Chloride is the most important extracellular anion in the human body — it is the essential component of the hydrochloric acid (HCl) in the gastric juice, where it is secreted by the parietal cells of the stomach at concentrations of approximately 150mEq/L, creating the highly acidic environment (pH 1.5-3.5) that is essential for the protein digestion, for the mineral ionisation, for the activation of the pepsinogen to pepsin, and for the antimicrobial defence in the stomach. The chloride is actively transported from the blood into the gastric parietal cells by the chloride channel (CFTR or TMEM16A), and it follows the secreted hydrogen ions (which are pumped by the H+/K+-ATPase into the gastric lumen) to form the HCl. Without adequate chloride and functional chloride channels, the HCl secretion is impaired, the gastric pH rises (becomes less acidic), and the hypochlorhydria develops — the hallmark of the chloride deficiency and the primary cause of the protein malabsorption, the mineral malabsorption, and the small intestinal bacterial overgrowth (SIBO) that are associated with the low stomach acid. The typical dietary chloride intake is 3-6g daily (from the table salt, the processed foods, and the vegetables), and the estimated minimum requirement is 2.3g daily for adults — but the chloride deficiency is common in people with the chronic vomiting, with the nasogastric suction, with the diuretic therapy, and in the elderly (who have the reduced gastric acid secretion as part of the normal ageing process). The chloride deficiency should always be suspected in people with the chronic hypochlorhydria, the protein malabsorption, and the recurrent digestive symptoms.
Chloride and the Hydrochloric Acid Secretion
The parietal cells of the stomach secrete the HCl by the H+/K+-ATPase (the proton pump) and by the chloride channel — the H+/K+-ATPase pumps the hydrogen ions from the parietal cell into the gastric lumen in exchange for the potassium ions, creating the highly acidic environment. The chloride channel allows the chloride ions to follow the hydrogen ions into the gastric lumen, maintaining the electroneutrality and forming the HCl. The chloride channel is regulated by the cAMP (cyclic AMP) and by the calcium signalling pathways — the histamine, the acetylcholine, and the gastrin all stimulate the gastric acid secretion through these signalling pathways, and they all require the functional chloride channel to secrete the HCl. Without adequate chloride and functional chloride channels, the HCl secretion is impaired regardless of the stimulus, and the hypochlorhydria develops. The hypochlorhydria is one of the most common and most underdiagnosed digestive problems — it affects up to 30-50% of the population over the age of 60, and it is associated with the protein malabsorption, the mineral malabsorption (particularly of the calcium, iron, and zinc), the bacterial overgrowth in the stomach and the small intestine, and the increased risk of the gastrointestinal infections.
The clinical importance of the chloride for the gastric acid secretion is underscored by the observation that the chronic use of the proton pump inhibitors (PPIs, such as the omeprazole, the pantoprazole, and the esomeprazole) is associated with the hypochlorhydria, the protein malabsorption, the mineral deficiencies, and the increased risk of the gastrointestinal infections — because the PPIs inhibit the H+/K+-ATPase and thereby reduce the HCl secretion, creating a functional chloride deficiency state in the stomach. The long-term use of the PPIs is also associated with the increased risk of the Clostridioides difficile infection, of the community-acquired pneumonia, of the bone fractures, and of the vitamin B12 deficiency — all of which are consequences of the persistent hypochlorhydria and of the impaired nutrient absorption that are associated with the PPI use.
Practical Application
For general chloride supplementation, the evidence-based approach is to ensure the adequate dietary salt (sodium chloride) intake — the chloride is obtained primarily from the table salt and from the processed foods that contain the added salt. The estimated minimum chloride requirement is 2.3g daily for adults, and this is easily achieved with a normal diet that includes the salt. For the people with the hypochlorhydria (whether due to the ageing, to the PPI use, or to the chloride deficiency), the supplementation with betaine hydrochloride (which is a source of the hydrochloric acid that can help to restore the gastric pH) may be beneficial — the typical dose is 650-2000mg of betaine hydrochloride taken with the protein-containing meals, starting at the low dose and increasing gradually until the beneficial effect is achieved. For comprehensive digestive and nutrient absorption support, chloride pairs well with the zinc (which is required for the gastric acid secretion and which is often deficient in people with the hypochlorhydria), with the vitamin D (which has immunomodulatory effects and which is important for the gut barrier function), with the glutamine (which is the primary fuel for the intestinal epithelial cells and which supports the gut barrier integrity), and with the probiotics (which can help to restore the healthy gut microbiome and which can help to prevent the bacterial overgrowth that is associated with the hypochlorhydria).
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