Multi-dimensional Clinical and Pathophysiological Profiles of Patients With Functional Dyspepsia and Effect of Gut Microbiota Manipulation Using Rifaximin for Its Treatment

Functional dyspepsia (FD) is a common clinical syndrome characterized by the presence of recurrent or chronic upper abdominal symptoms, such as epigastric pain, early satiety, and fullness, without any structural abnormalities on the upper gastrointestinal (UGI) endoscopy. FD is a heterogeneous disorder, in which different pathophysiological mechanisms underlie specific symptom patterns. It may result from a combination of visceral hypersensitivity, gastric motor dysfunction, and low-grade mucosal inflammation. Accumulating evidence including familial aggregation recently suggested that functional gastrointestinal (GI) disorders, including FD, might be contributed by genetic factors, identification of which may improve understanding of underlying pathophysiological mechanisms. Low-grade inflammation may play an important role in the pathogenesis of FD.

1. pylori infection may contribute to FD at least in a subset of patients. According to the current Rome algorithm, H. pylori infection needs to be eradicated before the diagnosis of FD is made in spite of the fact that a large proportion of patients do not improve in spite of its eradication. In addition to H. pylori, the gut microbiota is emerging to be an important player in the pathogenesis of several GI disorders including FD. In fact, several authors suggested that small bowel microbial dysbiosis, small intestinal bacterial overgrowth, and duodenal inflammation may be responsible for symptoms of FD. One of the reasons why H. pylori eradication may not give consistent results among patients with FD might be related to the fact that variable interaction between H. pylori and gut microbiota on gastric physiology might be an important player in patients with FD. Several experts suggested that variable effect H. pylori on gastric physiology may be related to its interaction with host factors and gut microbial dysbiosis might be responsible for variable efficacy of H. pylori eradication treatment in patients with FD. The role of gut microbial dysbiosis in patients with FD is supported by a recent randomized controlled trial from Hong Kong that showed rifaximin therapy targeted towards gut microbiota was useful in the treatment of patients with FD. One of the factors that may determine symptoms of FD, particularly the sub-type called epigastric pain syndrome is hypersecretion of gastric acid. Gastritis is associated both with hypochlorhydria and hyperchlorhydria; for example, antral-predominant gastritis is associated with hyperchlorhydria and body-predominant gastritis is associated with hypochlorhydria. Pepsinogen I and II ratio is a non-invasive method to assess the topography of gastritis, such as antral or body predominant. Pepsinogen is the inactive precursor of the gastric proteolytic enzyme pepsin. Human pepsinogen comprises two isoenzymes, pepsinogen I (or A) and pepsinogen II (or C). Pepsinogen I (PG-I) is secreted mainly by chief cells of fundic mucosa, whereas pepsinogen II (PG-II) is also secreted by pyloric glands and proximal duodenal mucosa. While serum levels of PG-I correlate with levels of acid secretion, PG-II shows an inverse relationship. Therefore, the PG-I/PG-II ratio is a useful tool to evaluate gastric acid secretion, gastritis, and intestinal metaplasia. Gastrin secretion is regulated by a negative feedback mechanism looped with acid secretion. In fact, the patients with functional gastrointestinal disorders (FGIDs) were earlier thought to be psychogenic in origin; this understanding might have resulted in the development of a belief among treating physicians/gastroenterologists that these patients are rather neurotic, apprehensive individual feigning an illness. Such erroneous belief might have resulted in disservice to these patients. However, recently accumulating evidence suggests that patients with FGIDs have several pathophysiological abnormalities in the gastrointestinal (GI) tract that might not be visualized by conventional investigations such as upper GI endoscopy but are often visible with more sophisticated tests including molecular techniques. Hence, we proposed that these disorders be called micro-organic disorders. In fact, experts in Rome Foundation in the Rome IV algorithm suggested that these disorders need to be considered as disorders of "gut-brain interaction" rather than "brain-gut interaction" reinforcing the importance of the peripheral rather than central mechanisms in the pathogenesis. Rome IV also suggests that in clinical practice, a multi-dimensional clinical profile of the FGIDs (which include the categorical diagnosis, subtype, severity, psychological factors, and physiological factors including biomarkers) needs to be uncovered before further treatment of these patients. This is a paradigm shift in understanding pathogenesis and treatment of the FGIDs including FD but needs more evidence particularly from tropical and sub-tropical areas of the World. Hence, the clinical and scientific importance of the proposed study can't be over-estimated. Functional dyspepsia (FD) is an enigmatic condition that may be contributed by a variable combination of psychosocial issues like anxiety, depression, insomnia, and micro-organic issues like Helicobacter pylori infection, gastritis, duodenitis, hypersecretion of acid, degree of gastric atrophy, gastric microbiota dysbiosis. Accordingly, we aimed to study these factors among patients with FD. Rifaximin has been shown to be useful in the treatment of FD in a recent randomized control trial from Hong Kong. Since microbiota dysbiosis may be an important issue in FD, we planned to treat them with rifaximin in a randomized placebo-controlled trial and repeat the parameters such as dyspepsia score, hospital Anxiety and Depression Scale (HADS) score, Pittsburgh Sleep Quality Index (PSQI). We wish to study the pathogenetic mechanism of FD and evaluate baseline factors that may help to predict response to gut microbiota manipulation in these patients.