized as a key molecule in mucosal protection.
Gastric Acid Secretion and Regulation
Food stimulates the gastric antrum, prompting G cells in the pyloric glands to secrete gastrin. Gastrin acts in both endocrine and paracrine manners on enterochromaffin-like (ECL) cells in the gastric body, stimulating histamine secretion. Histamine and gastrin bind to histamine H2 receptors and gastrin receptors on parietal cells, respectively, promoting the synthesis and secretion of hydrochloric acid. Somatostatin secreted by D cells in the gastric antrum exerts negative feedback regulation on all three cell types involved in this process.
The secretion of hydrochloric acid by gastric parietal cells occurs in three main steps:
- Histamine, acetylcholine, and gastrin stimulate their respective receptors on parietal cells.
- Within parietal cells, hydrogen ions are generated through pathways mediated by cAMP or calcium ions.
- The H+-K+-ATPase enzyme, also known as the proton pump, located in the secretory tubules and vesicles of parietal cells, pumps hydrogen ions against their concentration gradient into the gastric lumen.
Additionally, acetylcholine from the enteric nervous system modulates the functional states of parietal cells, G cells, and D cells through neuroendocrine mechanisms, resulting in significant variations in the regulation of gastric acid secretion.
Intestinal Mucosal Barrier
The intestinal mucosal barrier plays a critical role in protecting the body during its interaction with large amounts of food and the symbiotic microorganisms within the intestinal lumen. This barrier effectively prevents the translocation of commensal bacteria and their metabolites from the intestinal lumen to surrounding tissues and organs, thereby protecting the body from endogenous microorganisms and their toxins. The intestinal mucosal barrier is a unified structure-function system that isolates the contents of the intestinal lumen from the internal environment of the body, maintaining internal stability. It consists of the mechanical barrier, chemical barrier, immune barrier, biological barrier, and intestinal motility.
Mechanical Barrier
The mechanical barrier is composed of intestinal epithelial cells, tight junctions between these cells, and the mucosal biofilm. This structure is the most critical component of the intestinal barrier.
Chemical Barrier
The chemical barrier includes gastric acid and bile salts, which inactivate a large number of bacteria entering the intestine via the oral route. It also consists of mucus and digestive fluids secreted by intestinal epithelial cells, as well as antimicrobial substances produced by the normal gut microbiota.
Immune Barrier
The intestine serves as a major peripheral immune organ in the body. The immune barrier is composed of gut-associated lymphoid tissue (including intraepithelial lymphocytes, lamina propria lymphocytes, and Peyer's patches), mesenteric lymph nodes, Kupffer cells in the liver, secretory antibodies (sIgA) produced by plasma cells, and defensins secreted by immune cells. This barrier plays a vital role in both innate and adaptive immunity.
Innate immunity is a rapid, diverse defense mechanism that the body is born with. It lacks immunological memory and responds similarly to repeated exposure to the same pathogen.
Adaptive immunity is initiated when specific lymphocytes recognize foreign antigens. It involves lymphocyte proliferation and differentiation into effector cells. Although slower to activate, it is characterized by immunological memory and specificity, thereby enhancing and complementing the functions of innate immunity.
Biological Barrier
Details regarding the biological barrier are covered under the section on Intestinal Microecology.
Intestinal Motility
Intestinal motility acts as a "cleaner" for the gut. Conditions such as intestinal obstruction or paralysis are often accompanied by bacterial overgrowth in the small intestine.
Intestinal Microecology
Intestinal microecology comprises bacteria, fungi, viruses, and their metabolites, collectively referred to as the "second genome" of the human body. The human gut alone contains over 1,000 species of bacteria, numbering approximately 1012-1014, which is ten times the number of human cells. The genes of gut bacteria number around 3.3 million, which is 150 times the number of human genes. The ratio of anaerobic to aerobic bacteria in the gut is approximately 100-1,000:1. Anaerobic bacteria rarely translocate and inhibit the growth of potential pathogens, while aerobic bacteria are more prone to translocation and serve as a primary source of endotoxins in the circulation.
Gut microbiota can be broadly categorized into three groups:
Probiotics
These include anaerobic bacteria like Bifidobacterium and Lactobacillus, which are essential for human health. They adhere to the mucus layer, synthesize various vitamins, participate in food digestion, promote intestinal motility, prevent pathogenic bacteria from contacting intestinal epithelial cells, and degrade harmful substances.
Opportunistic Pathogens
These include bacteria like Escherichia coli and Enterococcus, which have dual roles. Under normal circumstances, they benefit health; however, uncontrolled proliferation or translocation to other parts of the body can lead to disease.
Harmful Bacteria
These include pathogens like Shigella and Salmonella, which can cause various diseases or impair immune system function when they proliferate excessively.
Factors such as age, sex, genetic background, geography, diet, exercise, and medications influence intestinal microecology. Through co-evolution, microorganisms and humans have developed a symbiotic relationship characterized by mutual dependence. Interactions among microorganisms, as well as between microorganisms and the host, significantly influence host physiological functions. The intestinal mucosal barrier and intestinal microecology have a bidirectional regulatory relationship, where each impacts the other. Intestinal microecology influences processes such as nutrition, metabolism, immunity, development, and aging. Notably, the effects of intestinal microbiota extend far beyond the gastrointestinal system, including impacts on the gut-liver axis and the gut-brain-microbiota axis.
Functions of Intestinal Microbiota
Metabolic Function
Intestinal microbiota secrete complex proteases, perform redox reactions, and facilitate the breakdown of food components. They also metabolize or transform endogenous and exogenous substances.
Nutritional Function
Microbiota synthesize various vitamins, amino acids, peptides, and short-chain fatty acids. Their metabolic products promote the absorption of minerals and nutrients, thereby influencing host nutritional metabolism.
Immune Function
Intestinal microbiota regulate the development and maturation of the host's immune organs and act as broad-spectrum antigens, stimulating immune responses, including both humoral and cellular immunity.
Intestinal Defense Function
As a critical component of the intestinal mucosal barrier, microbiota prevent the invasion or colonization of potential pathogens and maintain the structural and functional integrity of the intestinal barrier. Specific components of the gut microbiota can alter the expression of tight junction proteins in epithelial cells, while microbial metabolites such as butyrate play essential roles in maintaining epithelial barrier integrity. Microbial degradation and metabolism of bile acids can modify the bile acid pool, with certain bile acids (e.g., lithocholic acid and deoxycholic acid) acting as secretagogues in the colon.
The intestinal microbiota is associated with the development and progression of various digestive diseases, including inflammatory bowel disease (IBD), functional gastrointestinal disorders, celiac disease, colorectal cancer, and nonalcoholic fatty liver disease. Additionally, it influences the pathogenesis of metabolic diseases such as obesity and type 2 diabetes, cardiovascular diseases, neuropsychiatric disorders, immune dysfunction-related conditions, and multiple organ cancers. It even modulates the efficacy of certain drug therapies.
Gastrointestinal Peptides
Endocrine cells scattered throughout the gastrointestinal tract produce more than 50 types of gastrointestinal peptides, such as cholecystokinin, somatostatin, vasoactive intestinal peptide, and substance P. The digestive tract is considered the largest endocrine organ in the body. These gastrointestinal peptides play significant and complex roles in regulating gastrointestinal secretion, motility, substance transport, immunity, and the repair of intestinal epithelial cells. They also influence the functions of other organs in the body.
Digestion and Absorption of Major Nutrients and the Metabolic Functions of the Liver
Carbohydrates
Starch from food is hydrolyzed into disaccharides by pancreatic amylase and further digested into monosaccharides by disaccharidases located on the brush border of small intestinal epithelial cells. These monosaccharides are then absorbed into the bloodstream through the small intestine. A portion of the absorbed monosaccharides provides energy for the body, while the rest is stored as glycogen in the liver and muscles. Muscle glycogen primarily serves as an immediate energy source for muscle contraction, while liver glycogen plays a key role in maintaining blood glucose levels, which is particularly critical for the brain and red blood cells. When blood glucose levels decrease, liver glycogen is broken down into glucose and released into the bloodstream to replenish glucose levels. After fasting for more than 10 hours, most of the stored liver glycogen is depleted, and the liver begins gluconeogenesis, synthesizing glucose and glycogen from proteins and fats in the body. Impaired nutrient absorption in the small intestine can lead to malnutrition, while excessive absorption of carbohydrates can contribute to obesity. Liver damage can impair glycogen synthesis, breakdown, and gluconeogenesis, making it difficult to maintain normal blood glucose levels. This explains why chronic liver diseases are often associated with diabetes.
Fats
Lipids are emulsified by bile salts in the small intestine and digested by pancreatic lipase into monoglycerides, fatty acids, and cholesterol. These are absorbed in the upper jejunum into the portal vein. Within the smooth endoplasmic reticulum of intestinal epithelial cells, long-chain fatty acids and 2-monoglycerides are re-synthesized into triglycerides. These triglycerides combine with apolipoproteins, phospholipids, and cholesterol to form chylomicrons, which enter the lymphatic system and subsequently the bloodstream. True chylous ascites occurs when small intestinal lymphatic vessels rupture. In addition to the small intestine, the liver and adipose tissue also synthesize triglycerides, with the liver playing a particularly crucial role.
Monoglycerides, fatty acids, and cholesterol entering the liver can undergo oxidative breakdown to produce energy or be converted into glycogen and glucose through gluconeogenesis. Abnormal lipid absorption, increased triglyceride synthesis in hepatocytes, and reduced triglyceride export from hepatocytes are key pathophysiological mechanisms underlying fatty liver disease.
Proteins
Proteins are hydrolyzed by gastric and pancreatic proteases into amino acids (1/3) and oligopeptides (2/3). Oligopeptides are further broken down into amino acids by oligopeptidases on the brush border of small intestinal epithelial cells. Amino acids are actively transported into cells via amino acid carrier proteins coupled with sodium ions (Na+). The γ-glutamyl cycle facilitates the transport of amino acids into intestinal cells. The absorbed amino acids (exogenous) mix with amino acids produced by the breakdown of body proteins (endogenous) to form the amino acid pool, which is distributed throughout the body. The primary functions of this pool include the synthesis of proteins and peptides. The liver synthesizes proteins for its own needs as well as albumin, certain globulins, fibrinogen, prothrombin, and coagulation factors. Amino acid catabolism mainly involves deamination, α-keto acid metabolism, and the conversion of ammonia into urea in the liver for detoxification. Undigested proteins may exhibit antigenic properties, contributing to allergic reactions or exacerbating intestinal mucosal immune diseases. Intestinal bacteria can putrefy undigested proteins, producing harmful metabolites.
Severe liver damage significantly reduces albumin synthesis, leading to edema or ascites. Hepatocyte destruction elevates serum alanine aminotransferase levels, while impaired ammonia clearance increases blood ammonia levels, a critical factor in the development of hepatic encephalopathy.
Metabolic and Detoxification Functions of the Liver
The liver is a vital organ primarily responsible for metabolism and detoxification. Its functions involve four main types of biochemical reactions:
Oxidation
Ethanol is oxidized in the liver to acetaldehyde, acetic acid, carbon dioxide, and water, a process known as oxidative detoxification.
Reduction
Trichloroacetaldehyde undergoes reduction to trichloroethanol, losing its hypnotic effect.
Hydrolysis
Hydrolytic enzymes break down various drugs or toxins through hydrolysis.
Conjugation
Conjugation is the most important mechanism of hepatic biotransformation, where drugs or toxins combine with glucuronic acid, facilitating their excretion via bile or urine.
All biochemical reactions in the liver depend on the participation of various enzyme systems within hepatocytes. In cases of severe liver disease or when portal hypertension and portosystemic shunting occur, careful consideration must be given to drug selection and dosage to avoid increasing the liver's burden and minimizing adverse drug reactions.
Coordinated Movement of the Biliary Tract
Hepatocytes produce bile, which is secreted starting from the bile canaliculi. The secretion of bile in the canaliculi is regulated by bile salt-dependent and bile salt-independent transport systems located on the apical membrane of hepatocytes. The bile canaliculi, with a diameter of approximately 1 μm, transport bile in a direction opposite to that of portal blood flow toward the canals of Hering. Bile then flows sequentially through the interlobular bile ducts, the right and left hepatic ducts, the common hepatic duct, and eventually forms the common bile duct upon merging with the cystic duct, before entering the duodenum. Epithelial cells lining the bile ducts secrete significant amounts of water and bicarbonate, which mix with bile. Together with the gallbladder, these ducts form a system for the collection, storage, and transport of bile. The sphincter of Oddi, located between the terminal bile and pancreatic ducts and the duodenal papilla, plays roles in regulating gallbladder filling, controlling the flow of bile and pancreatic juice into the duodenum, preventing reflux of duodenal contents, and maintaining normal pressure within the biliary and pancreatic systems.
The liver continuously secretes bile, but bile is only directly released into the duodenum during food digestion. During the interdigestive phase (fasting state), the sphincter of Oddi contracts, the terminal end of the common bile duct closes, and pressure within the duct lumen increases. This causes the gallbladder wall to relax, allowing bile to passively flow into and fill the gallbladder. Most of the water and electrolytes in bile are absorbed by the gallbladder, concentrating the bile and reducing its volume. The gallbladder typically stores 20-50 mL of bile.
After food intake, cholecystokinin secreted by the small intestine promotes gallbladder contraction while simultaneously relaxing the sphincter of Oddi, allowing bile to be released into the duodenum. Gallstones moving with bile within the biliary tract can lead to a wide variety of clinical manifestations. Given the irreplaceable role of the common bile duct, diseases affecting it are ideally treated using minimally invasive approaches.
Synthesis, Activation, and Physiological Mechanisms Preventing Autodigestion in the Pancreas
Under physiological conditions, multiple inactive pancreatic zymogens (e.g., trypsinogen, amylase precursor, lipase precursor, elastase precursor, phospholipase precursor, and chymotrypsinogen) and lysosomal hydrolases are synthesized in the rough endoplasmic reticulum of acinar cells and transported to the Golgi apparatus. Lysosomal hydrolases undergo glycosylation and phosphorylation and are transported to lysosomes through specific binding with mannose-6-phosphate receptors. Trypsinogen, however, does not bind to mannose-6-phosphate receptors. Through these two distinct pathways, digestive enzyme precursors and lysosomal hydrolases synthesized in the rough endoplasmic reticulum are ultimately "sorted" into different secretory vesicles, forming zymogen granules and lysosomes, respectively.
Upon various physiological stimuli, acinar cells release zymogen granules by increasing intracellular calcium ion concentrations. These zymogens are transported via the pancreatic ducts and duodenal papilla into the duodenum, where they are activated by enterokinase to perform their digestive functions. Since trypsin can activate multiple other pancreatic enzymes, the activation of trypsinogen into trypsin is the most critical step in the cascade activation of pancreatic enzymes.
Under normal physiological conditions, small amounts of trypsinogen secreted by acinar cells may become prematurely activated within the pancreas. However, specific enzyme inhibitors produced by pancreatic stromal cells (e.g., α1-antitrypsin and α2-macroglobulin) rapidly inactivate prematurely activated trypsin, thereby preventing pancreatic autodigestion.