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Page 1, 2, 3 Abstract

Three main, interrelated reasons for widespread digestive disorders in the modern world might be chronic metabolic acidosis, low exocrine pancreatic function, and intestinal dysbiosis. Chronic metabolic acidosis mainly distresses two alkaline digestive glands: the liver and pancreas, which secrete alkaline bile and pancreatic juice with a great amount of bicarbonate. The acidic shift in the bile and pancreatic juice pH can cause serious biochemical/biomechanical problems. The pancreatic digestive enzymes need an alkaline milieu to function properly; therefore, low pH disables their activity. This may be the crucial cause of indigestion. Acidification of the pancreatic juice decreases its antimicrobial activity, promoting intestinal dysbiosis. Reducing the pH of the pancreatic juice can lead to the premature activation of the proteolytic enzymes inside the pancreas, potentially leading to pancreatitis. The acidification of bile produces bile stone formation and precipitates aggressive bile acids, which irritate the entire biliary system. An aggressive combination of the acidic bile and the pancreatic juice can activate irregular spasms of the duodenum's walls and consequent bile reflux into the stomach and the esophagus. The normality of the exocrine pancreatic function is the core of proper digestion. Presently, there is no efficient and safe treatment for enhancing exocrine pancreatic function. Reinstating normal acid-base homeostasis can be a pathophysiological therapeutic approach for numerous gastrointestinal disorders. There is strong scientific research and practical evidence that restoring the HCO3− capacity in the blood can improve digestion. Introduction

The interrelated combination of chronic metabolic acidosis, low exocrine pancreatic function, and intestinal dysbiosis can explain the widespread digestive disorders in the modern world. Altogether, these causes create a vicious circle.1There is not enough time for genetics to be implicated in these disorders; therefore, many scientists and doctors pay attention to environmental factors, such as food, water, stress, lifestyles, toxic chemicals, alcohol consumption, and the inner ecology.



The acid-base balance, or acidity/alkalinity balance, is a critical factor in the health and functioning of the body. Optimal health depends on the body's ability to maintain a slightly alkaline state. Pathophysiology of Metabolic Acidosis

Normally, blood is slightly alkaline, with a pH range of 7.35 to 7.45. The consistency of the blood pH is essential to the body's ability to maintain a relatively stable internal environment. Its importance is demonstrated by the fact that a human being cannot live if the blood's pH goes below 7.0 or above 8.0. For example, blood with a pH of 6.95, which is only slightly acidic, can lead to coma and death.



Many body functions are designed to control the acid-base balance, including respiration, digestion, circulation, excretion, and cellular metabolism. The acid-alkaline regulation systems are interrelated and work together to prevent acute or chronic changes in the body's acid-base balance.



What causes the body to be too acidic? The main persistent factors are: The creation of too many acidic materials by human cells. For instance, the end products of cellular metabolism are amino acids, fatty acids, carbonic, and lactic acids.

Intestinal dysbiosis (candidiasis and SIBO-small intestine bacterial overgrowth) causes an intensive, constant, fermentation process through the release of lactic acid, toxic alcohols, and other acidic compounds.

Diet-induced chronic metabolic acidosis caused by the consumption of processed foods, red meat, sugars, white flour and rice, and others.

Chronic toxicity caused by acid-forming compounds, such as alcohol, some medications, environmental chemicals, and others.

Dysfunction of the lungs, kidneys, skin, liver, and gastrointestinal organs, which are responsible for releasing acidic radicals.

Dehydration and poor microcirculation.

Chronic deficiency of the major electrolytes such as sodium, magnesium, potassium, and calcium.

Low capacity of blood buffer systems and, specifically, the low capacity of bicarbonate buffer. The CO2-bicarbonate buffer system (or the "bicarbonate buffer") is the main buffer system in the blood. It works as lung◊ CO2 + H2O <–>H2CO3<–>H+ + HCO3 − ◊kidney.



The pH of blood is steady, and human beings struggle to maintain a stable state to protect the vital organs, such as the brain, lungs, and heart, which completely stop if the pH in the blood drops even slightly. During metabolic acidosis, human beings make the intelligent choice to survive by saving the life important organs, such as the heart, lungs, and brain at the expense of peripheral "less essential" organs and tissues. The alkaline digestive glands pancreas and liver are affected most by changes in the blood pH because they manufacture pancreatic juice and bile, which are generally highly alkaline solutions. Negative Effect of Metabolic Acidosis on Pancreatic Juice, Bile, and the Entire Digestive System

Under normal conditions, the pH of liver bile is 7.5 to 8.8, and the pancreatic juice has a pH of 7.1 to 8.2.2 Consequently, the liver, gallbladder, and pancreas are the inner organs, directly involved in the body's acid-base balance. On the other hand, metabolic acidosis alters the bile and pancreatic pH in an unhealthy way, leading to serious digestion problems. The Importance of Bicarbonate

To maintain the alkalinity of the pancreatic juice, the bile, the liver, and particularly the pancreas extract bicarbonates and minerals from the blood. The bicarbonate content is a key reason for the alkalinity of bile and pancreatic juice. Content Of Bicarbonate (mEq/Liter) in Human Plasma, Pancreatic Juice, and Bile 3 Body Fluid Bicarbonate Blood (plasma) 27 Pancreatic Juice 92–145 Bile 45 As seen in bile, and particularly in pancreatic juice, there is a lot of bicarbonate. The pancreatic bicarbonate output and duodenum pH are strongly interrelated. The interaction of digestive hormones, primarily secretin and cholecystokinin, with the autonomic nervous system regulates this very complicated mechanism.4,7,8



The researchers found that the pancreas and liver extract bicarbonate ions mostly from the blood. For instance, intravenously administered bicarbonate labeled with the C radioisotope appears rapidly in the pancreatic juice.11 Experiments showed that "most if not all the bicarbonate of pancreatic juice must come from plasma." 4-6 There is substantial evidence that in pancreatic disorders there is a decreased amount of bicarbonate in the pancreatic juice and bile.7, 9



Duodenal acidity primarily depends on a lesser amount of bicarbonate in the pancreatic juice and bile. In chronic pancreatitis patients with exocrine pancreatic insufficiency, the duodenal pH is persistently low.7,10 The pancreatic enzymes work only in the alkaline milieu. The Optimal pH for the Activity of Pancreatic Digestive Enzymes 36 Pancreatic Digestive Enzymes Enzyme Optimal pH Lipase 8.0 Trypsin 7.8–8.7 Amylase 6.7–7.0 Therefore, the acidic milieu in the duodenum where general digestion occurs is a central factor of indigestion. There is also a direct connection between the bicarbonate concentration and pancreatic juice flow and the elimination of enzymes.11,12



McClave believed that while healthy people have a high bicarbonate concentration in the duodenum, patients with chronic pancreatitis have low bicarbonate concentrations. In this case, the acidic fluid in the duodenum inactivates enzymes. Pancreatic lipase stops working if the duodenal pH is <4.5.8



Talamini adds a new possible risk factor for pancreatic cancer after chronic pancreatitis; namely, duodenal acidity. Patients with chronic pancreatitis frequently present with pancreatic exocrine insufficiency combined with a persistently low duodenal pH in the postprandial period. Duodenal acidity may raise the risk of pancreatic cancer in patients with chronic pancreatitis.10



The relationship between the rate of low pancreatic HCO3− secretion and high plasma H+-ion concentration has been investigated in numerous experiments. A proportional relationship was found between HCO3− secretion and plasma pH. Different relationships were discovered between pancreatic HCO3− secretion and plasma HCO3− concentration during metabolic acidosis. Pancreatic HCO3− secretion fell to 41 ± 4% of that of the control during acidosis. The plasma H+-ion concentration, therefore, seems to determine the rate of pancreatic HCO3− secretion. 35



The importance of plasma bicarbonate is also illustrated by in vivo experiments in which pancreatic secretion was studied under conditions of metabolic acidosis. Canine pancreatic secretion was halved when the plasma bicarbonate was lowered to 16 mEq/L. 13 Trypsinogen Activity and pH

Acidity also promotes the premature activation of trypsinogen (inactive enzyme) to trypsin (active enzyme) in the pancreatic ducts. Trypsinogen, like all other zymogens, is packaged in zymogen granules, which further retard trypsinogen activation. The high pH (an alkaline state) in the duct inhibits activation of trypsin.14,15 The more alkaline the pancreatic juice, the higher the possibility of keeping trypsin inactive within the pancreas. Even a neutral pH of 7.0 can lead to this activation pathway. 16



Niederau and Grendellin suggested that the acidification of the pancreatic juice may play a role in the progression of acute pancreatitis.17 Bhoomagoud et al. also suggested that metabolic acidosis may be a risk factor for developing pancreatitis. They confirmed experimentally in vivo and in vitro that decreasing pH (acidifying) increases the sensitivity of the acinar cells to zymogen activation.18



Both experimental and clinical observations suggest that acidosis may increase the risk of developing acute pancreatitis. Hegyi et al. further demonstrate that the failure of pancreatic ductal bicarbonate secretion (i.e., a decrease of the luminal pH) can increase the risk of or lead to pancreatitis. 37



Magnesium is an alkalized mineral. Thus, it can attenuate the intracellular activation of proteases in the pancreas and lessen the severity of experimental pancreatitis when administered either intravenously or as a food supplement. A multicenter randomized controlled trial of magnesium sulfate in the prevention of post-ERCP pancreatitis shows the benefits of magnesium. 38 Flushing Inactive Pancreatic Enzymes Stops Their Premature Activation

Another protective mechanism to prevent the premature activation of trypsinogen to trypsin inside the pancreatic duct is rapidly sweeping out zymogens from the pancreas. Washing out and draining pancreatic juice that is full of inactive enzymes and zymogens (trypsinogen) to the duodenum as quickly as possible is an essential mechanism to prevent premature activation of digestive enzymes inside the pancreas. This flushing mechanism is significant in protecting the pancreas from premature activation of the proteases and self-digestion and thus from the development of recurrent acute and chronic pancreatitis.



The duct cells lining the pancreatic duct secrete ions, fluid, and bicarbonate. A high concentration of ions causes water to enter the lumen by osmosis. Afterward, water flushes the contents of the pancreatic duct lumen (including zymogens) out of the pancreas and into the intestine. On the other hand, a low bicarbonate output can reduce the amount of water within the pancreatic ducts. This in turn raises the viscosity of the pancreatic juice and slows its elimination.



Matsuno et al. mentioned that bicarbonate plays a critical role in the viscosity of pancreatic juice. In patients with pancreatitis in which bicarbonate secretion and bicarbonate output declined, the viscosity of the pancreatic juice was considerably increased. They also believed that concentrated pancreatic juice can cause the progression of chronic pancreatitis. 7 Acidification of Bile and Bile Refluxes

Bile secretion has similar regulatory and closed pathways for pancreatic juice. If the bile becomes extra acidic, it turns out to be very "aggressive." Precipitated bile acids in acidic bile corrode and irritate the bile and pancreatic ducts, the gallbladder, the ampulla of Vater, the sphincter of Oddi, and the duodenum.



Irritations of the duodenum's mucosa by precipitated bile acids lead to erosion, ulcers, and spasmodic, chaotic contractions, which dislocate the aggressive bile/pancreatic juice mixture. This causes spasms, bile reflux, refractory heartburn, irritation, inflammation, ulcers, and other symptoms. In a review of the refractory gastroesophageal reflux disease literature, Fass mentioned that experimental data support a role for persistent bile acids in the reflux as a potential factor involved in refractory heartburn.40



Aggressive, acidic bile/pancreatic juice mixtures often cause bile reflux, or backflow, into the pancreatic duct. Bile from the duodenum can flow upward, into the stomach and esophagus. Bile refluxes, which involve the duodenum, stomach, and esophagus, lead to inflammation, ulcers, and cancer.19 Bile reflux often occurs along with stomach acid reflux, and together they are a horrible pair, inflaming the lining of the esophagus and potentially increasing the risk of esophageal cancer.20,21



Biliary pancreatic reflux occurs when the bile returns to the pancreatic duct. It activates proteolytic enzymes within the pancreas, and initiates acute pancreatitis and/or exacerbates chronic pancreatitis.



Rege and Moore found that the acidification of bile is a major factor in the development of gallbladder stones, which have been documented to block the bile and pancreatic ducts and severely damage the liver and pancreas. 22 Page 1, 2, 3