Proton Pump Inhibitors Kill Mitochondria And Brain Function

The Actual Dangers of Taking Proton Pump Inhibitors and What You Can Do About It

Proton pump inhibitors are very commonly given by gastroenterologists to anyone with "stomach issues".

It is probably the first thing they will give a patient before looking further into what the real cause is.

They have serious short-term and long-term downsides and are destroying our brain and our gut.

 
 

Basics

 
 

Proton pump inhibitors (PPIs) also known as acid-suppression medications (ASMs) are drugs that act on blocking proton pumps within the cell (I'll explain how this works a little further down). R

A few names of these drugs are called tenatoprazole, lansoprazole, pantoprazole, rabeprazole, esomeprazole and dexlansoprazole. R

In the US, about $11 billion of ASMs are sold annually and most are sold over the counter. R

Worldwide, there are approximately 13.5 million people (1 out of 9 people) on PPIs, with 1 out of 4 of those people having no reason to be on PPIs. R R

They have been used clinically and are approved by the FDA to block proton pumps in the stomach. R

This blocking of these pumps in the stomach reduces stomach acid and may benefit: 

  • Asthma (from GERD) R
  • Combination therapy for H. pylori infection R
  • Dyspepsia R
  • Erosive esophagitis R
  • Esophageal cancer (highly disputed) R
  • Gastrointestinal bleeding R
  • Gastroesophageal reflux disease (GERD - studies show that 1/3 of GERD patients get no benefit from PPIs) R
  • Hyperoxia induced lung injury R
  • Nonerosive gastroesophageal reflux disease (NERD) R
  • NSAID-induced cancer and lesions R
  • Sepsis and Sepsis Shock (by inhibiting pro-inflammatory cytokines normally produced by LPSs) R
  • Some gastric ulcers (peptic ulcer disease) and bleeding associated with it R
  • Zollinger-Ellison syndrome (when a tumor in the stomach produces too much stomach acid) R

Many of the benefits shown above have been reported by conflicting studies (such as pharmaceutical companies funding those studies). R

But apart from the few possible positives, there are many detrimental downsides (which we'll discuss below).

One of the problems with PPIs is that they will be used in long term situations and are commonly given out like candy by gastroenterologists. R

It's paramount to know that PPIs have a black-box warning on them, saying that PPIs should not be used longer than 2 weeks at a time. R R

Downsides Of PPIs

1. Damage Mitochondrial Function

 
#9 in this diagram are mitochondria

#9 in this diagram are mitochondria

 

Mitochondria (the part of the cell that creates energy) is very important for cellular health of your whole body. R

Decreased mitochondrial function has been linked to almost every disease, but in this way (described below) may help with cancer. R

For example PPIs increase oxidative stress to the gut, while depleting glutathione (the body's natural anti-oxidant). R

That means PPIs increase reactive oxygen species (ROS - free radicals) by creating mitochondrial dysfunction and increasing NADPH oxidase (which can create more damaging free radicals). R

ROS can also change the structure and function of DNA, RNA, lipids and proteins. R

Essentially, PPIs kill mitochondria's ability to produce energy in every cell in the body via their own proton pumps. R

2. Damage The Brain

PPIs pass the blood brain barrier and cause problem with the brain's mitochondria as well. R

Since neurons depend on proton pumps for a number of functions, inhibiting proton pumps will inhibit some of these functions and can cause decreased brain function and increased brain fog. R

There is also a positive correlation between PPIs and increased rates of Dementia and Alzheimer's Disease (AD). R

In an analysis of 73,679 patients over 75 years old using PPIs, those using PPIs had a 73.6-77.9% increased risk of developing dementia, compared to those who had not received PPIs. R

In another analysis in Asia with 15,726 participants over 40 years old, PPI usage was correlated with significantly increased risk of developing dementia, as well as depression, high cholesterol levels, heart attacks, and hypertension. R

One reason for this is because PPIs enhance the production of amyloid-beta in the brain (the plaque that is seen in the pathogenesis of AD). R

Another reason for this is because V-ATPases are inhibited by PPIs. R

V-ATPases play a key role in the homeostasis of cellular pH and the cell's ability to hand oxidative stress. R

Another reason for this is because PPIs decrease the ability to absorb vitamin B12 (more in-depth further below). R

Poor vitamin B12 status can cause neurological damage by impaired DNA synthesis, methylation, and homocysteine neurotoxicity. R

Furthermore, many antacids may contain dietary aluminum and aluminum ingestion has shown to increase the chances of developing dementia. R

All of these (the points discussed above) increase inflammation and oxidative stress on the brain. R

PPIs also increase the chance of developing delirium (hallucinations and confusion). R

They also increase the risk of having a stroke. R

PPIs also inhibits some actions of the vagus nerve (the nerve that connects the brain to all the major organs), changing the communication between the brain and the gut. R

3. Increase Chances Of Infection

 
 

Gastric acid plays a pivotal role in the defense system to protect against ingested pathogens. R

PPIs block this and increase the chances of developing:

  • Campylobacter jejuni infection R
  • Candida overgrowth R
  • Clostridium difficile infection (and chances of developing diarrhea from it) R R R
  • Enterococcus overgrowth R
  • Escherichia Coli overgrowth R
  • Giardia R
  • Norovirus R
  • Pneumonia R
  • Salmonella infection R
  • Shigella infection R
  • Staphylococcus overgrowth R
  • Streptococcus overgrowth R

This is because of the change in the gut flora (bacteria that hang out in the gut). R

Another result of reduced stomach acid is an increase in Small Intestinal Bacterial Overgrowth (SIBO). R

SIBO is when there is too much bacteria from the colon in the small intestine. R

This is because stomach acid is necessary to prevent bacteria that normally hangs out in the colon from reaching the small intestine. R

PPI use has been shown to alter gastrointesitnal motility as well as increase intestinal permeability (leaky gut). R

PPIs can directly induce dysbiosis. R

On top of that, PPIs decrease the gut biome's diversity and allow for more oral bacteria to get into the gut. R

Combining PPIs with broad spectrum antibiotics may increase all the problems described above. R

PPIs can also increase the risk of developing pneumonia by 3x (since there are more foreign bugs in the body). R R

PPIs may also increase the risk of developing celiac disease. R

4. Increase Chances Of Death And Liver Complications

Another complication with PPIs and SIBO is the ability to cause cirrhosis (scarring of the liver) and non-alcoholic fatty liver (NAFLD). R R R

Because of this complication, many studies have shown PPIs to to increase mortality (death) in cirrhotic patients. R

Cirrhosis from PPIs has shown to cause bacterial peritonitis (infectious fluid that builds in the abdomen). R

PPIs have also been linked to causing liver abscesses (pockets of pus in the liver). R

PPIs also increase mortality rates in elderly patients. R R

5. Decrease Bone Density

PPIs increase the risk of developing osteoporosis (less bone density in the bone). R

Use of PPIs are correlated with increase in hip, wrist, and spinal fractures, even in short term use. R

PPIs cause calcium malabsorption (the inability to absorb calcium into the body for use). R

Normally calcium is absorbed in the gut via a transport mechanism called transient receptor potential vailloid 6 (TRPV6). R

When there is very little stomach acid, the ability for calcium to get absorbed via TRPV6 is significantly decreased. R

PPIs also decrease the ability for certain drugs that promote bone density from working (such as the drug alendronate, which is stated to help with Paget's Disease and osteoperosis). R

6. Cause Malnutrition

 
 

On top of calcium malabsorption, PPIs cause decreased absorption of iron. R

This is because stomach acid and vitamin C in the body make the absorbable form of iron. R

PPIs stop this process by not allowing stomach acid to get acidic (it needs to be at a pH of less than 3) enough to convert the primary form of iron (ferric iron) into a soluble/available form (ferrous). R

Deficiency in iron can lead to iron-deficient anemia. R

PPIs also have shown to lower hemoglobin levels. R

PPI use is associated with low vitamin B12 (cobalamin) levels. R

Vitamin B12 is a protein-bound vitamin that requires stomach acid and pepsin to be released from the foods so the gut biome can metabolize it. R

By PPIs ability to lower stomach acid, the vitamin is not readily available and this is one reason why there is decreased absorption of vitamin B12. R

Deficiency in B12 can lead to B12-deficient anemia. R

Stomach acid is necessary to make amino acids from consumed protein. R R

Since PPIs lower stomach acid, there is less breakdown of protein to amino acids, which can make you deficient in protein for muscle development. R

This can cause muscle wasting AKA sarcopenia. R

For example, PPIs significantly increase serum creatinine levels (a marker for waste product that comes from the normal wear and tear on muscles of the body). R

PPIs can also cause hypomagnesaemia (which is excessively low magnesium levels). R

This is because PPIs can inhibit the magnesium intestinal transport (necessary to absorb magnesium in the gut). R

7. May Cause Thyroid Problems and Seizures

PPI-associated hypomagnesaemia has shown to increase the chance of having seizures. R R

This is because hypomagnesaemia can either increases parathyroid hormone (PTH) secretion or fully inhibit PTH secretion. R R

This causes hypoparathyroidism. R

This can be exacerbated by having a mutation in the TRPM6 or TRPM7 gene. R R

Hypomagnesaemia can also cause muscle twitching, weakness, convulsions, and cardiac arrhythmias. R

8. Increase Risk of Heart Disease

PPIs increase the risk of heart attack by 1.16 times. R R

They also increase the risk of having death from a heart-related event by 2x. R

In patients with coronary artery disease (CAD), PPIs increase the chance of hypertension, atrial fibrillation, heart failure and death. R

9. Increase Chances of Developing Diabetes

 
 

PPIs inhibit the pancreas's ability to secrete necessary enzymes to break down food. R R

Because of this, it increases the rate of developing chronic pancreatitis (CP - inflammation of the pancreas). R

This causes a loss of enzyme production (such as amylase, trypsin, and bicarbonate secretion) and loss of beta-cell function. R

Destruction of beta-cells is a main staple of diabetes and insulin resistance. R

PPIs also increase the risk of developing pancreatic cancer. R

Also in the pancreas, PPIs have shown to increase the risk of developing bile stones. R

10. May Cause Kidney Failure

PPIs can cause chronic kidney damage and chronic kidney disease (CKD). R

Acute interstital nephrtiis (AIN - inflammation of the spaces between renal tubules in the kidneys) is the most common problem seen with PPI usage. R

For example, in a long term study done with 572,661 patients without history of kidney disease, the risk of AIN was 5x higher for PPI users than non-users. R

PPIs can also cause electrolyte imbalances. R

This is because PPIs change the excretion of antidiuretic hormone (ADH - the hormone that signals urination). R

11. Increase Risk For Certain Cancers

PPIs have shown to cause cancer and other rare gastrointestinal tumors. R

They are correlated with increasing chances of gastric cancer and colon cancer. R

There are also conflicting studies showing that PPIs do not reduce the risk of esophageal cancers. R

PPIs can also cause polyps. R

12. Increase Risk of Developing Depression

 
 

PPIs may increase the risk of developing depression. R

For example, in the Women’s Health Initiative, those who took PPIs had poorer health, had a higher prevalence of depression. R

Reasons for developing depression may be related to the ability to cause dysbiosis and damage the brain (both discussed above). R

13. Induce Weight Gain

In the same study (from Women's Health Initiative) patients also had a higher association with obesity, cigarette smoking, and alcohol consumption. R

Also, in other studies, PPIs have shown promote weight gain in patients. R R

It does this by changing the gut microbiome, specifically by increasing Firmicutes (bacteria that induces weight gain) and lowering Bacteriodetes (induces weight loss). R R

14. Damage The Skin

PPIs decrease melanogenesis in melanocytes (cells that produce pigmentation of the skin). R

This can increase risks to developing vitiligo. R R R

15. Worsen Allergies

As we discussed above, PPIs can increase gut permeability, which allows more small peptide antigens to be absorbed into the gut. R

This makes you more sensitive to food allergens. R

For example, patients that went on PPIs for 3 months had increased plasma IgE (immune response to an allergen) levels and new food-specific IgE levels. R

16. Disrupt Sleep

 
 

PPIs have not shown to fully stop stomach acid secretion at night and can also cause nocturnal acid breakthrough (NAB - acid reflux during the night). R

For example, among patients taking PPIs twice per day, nearly 40% had to increase their dosage because of persistent nocturnal symptoms. R

Among those, only 50% of those found relief. R

There is also evidence for PPIs to disrupt clock genes (genes that control your 24hr circadian rhythm). R

17. May Have Rebound Effects

Going off PPIs can have rebound effects such as:

  • Increased chance of developing GERD, dyspepsia, heartburn, and acidic regurgitations R
  • Increased chance of developing stomach ulcer and ulcer bleeding R
  • Increased chance of developing carcinoid tumors R
  • Increased gastric acid secretion (rebound acid hypersecretion - RAHS) R R R

Alternatives To PPIs

 
 

Transient lower esophageal sphincter relaxations (TLESRs or TLOSRs) are the main reason for developing GERD. R R

Cannabinoids can reduce TLESRs and help with GERD by enhancing the vagus nerve's tone. R R

Also, blocking the 5-HT3 receptor or GABAB receptor agonists would help GERD by reducing TLESRs . R

Usually "reflux" may be caused by problems with naturally produced digestive enzymes. R

First, this can be solved by proper food combining.

Taking HCL acid (or apple cider vinegar) and bile can help. R

If that doesn't work, then a stronger digestive enzyme can be taken. R

Using the right probiotics can help (see below). R R

Diet

Eating a diet high in fibers (such as the ones below) can prevent GERD and ulcers. R

Fix The Cause

Lifestyle changes can be made to fix the underlying cause.

Substitutes for ASMs

If You Must Go On A PPI

If you must go one one, it is paramount to get certain blood levels checked every few weeks:

Also it is a good idea to check to see if you have a H. Pylori infection. 

It is a bad idea to go on a nonsteroidal anti-inflammatory (NSAID), as that will increase the inflammation of the PPI on the gut.

You also want to supplement and do some things that will counteract some of the negatives of PPIs:

Mechanism Of Action

 
https://www.ncbi.nlm.nih.gov/pmc/articles/PMC5101661/figure/Fig1/

https://www.ncbi.nlm.nih.gov/pmc/articles/PMC5101661/figure/Fig1/

 

Simple:

  • PPIs increase oxidative stress on the cells in the body and brain, as well as mitochondria, hindering their natural activities.
  • They also lower the body's natural defense against consumed pathogens, and may increase the chances of developing bad bacteria (dysbiosis) in the gut or small intestinal bacterial overgrowth (SIBO).
  • The reduction in digestive enzymes as well as dysbiosis, lowers the body's ability to absorb nutrients. 

Advanced:

  • Acid suppression medications (ASMs) can be divided into two groups: proton pump inhibitors (PPIs) and H2-receptor antagonists (H2RA). R
  • They can be delivered orally (enteric-coated tablets, gelatin capsules or coated granules) or by intravenous (IV). R
  • Short-acting PPIs normally have a serum half-life of 2 hours, whereas long-acting ones have a half-life around 7 hours. R
  • PPIs bind covalently to cysteine residues on the H+/K+ ATPase and act to inhibit acid secretion (for up to 36 hours). R
  • They are degraded by P450 enzymes and inhibit the CYP2C19 or CYP3A4 pathway, so they may interact with some drugs, like anti-platelet drugs. R R
  • The metabolites are excreted in urine or via bile. R
  • Also PPIs reduce the absorption of some drugs that need stomach acid to get into the body. R
  • In the brain, PPIs can cross the blood–brain barrier and block the vacuolar-type ATPase proton pumps (V-ATPases). R
  • By blocking V-ATPases, this  results in increased pH of microglial lysosomes, leading to decreased degradation of Aβ by microglial phagocytosis. R
  • PPIs inhibit ATP7A gene expression, decrease TYR, TRP1, TRP2, and increase copper chelating activity. R
  • Blocking TYR and similar pathways can increase the chances of developing Parkinson's Disease (PD). R
  • There are also case reports of PPIs interacting with PD drugs like Levodopa. R
  • PPIs decrease solubility of Tyrosine kinase inhibitors (TKIs). R
  • PPIs also inhibit TNF-alpha and IL-1b secretion by Toll-like receptors (TLRs). R
  • PPIs block of K+ efflux and consequent inhibition of NLRP3 inflammasome activation. R
  • Families Streptococcoceae, Micrococcoceae, genus Rothia and species Lactobacillus salivarius are increased in participants using PPIs. R
  • In GERD, there is an increase in Neuropeptide Y (NPY), decrease in proopiomelanocortin (POMC) expression in the hypothalamus, decrease in orexin expression and higher levels of ghrelin. R
  • Also in GERD, there is high levels of TRPV1 expression that is related to both nerve growth factor and glial cell derived neurotrophic factor. R
  • Some PPIs can inhibit T-cell-originated protein kinase (TOPK). R
  • PPIs can increase blood pressure by using up nitrates. R
  • For example, PPIs inhibit dimethyl arginine dimethyl amino hydrolase (DDAH) activity. R
  • DDAH metabolizes asymmetric dimethyl arginine (ADMA), which is an endogenous and competitive inhibitor of nitric oxide synthase (NOS). R
  • PPIs can induce colitis (IBS like pain) via increased expression of collagen. R

More Research

  • Gastro ulcers are extremely frequent (up to 100 %) in patients submitted to hepatic intra-arterial chemotherapy. R
  • Proton pump inhibitors enhance the effects of cytotoxic agents in chemoresistant epithelial ovarian carcinoma. R
  • During chemotherapy for breast cancer, using PPIs intermittently may be the best way to use them. R
  • Proton pump inhibitors are associated with a reduced likelihood for sexually transmitted diseases in women in the emergency department. R
  • Infants prescribed antacids have increased risk of fractures during childhood. R