Role of Probiotics in PPI-induced Gastroparesis: A Review

Gastroparesis refers to a disorder of deranged digestive function of the proximal gastrointestinal tract with evidence of abnormally extended retention of gastric contents in the absence of apparent mechanical obstruction. (1) The clinical presentation comprises postprandial fullness, early satiety, nausea, and bloating. Abdominal discomfort is identified as one of the most pervasive symptoms of this disease (2). Recent research indicates that idiopathic gastroparesis (IG) constitutes the most common etiology of this disease. However, strong associations are found with diseases like diabetes and in patients post surgeries and post-infections. (1)

Tracing the link between the use of medications and gastroparesis, experts now affirm that using proton pump inhibitors (PPIs) (3) can contribute to gastroparesis.

PPIs and gastroparesis-An Established Interaction

PPIs are one of the most widely used groups of medications for Gastroesophageal reflux disease, peptic ulcer diseases, and functional dyspepsia. Scientific studies show that PPIs delay gastric emptying of solids from the gut. The mechanisms are summarized below. (4)

• Impaired Peptic Digestion-Reduced gastric acidity due to PPIs deactivates pepsin and impedes the hydrolytic process, extending the time for ingested particles to remain in the stomach. The "acid-pepsin maldigestion hypothesis" is the long-held concept for explaining PPIs-induced impairment of gastric emptying of solids.
• Hypochlorhydria-induced Hypergastrinemia-PPI-induced hypochlorhydria results in a compensatory, mild rise in serum gastrin concentrations. It is pointed out that the slowing of gastric emptying under the hypergastrinemic state is directly related to the hyperacidity induced by gastrin. 

From symptomatic treatment to managing the root cause of gastroparesis -How far have we come?

Till recently, Treatment for gastroparesis was symptomatic only, with a co-prescription of drugs like prokinetics, antiemetics, and neuromodulators to control the symptoms. But with increasing reports of drug-drug interactions (due to concurrent metabolism by liver cytochrome P-450 enzymes), the potential risks associated with these pharmacological classes are a matter of concern. (1) To overcome such complications associated with conventional symptomatic pharmacotherapy, research has shifted focus on rationalistic and pathophysiologic options in managing gastroparesis. Probiotics have emerged as a viable option for managing the disease more efficiently.

Probiotics- Overview of Use in GI Diseases- Over the last decade, the molecular knowledge of gastroparesis has advanced substantially, documenting the established role of the loss or dysfunction of the interstitial cells of Cajal (1). A large body of research also reveals an innate immune dysregulation in gastroparesis, concluding that immunological interactions may be causing injury to the enteric nervous system (ENS) and ICC. (1)

Interestingly, for a long time, probiotics have been utilized as therapy in various indications such as antibiotic-associated diarrhea, travelers' diarrhea, irritable bowel syndrome (IBS), Helicobacter pylori infection, lactose intolerance, and intestinal motility disorders owing to their ability to influence the GI tract's functionality and restore the natural bacterial microflora. (5)

Can probiotics be the answer to overcoming the challenges in PPI -induced gastroparesis?

Potential Mechanisms of action of probiotics (5) -

• Modulation of GI immunity through alterations in inflammatory cytokine profiles, suppression of proinflammatory cascades, or induction of regulatory mechanisms in a strain-specific manner.
• Displacement of gas-producing, bile salt-deconjugating bacterial species leads to potent inhibition of pathogenic bacterial adhesion.
• Modification of bacterial flora by acidification of the colon by nutrient fermentation.
• Enhancement of the gut epithelial barrier function.
• Induction of m-opioid and cannabinoid receptors in intestinal epithelial cells and,
• Reduction of visceral hypersensitivity, spinal afferent traffic, and stress response.

Deciphering evidence: Supporting Studies on the Efficacy of Probiotics in Gastroparesis

• Wang et al. assessed the effectiveness of the multi-strain probiotic containing Lactobacillus on gastric emptying function (6). The study included healthy volunteers, divided into two groups, who were given probiotics and placebo capsules twice daily after meals for three weeks with crossover in the subsequent three weeks. The study results indicated that multi-strain Lactobacillus probiotics are safe and could accelerate gastric emptying in healthy individuals efficiently. The team further elaborated that the Lactobacillus probiotics could potentially treat pathological gastric emptying delays, notably in diabetic gastroparesis.
• Studies (7) highlight that probiotics may help decrease gut transit time. A recent systematic review and meta-analysis concluded that administration of probiotics reduced gut transit time by 12 hours and increased stool frequency by 1.5 stools/wk and improved constipation-related symptoms.
• Cherbut et al. (1997) noticed that the motility of the terminal colon rises while sleeping in humans supplemented with Lactobacillus casei. (8)
• Marteau et al. (2002) reported Bifidobacterium lactis strain DN 173010 to reduce colonic transit time in healthy female individuals. Waller et al. (2011) explained that whole gut transit time (WGTT) decreased in a dose-dependent manner in males and females treated with different doses of Bifidobacterium. (8)

Key pointers-

• Gastroparesis is described as a delay in gastric emptying (GE) when the gastric outlet is not mechanically obstructed.
• With evolving research, the treatment options for gastroparesis have undergone drastic changes-from combined drug therapies (aimed at managing the symptoms only) with more pathophysiologic therapeutic options (aimed at alleviating the underlying cause) like probiotics.
• Research has consistently supported the efficacy of probiotics in managing gastroparesis and related complications.
• Physicians should keep an open eye on the ongoing promising studies on probiotics to be able to identify and manage PPI-induced Gastroparesis more effectively.

The way forward- An in-depth understanding of genetic, microbial, and environmental triggers will aid in understanding the onset of gastroparesis and other upper gastrointestinal motility disorders. With more research focusing on the disease, the last few years have witnessed a complete change in our knowledge of the clinical presentation and management of gastroparesis. To summarize, advances in the previous decade have resulted in a better understanding of gastroparesis and a better treatment option for managing this morbid condition.

Growing evidence on the potential of probiotics and continued future research on this promising field will help physicians get to a stage where gastroparesis may be treated more precisely, successfully, and therapeutically, thus, improving patient care.

The above article has been published by Medical Dialogues under the MD Brand Connect Initiative. For more details on Probiotics, click here.

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