Treatment challenges in managing Gastroparesis related to PPI Use: Analyzing scope of Probiotics

Gastroparesis or gastric palsy is a pathological condition characterized by delayed or absent gastric emptying in the absence of mechanical obstruction (1). It is a debilitating disease causing significant psychological distress and affecting the quality of life (2). It affects about 1.3% to 1.4% of the general population (3). Systemic diseases such as diabetes, and post-surgical and idiopathic conditions are some of the causative factors for Gastroparesis. Idiopathic gastroparesis which is frequently seen in young or middle-aged women accounts for about 36% of the etiologies. (4) A high prevalence of gastroparesis has been reported in type 1 diabetics (40 %) and type 2 diabetics (10–20 %), however, delayed gastric emptying is found to be more pronounced in patients with type 1 DM.

Nausea, vomiting, early satiety, postprandial fullness, bloating, and upper abdominal distention are some of the common symptoms associated with gastroparesis.

Gastroparesis may last for over a year in patients with the viral prodrome and may take several years to resolve if associated with autonomic disorders. (4)

The use of Proton pump inhibitors (PPIs) (5), neurological disorders, connective tissue disorders, and renal insufficiency (6) are the common conditions that are known to be associated with gastroparesis.

How do PPIs induce Gastroparesis?

PPIs are used to treat various acid-related disorders like gastroesophageal reflux disease, peptic ulcer disease, and functional dyspepsia may often cause Gastroparesis by abnormal gastric emptying. (5) There are various mechanisms by which PPIs delay gastric emptying.

PPIs cause alterations in gastric motility and impair intragastric peptic digestion. PPIs by reducing gastric acidity, deactivate pepsin which in turn slows down the hydrolysis of solids leading to the persistence of indigested large food particles and causing delayed gastric emptying. PPIs-induced hypergastrinemia has also been linked to causing delayed gastric emptying (7). Pyloric fibrosis and loss of interstitial cells of Cajal may be seen in gastroparesis (8).

Tougas et al carried out a study to analyze the impact of Omeprazole on gastric emptying. They noted a significant delay in gastric emptying expressed by lag-phase duration, time to gastric half emptying, and gastric retention of meals at 60 m and 120 m after ingestion in omeprazole monotherapy. The magnitude of delay in gastric emptying ranged from 15-to 40% (9). In another study by Lim et al, it was found that PPI monotherapy was associated with a significant delay in gastric emptying. There was a 53.9% increase in T1/2 compared to baseline. This delay effect was seen by an increase in the percent of meals retained at different time intervals (10).

Ideally, therapy for gastroparesis should improve cardinal signs and symptoms, reverse cellular defects, and fasten gastric emptying. Since gastroparesis is a multifactorial disease, current treatments are mainly based on their efficacy in reducing the symptoms. Combination therapies have been proposed as different pathogenic mechanisms may coexist in the same individual (11). Interventions such as probiotics have great potential in gastroparesis therapy due to their unique mechanism of action and the production of diverse agents (12).

How do Probiotics Help?

Probiotics by definition are 'live microorganisms that, when administered in adequate amounts, confer a health benefit on the host' (13). The mechanism by which they act is varied and includes direct interactions with the gut luminal microbiota, metabolic effects that result from enzymatic activities, effects on barrier function, and interaction with the central nervous system and enteric immunity (14).

The action of Probiotics in Gastroparesis: Probiotics act by ameliorating the rhythmic contraction of the colon. (15)

Probiotics also colonize the intestine and modify the balance of the existing intestinal microflora and its metabolic activity, thus benefiting the host. The end products of Lactic acid bacteria fermentation affect the local and distal motor events (12).

It is conjectured that probiotics are effective in treating gastroparesis. Several clinical studies have focused on this effect, some of them are as follows:

• Wang et al evaluated the efficacy of the multi-strain probiotic lactobacilli capsule on gastric emptying. They enrolled 15 healthy participants which were further divided into 2 groups and were given a placebo and probiotic capsules twice a day after meals for 3 weeks with crossover in the following 3 weeks. The study noted that a multi-strain Lactobacillus capsule is safe and effective for accelerating gastric emptying in healthy adults. They further expressed that the Lactobacillus capsule has therapeutic potential for pathological gastric emptying delay, particularly in diabetic gastroparesis. (12)
• Ringel et.al analyzed the clinical efficacy of Lactobacillus acidophilus and Bifidobacterium lactis in non-constipation functional bowel disorders (FBDs). The study included sixty patients who were provided with L-NCFM and B-LBi07 twice a day over 8 weeks. The study noted that L-NCFM and B-LBi07 twice a day are effective for improving symptoms such as bloating in patients with FBDs and as well the potential role of Probiotics in managing these disorders. (16)
• A randomized study conducted by Indrio et.al analysed the putative effects of probiotics on the frequency of regurgitation and gastric emptying time in infants with functional gastroesophageal reflux (GER). They enrolled forty-two infants with regurgitation who were randomized to assume Lactobacillus reuteri per day and placebo for 30 days. The paper concluded that among infants with functional GER, L. reuteri reduces gastric distension and accelerates gastric emptying. The paper further noted that this probiotic strain appears to decrease the frequency of regurgitation (15).

Clinical Summary:

• Gastroparesis is a pathological condition characterized by the absence of or delayed gastric emptying without any mechanical obstruction.
• PPIs which are prescribed for acid related disorders can trigger gastroparesis
• Probiotics may be used to alleviate symptoms of gastroparesis like bloating and delayed gastric emptying and may open new horizons for ameliorating other symptoms of Gastroparesis.

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

References:

1. Usai-Satta P, Bellini M, Morelli O, Geri F, Lai M, Bassotti G. Gastroparesis: New insights into an old disease. World J Gastroenterol. 2020;26(19):2333-2348. doi:10.3748/wjg.v26.i19.2333

2. Syed AR, Wolfe MM, Calles-Escandon J. Epidemiology and Diagnosis of Gastroparesis in the United States: A Population-based Study. J Clin Gastroenterol. 2020;54:50–54.

3. Ohtsu T, Haruma K, Ide Y, Takagi A. The Effect of Continuous Intake of Lactobacillus gasseri OLL2716 on Mild to Moderate Delayed Gastric Emptying: A Randomized Controlled Study. Nutrients. 2021;13(6):1852. Published 2021 May 28. doi:10.3390/nu13061852

4. Camilleri M, Parkman HP, Shafi MA, Abell TL, Gerson L American College of Gastroenterology. Clinical guideline: management of gastroparesis. Am J Gastroenterol. 2013;108:18–37.

5. Moshiree B, Potter M, Talley NJ. Epidemiology and Pathophysiology of Gastroparesis. Gastrointest Endosc Clin N Am. 2019 Jan;29(1):1-14. doi: 10.1016/j.giec.2018.08.010.

6. Camilleri M, Chedid V, Ford AC, Haruma K, Horowitz M, Jones KL, Low PA, Park SY, Parkman HP, Stanghellini V. Gastroparesis. Nat Rev Dis Primers. 2018;4:41.

7. Sanaka M, Yamamoto T, Kuyama Y. Effects of proton pump inhibitors on gastric emptying: a systematic review. Dig Dis Sci 2010;55:2431–40.

8. Bekkelund M, Sangnes DA, Gunnar Hatlebakk J, Aabakken L. Pathophysiology of idiopathic gastroparesis and implications for therapy. Scand J Gastroenterol. 2019;54:8–17.

9. Tougas G, Earnest DL, Chen Y, Vanderkoy C, Rojavin M. Omeprazole delays gastric emptying in healthy volunteers: an effect prevented by tegaserod. Aliment Pharmacol Ther. 2005;22(1):59-65. doi:10.1111/j.1365-2036.2005.02528.x

10. Lim HC, Kim JH, Youn YH, Lee EH, Lee BK, Park H. Effects of the Addition of Mosapride to Gastroesophageal Reflux Disease Patients on Proton Pump Inhibitor: A Prospective Randomized, Double-blind Study. J Neurogastroenterol Motil. 2013;19(4):495-502. doi:10.5056/jnm.2013.19.4.495

11. Grover M, Farrugia G, Stanghellini V. Gastroparesis: a turning point in understanding and treatment. Gut. 2019;68(12):2238-2250. doi:10.1136/gutjnl-2019-318712.

12. Wang, Y.-F.; Huang, H.-Y.; Chiu, Y.-W.; Chao, W.-H.; Chuang, T.-L.; Lu, Y.-C.; and Lin, M.-Y. (2012) "Evaluation of multi-strain Lactobacillus capsule on gastric emptying function by Tc-99m scintigraphy in a crossover placebo-controlled clinical trial," Journal of Food and Drug Analysis: Vol. 20 : Iss. 3 , Article 20.

13. Hill, C.; Guarner, F.; Reid, G.; Gibson, G.R.; Merenstein, D.J.; Pot, B.; Morelli, L.; Canani, R.B.; Flint, H.J.; Salminen, S.; et al. Expert consensus document. The International Scientific Association for Probiotics and Prebiotics consensus statement on the scope and appropriate use of the term probiotic. Nat. Rev. Gastroenterol Hepatoll. 2014, 11, 506–514.

14. Cheng J, Ouwehand AC. Gastroesophageal Reflux Disease and Probiotics: A Systematic Review. Nutrients. 2020;12(1):132. Published 2020 Jan 2. doi:10.3390/nu12010132.

15. Indrio F, Riezzo G, Raimondi F, et al. Lactobacillus reuteri accelerates gastric emptying and improves regurgitation in infants. Eur J Clin Invest. 2011;41(4):417-422. doi:10.1111/j.1365-2362.2010.02425.x

16. Ringel-Kulka T, Palsson OS, Maier D, et al. Probiotic bacteria Lactobacillus acidophilus NCFM and Bifidobacterium lactis Bi-07 versus placebo for the symptoms of bloating in patients with functional bowel disorders: a double-blind study. J Clin Gastroenterol. 2011;45(6):518-525. doi:10.1097/MCG.0b013e31820ca4d6