Understanding Role of Probiotics in Functional dyspepsia eradication
Functional dyspepsia (FD), regarded as a chronic disorder characterized by recurrent or persistent upper abdominal symptoms that occur mainly during or after meals (1), poses a challenging clinical problem among physicians. According to the Rome IV criteria, Functional dyspepsia is defined as the presence of at least one of the following symptoms: postprandial fullness, early satiation, epigastric pain, or burning, a lack of evidence of structural disease to explain the symptoms fulfilling the time criteria of the last 3 months with symptom onset at least 6 months before diagnosis and a frequency of at least 3 days per week (2)
High prevalence rates have been documented globally, ranging from 10% to 40% in Western countries and 5% to 30% in Asian countries (2). The recurrent nature of the symptoms coupled with the fact that an estimated 40% of persons suffering from FD consult a physician due to unbearable symptoms (2), makes this disease a major healthcare burden.
Considering such scenarios, this article aims to summarize the disease, its etiology, while focusing on the growing role of probiotics in managing Functional dyspepsia successfully.
Pathophysiology -What makes Functional dyspepsia difficult to treat
The typical dyspeptic symptoms in functional dyspepsia include epigastric pain, sensations of pressure and fullness, nausea, and early subjective satiety (3). The fact that in the majority of cases, symptoms disappear only to return frequently in the long-term further complicates matters.
While the exact pathophysiology of Functional dyspepsia remains to be explored, gastric motility disturbance, dysregulation of the gut-brain axis, psychological disturbances, low-grade inflammation, immune system dysfunction, and visceral hypersensitivity have been postulated as critical underlying mechanisms (2). The evidence further elaborates that intestinal flora imbalance is involved in the development of FD (2). Recent studies have shown that increased duodenal mucosal permeability is also an important mechanism of this disease .
How are probiotics effective? Summarizing the mechanism of action of probiotics-
Considering that the etiological background of Functional dyspepsia is still ambiguous, there is no definitive treatment that is beneficial to all individuals.
It has been postulated that probiotics exert their action on the GI system by inhibiting pathogenic bacteria in intestinal epithelial cells, strengthening the barrier function of the intestinal epithelium, acidifying the colon, inhibiting the growth of pathogens, regulating immunity, inhibiting visceral hypersensitivity, changing mucosal stress response, and improving intestinal motor function (2). A recent study noted  that probiotics appear to be a beneficial therapy for Functional dyspepsia by reducing the abundance of Escherichia/Shigella, a major source of toxic lipopolysaccharides, in the upper GI tract as well as restoring the change in the gastric microbiota.
The said study further addressed that the abundance of bacteria increases gradually from the stomach, duodenum to the small intestine, and probiotics improve mucosal permeability by improving abnormalities in the gut microbiota or producing short-chain fatty acids via the fermentation of intestinal contents. Thus, probiotics can directly participate, without the microbiota, in the amelioration of enhanced duodenal permeability, which is regarded to be a cause of FD . Moreover, research has shown that short-term active lactic acid bacteria treatment for diarrhea- predominant irritable bowel syndrome (D-IBS) improved mucosal barrier function. 
Recent studies focusing on the efficacy and benefits of using probiotic therapy for Functional dyspepsia have been listed below.
1. A meta-analysis carried out by Zhang et al (2) aimed at assessing the efficacy and safety of probiotics in patients with FD. The study concluded that probiotics appear to be a beneficial therapy for FD.The authors also noted that among the included studies, Lactobacillus was the most commonly used probiotic strain for the treatment of FD, followed by Bifidobacterium, Streptococcus, and Bacillus. An important observation from the results was that the combination of multiple probiotics to treat FD exerted a more obvious effect, suggesting that probiotics can be considered to restore the disordered GI microecology and improve FD symptoms.
2. Agah et al (1) performed a systematic review and meta-analysis of the currently available randomized controlled trials (RCTs) to evaluate the potential beneficial effects and risks of probiotics in functional dyspepsia. The analysis concluded that Lactobacillus strains showed potential positive effects in terms of improving upper gastrointestinal (GI) symptoms in patients with FD. Probiotic supplementation tended to improve global dyspepsia score (n = 3 RCTs, risk ratio [RR]: 1.35, 95% CI 0.99 to 1.84; P = 0.061) and bacterial composition in the GI tract. Probiotics were well tolerated without any serious adverse events. The authors elaborated that Lactobacillus reuteri significantly decreased the severity of nausea, abdominal pain, acid regurgitation, abdominal distension, and increased flatus after 8 weeks of supplementation (Emara et al., 2014). This systematic review also indicates that the effects on FD symptoms may be strain-specific; in particular, Lactobacillus gasseri and Lactobacillus reuteri species may have larger effects on GI symptoms.
3. Rousseaux C et.al (2007) assessed the ability of five well-known and representative probiotic bacteria belonging to the Lactobacillus and Bifidobacterium genera, and compared them to commensal and adherent-invasive (LF82) Escherichia coli, to induce the expression of analgesic receptors. They found that oral administration of specific Lactobacillus strains induced the expressions of µ-opioid and cannabinoid receptors in intestinal epithelial cells, and mediated analgesic functions in the gut—similar to the effects of morphine. These results suggest that the microbiology of the intestinal tract influences our visceral perception, and suggest new approaches for the treatment of abdominal pain and irritable bowel syndrome (5)
4. Zhang et.al (2020) as cited in Gudina et.al (2010) addressed that Lactobacillus paracasei can improve intestinal motility by reducing glycogen synthesis, promoting the degradation of blood lipids, interfering with energy metabolism, and normalizing the smooth muscle function of the GI tract .
5. A study by Igarashi M et al (6), aimed to comparatively analyze the gastric fluid (GF) microbiota between patients with functional dyspepsia and healthy controls (HC), and assess the effect of probiotics on the microbiota. Interestingly, the authors noted alteration in the GF microbiota in patients with FD as compared to healthy volunteers. Reflux of the small intestinal contents, including bile acid and intestinal bacteria, to the stomach, was suggested to induce a bacterial composition change and be involved in the pathophysiology underlying FD. They concluded that probiotics were effective in the treatment of Functional dyspepsia through the normalization of gastric microbiota.
● Functional dyspepsia is a major health burden with a high global prevalence.
● In the absence of an established effective cure for Functional dyspepsia, probiotics have proved to be a promising therapy.
● Physicians encountering FD patients regularly should be aware of recent updates on the various probiotics and the different beneficial strains to provide the best available cure for this disease.
How far have we come- Taking into account the etiological basis of FD, it is now apparent that antibiotics alone are not sufficient for its resolution; rather they may deplete the gut microbiota. Probiotics, backed up by accumulating research, have the potential to open up new horizons in managing FD along with the amelioration of associated symptoms. As research continues to support the rational use of probiotics in treating FD successfully, the medical fraternity should keep an open eye on the same.
The above article has been published by Medical Dialogues under the MD Brand Connect Initiative. For more details on Probiotics, click here
1. Agah, S., Akbari, A., Heshmati, J., Sepidarkish, M., Morvaridzadeh, M., Adibi, P., ... & Feinle-Bisset, C. (2020). Systematic review with meta-analysis: Effects of probiotic supplementation on symptoms in functional dyspepsia. Journal of Functional Foods, 68, 103902.
2. Zhang, J., Wu, H. M., Wang, X., Xie, J., Li, X., Ma, J., ... & Tang, X. (2020). Efficacy of prebiotics and probiotics for functional dyspepsia: a systematic review and meta-analysis. Medicine, 99(7).
3. Madisch A, Andresen V, Enck P, Labenz J, Frieling T, Schemann M. The Diagnosis and Treatment of Functional Dyspepsia. Dtsch Arztebl Int. 2018;115(13):222-232. doi:10.3238/arztebl.2018.0222
4. J. ZENG, Y.-Q. LI, X.-L. ZUO, Y.-B. ZHEN, J. YANG & C.-H. LIU Clinical trial: effect of active lactic acid bacteria on mucosal barrier function in patients with diarrhoea-predominant irritable bowel syndrome. DOI:10.1111/j.1365-2036.2008.03818.x
5. Rousseaux C, Thuru X, Gelot A, et al. Lactobacillus acidophilus modulates intestinal pain and induces opioid and cannabinoid receptors. Nat Med 2007;13:35.
6. Igarashi M, Nakae H, Matsuoka T, et al. Alteration in the gastric microbiota and its restoration by probiotics in patients with functional dyspepsia. BMJ Open Gastro 2017;3:e000144. doi:10.1136/bmjgast-2017- 000144