The long term use of stomach acid-lowering drugs such as proton pump inhibitors (PPIs) in the cystic fibrosis (CF) population, both adults and children, has been common for approximately 20 years. Today, more than 50% of CFers are using PPIs[i]. They are used for two main reasons: to treat gastroesophageal reflux and to improve supplemental pancreatic enzyme activation, particularly lipase. However, there are flaws in the reasoning for use of acid-lowering drugs in both of these situations. Firstly, the cause of reflux is not excessive secretion of stomach acid but dysfunction of upper gastrointestinal (GI) motility and secretions[ii], and further reducing gastric acidity with PPIs or antacids will further exacerbate reflux, causing a dependency on the drugs and worsening symptoms over time. Furthermore, the long-term use of PPIs has significant and far-reaching side effects that can negatively affect CF prognoses. Secondly, although several preliminary studies have demonstrated that the pH of the duodenum can be too low to provide the right environmental for supplemental pancreatic enzyme activation, it is not completely clear that bicarbonate secretion is inadequate in all cases, even if steatorrhea is present. A 2014 Cochrane Review of the use of PPIs in CF found that related clinical trials were not only biased, but showed zero or overall insignificant improvement in gastrointestinal symptoms[iii]. In fact, there may be other mechanisms at play within the duodenum that cause steatorrhea and contribute to low duodenal pH, namely inadequate bile secretion, possibly due to a diet low in bitter plant constituents. Here, I will discuss the issue of gastroesophageal reflux disease (GERD) in CF and the negative consequences of using PPIs to treat it. I will also discuss the many negative side effects of long term PPI use in the CF and general populations. In addition, I will discuss the low bicarbonate theory in its relationship to pancreatic enzyme activation, and how the use of PPIs may not be helpful in this situation. Lastly, I will discuss the role of bitter plant constituents in stimulating release of GI hormones and bile in the duodenum, their relationships to macronutrient absorption, and how the use of bitter tastants in the CF population may kill two birds with one stone: addressing GERD by correcting gastric sphincter function and GI secretions, and improving lipase activation by stimulating release of bile which emulsifies fats and stimulates bicarbonate secretion.
Gastroesophageal Reflux Disease
Gastroesophageal reflux disease is a common complaint in the CF population. Possible causes for the prevalence of GERD include frequent antibiotic use (for treatment of respiratory infections) that disrupts the gastrointestinal microbiome[iv], and the Standard American Diet and CF diet recommendations. These diets are high in low-quality fats (i.e. industrial seed oils) and refined carbohydrates, guaranteeing a shift in the gut microbiome[v] that can also contribute to GERD. Another likely contributing factor of GERD in CF is a low-plant diet. In terms of GERD treatment, the use of PPIs and other acid-lowering drugs actually makes GERD worse over time and significantly increases the likelihood of patients becoming increasingly dependent on PPIs to address symptoms of reflux. Reflux coincides with low stomach acid in the majority of cases[vi] [vii] [viii], because the lower esophageal sphincter (LES) closes upon release of gastrin[ix] and exposure to stomach acid, preventing acid from moving upward into the esophagus. Episodes of reflux are most commonly the result of transient lower esophageal sphincter relaxations (TLESRs) that happen during stomach distention and subsequent gas release after meals, and are exacerbated with consumption of fermentable carbohydrates[x] [xi]. This could mean that excessive bacterial carbohydrate fermentation due to intestinal dysbiosis is a likely comorbidity in reflux diseases, and therefore the most sustainable treatment method would be to correct the underlying dysbiosis with dietary, herbal, and lifestyle changes.
Most health care practitioners still believe that reflux is caused by excessive stomach acid production, thus many practitioners rely almost exclusively on acid-lowering drugs to treat GERD. PPIs work by blocking the gastric acid pump in the parietal cells of the stomach from secreting protons[xii]. By blocking acid secretion they can produce a short-term reduction of acid reflux into the esophagus by reducing total gastric acid load. However, studies have also shown that low stomach acid (hypochlorhydria) contributes to delayed gastric emptying (gastroparesis)[xiii] [xiv], which is a major contributing factor of stomach distention and subsequent weakening of the LES, leading to TLESRs[xv]. Gastroparesis is a fairly common complaint in cystic fibrosis, especially in children, and is likely due to hypochlorhydria. Therefore, taking acid-lowering drugs reduces LES tone, allowing stomach acid to continually reflux up into the esophagus with no way to suppress tissue damage by the acid except with more acid-lowering drugs, creating a vicious cycle and drug dependency.
In addition to over-relaxation of the LES, long term PPI use can result in protein malabsorption and protein-bound nutrient deficiencies, since gastric acid is an essential part of protein digestion. This is especially concerning for CFers who commonly already have protein and fat malabsorption issues. Gastric acid digestion of protein is an important first step in protein digestion before proteases (contained in pancreatic enzymes) can work effectively. Furthermore, a number of insidious nutrient deficiencies can result from hypochlorhydria including vitamin B12 deficiency, iron deficiency and anemia, calcium deficiency and osteopenia, and magnesium deficiency[xvi] [xvii].
Moreover, having low stomach acid significantly increases the risk of gastric and enteric infections from pathogens such as Clostridium difficile[xviii], which have become more common in the CF population, especially during hospitalizations[xix]. Stomach acid is a primary barrier against infection of the human digestive system, and low stomach acid can lead to dysbiosis[xx]. A multi-center study showed that in children, acid-suppressing drugs increased the risk of both GI infections and community-acquired pneumonia, likely due to disruption of the microbiome and interference with normal white blood cell activity[xxi]. Acid-lowering drugs dampen the immune response by effecting leukocyte activity, especially the bactericidal activity of neutrophils[xxii].
Lastly, use of PPIs in the CF population increases the frequency of pulmonary exacerbations[xxiii] likely due to increased risk of aspiration of stomach acid and bile acids, as well as functional changes in white blood cell activity. In GERD, not only is LES tone reduced, but often pyloric sphincter tone is also reduced, allowing bile acids to move from the duodenum into the stomach and reflux into the esophagus. One study found that bile acids were present in 86% of the aspirate of people with GERD, compared to 58% in normal subjects, with aspiration worst after meals and laying down[xxiv]. Another study found that people with advanced lung disease are more likely to aspirate bile acids, which contribute to further lung injury[xxv]. Bile acid reflux and aspiration is higher in CF than in healthy controls, with post-transplant patients at even higher risk. Bile acid reflux also corresponded to unexplained cough episodes in the CF study group. PPI use doe not help patients with bile acid reflux[xxvi], and may even exacerbate it. Mucosal damage is much greater when bile acids are present in refluxate compared to acid reflux alone, and a major cause of alkaline (bile acid) reflux is gallbladder removal[xxvii] and/or inadequate choleresis. Cholecystokinin (CCK) is a hormone released when the GI tract detects fats or bitter substances, and is responsible both for the closure of the pyloric sphincter and release of bile from the gallbladder[xxviii]. Without adequate secretion of CCK (due to a diet deficient in bitter plants and/or fats) the pyloric sphincter may not close properly and bile acid reflux may result. A slow leakage of bile from an unstimulated gallbladder, or from the liver when the gallbladder has been removed, can contribute to bile acid reflux when pyloric sphincter tone is weak. Furthermore, proteolytic enzymes are activated when pH is above 2 for pepsin, and 5 for trypsin, and so if these activated enzymes are refluxed into the esophagus and possibly aspirated, this can cause even greater mucosal damage[xxix]. This is another important reason why gastric pH must be kept acidic: to prevent activated enzyme reflux.
Duodenal Acidity and Pancreatic Enzyme Activation
The second reason that PPIs are used in CF is that some studies have shown duodenal pH to be excessively acidic[xxx] [xxxi]. It has been theorized that deficient pancreatic bicarbonate secretion is responsible for this. In vitro and animal studies have shown that mutations in the CFTR do impair bicarbonate secretion[xxxii]. Although several studies have measured duodenal pH in the CF gut, I could find none that measured bicarbonate secretion directly. Therefore, the mainstream assumption that bicarbonate secretion is inadequate in the CF gut is largely unsupported by scientific evidence. By raising gastric pH, PPIs subsequently raise the pH of chyme leaving the stomach, providing a more alkaline environment for supplemental enzymes’ enteric coating to break down (which dissolves above a pH of 5.8) and preventing the enzymes from being denatured at a pH of 4.0 or below[xxxiii]. While taking PPIs may indeed help bring the pH of chyme to a level appropriate for enzyme activation, the effect that they have on reducing overall stomach acid levels will produce all of the side effects previously mentioned when used long term. Using these drugs for the purpose of enhancing fat absorption will conversely reduce absorption of protein and protein-bound nutrients. Furthermore, studies have shown duodenal pH in CFers varies greatly, and in some it is normal[xxxiv]. Clinical experience has shown that introduction of PPIs does not guarantee improved fat absorption but instead may create serious side effects with long-lasting or permanent consequences[xxxv].
In CF, an alternative reason why fat malabsorption may be present (even concurrent with PPI therapy) is deficient bile production and/or bile flow, given that some CF patients may develop liver and/or gallbladder pathologies, or functional inadequacies. Bile is a critical part of fat digestion as it emulsifies fats, breaking them into micelles so that lipase can further break them down into fatty acids for absorption into the portal vein. Without adequate bile, supplemental lipase may not work effectively. I propose that a major cause of fat malabsorption in CF is inadequate bile secretion due to a common absence of bitter constituents in the CF diet. Bile itself has a moderately alkaline pH of between 6 and 8.5 [xxxvi], therefore it may contribute somewhat to the neutralization of acid in chyme entering the duodenum. Furthermore, the presence of bile stimulates the release of pancreatic bicarbonate into the lumen[xxxvii], therefore bile secretion may also have an indirect role in neutralizing the acid in chyme. In addition, the presence of acidic chyme entering the duodenum stimulates the secretion of secretin, a hormone that stimulates bicarbonate release from the pancreas, bile production in the liver, and inhibits gastrin and stomach acid secretion[xxxviii]. If the chyme entering the duodenum is not acidic enough (due to hypochlorhydria and/or PPI use) to trigger the release of secretin, this may further impede mechanisms to alkalize the duodenum. It is therefore possible that fat malabsorption in CFers taking pancreatic enzyme supplements is due not from a pathological inability to produce enough bicarbonate, but from a functional (and therefore reversible) bile deficiency, or even hypochlorhydria. I will next discuss how bitter plant constituents may help with these issues.
Bitter Plant Constituents’ Roles in Aiding Digestion in CF and Beyond
Mainstream nutritional recommendations given to CF patients emphasize calories from fat, protein, and refined carbohydrates at the expense of foods that are high in phytonutrients but low in calories (i.e. vegetables and fruits). One important class of plant constituents contained in many vegetables, especially leafy greens, is bitter tastants. Bitter compounds in plants, especially wild plants or gently bred food crops like kale or arugula, include lactones, iridoids, and alkaloids[xxxix]. Bitter compounds agonize the TAS2R bitter taste receptors located on the tongue, all along the GI tract, on immune cells, on respiratory cells, and even in the brain[xl] [xli]. The human digestive system coevolved with these bitter constituents in plants and the lack of them in the modern diet can cause significant functional deficiencies that lead to gastrointestinal distress and malabsorption, especially in populations who already have primary GI pathologies, such as cystic fibrosis.
Bitter taste receptor stimulation has cascading effects mediated by the vagal nerve. In the GI tract, agonism of bitter receptors stimulates the release of CCK, which stimulates gastric secretions, bile release, insulin production, pancreatic enzyme secretion, and eventually leads to bicarbonate release from the pancreas[xlii]. Bitter stimulation and release of CCK will also constrict the pyloric sphincter, preventing alkaline reflux[xliii]. Human coevolution with plants created these responses to prepare the digestive tract for potentially harmful plants ingested, as maximization of digestive secretions ensures reduced ingestion and optimal metabolism of toxic chemicals, many of which taste bitter. With a deficiency of bitter tastants in the diet, the GI tract lacks the cues it needs to stimulate adequate release of GI secretions, leading to low stomach acid, poor fat metabolism, deficient pancreatic enzyme release in the non-CF population, sluggish hepatic metabolism, inadequate bicarbonate release, and acid/alkaline reflux. That is, in general, a lack of bitters can lead to indigestion. Increased GI secretions with bitter taste receptor stimulation means more efficient digestion of food and increased nutrient absorption, two things that the CF population is generally very concerned about.
In several studies on healthy humans and animals, agonism of the bitter taste receptors reduces appetite, induces feeling of satiation earlier in the meal, and slows gastric emptying[xliv]. However, in populations with already decreased appetite and delayed gastric emptying, as in many people with CF, bitter taste stimulation seems to have the opposite effect, increasing appetite and possibly even hastening gastric emptying[xlv]. The amphotericity of bitter tastants may be due to the fact that in many people with CF gastrointestinal secretions are reduced at baseline, leaving one ill-prepared for a meal. But when stimulated with a bitter tastants, secretions may increase to physiologic levels, which may have a positive effect on appetite and gastric emptying.
To stimulate GI secretions and to prepare the digestive tract for an impending meal, bitter tastants from plants can be taken by mouth 5-15 minutes before a meal. This can be in the form of a salad of bitter greens like arugula or dandelion greens, or a medicinal preparation (often alcohol extract) of bitter herbs like gentian root, dandelion root, motherwort, artichoke leaf, yellowdock root, and many others. It is traditional in many cultures for a pre-meal appetizer to feature bitter or pickled foods or herbs before the main course as a digestive aid. If the individual currently suffers from painful GERD symptoms and/or is using PPIs, introduction of bitters may need to slow as the GI tissue is encouraged to heal with soothing anti-inflammatory herbs, and as the individual is slowly weaned off of PPIs.
It is clear that there is indeed great promise for the use of bitter tastants in the management of GERD, enhancement of fat absorption, and improvement of appetite and gastric emptying in CF patients. This is especially true since pharmaceutical options for treatment of these issues, such as PPIs, are inadequate at best and iatrogenic at worst. Further study is needed on the use of digestive bitters as GI secretory stimulants, as well as their ability to improve clinical outcomes in gastrointestinal pathologies of CF patients.
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Mica (they/he) is a clinical herbalist, nutritionist, ecologist, and writer living in Abenaki territory (Vermont).
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