Research trends in the field of the gut-brain interaction: Functional dyspepsia in the spotlight – An integrated bibliometric and science mapping approach

Visceral hypersensitivity and abnormal gastric motility are thought to directly contribute to FD symptoms, but other factors such as increased gastric acid secretion, infection with H. pylori, dysbiosis, psychological disorders, diet, lifestyle, and stomach shape modify those physiological abnormalities and thus modify FD symptoms. Collectively, symptoms of dyspepsia result from the above factors interacting in a complex way.

Evidence is mounting suggesting that these interactions primarily occur in the duodenum, a key organ involved in the pathophysiology of FD, where the aforementioned factors cause symptoms by affecting the organ; the duodenum is thought to be essential for regulating the physiological processes of the stomach, and in FD, gastric malfunction is thought to be secondary to duodenum stimulation, thus causing dyspeptic symptoms.

In light of the idea that gastric dysmotility and gastric hypersensitivity may be the downstream effects of duodenal pathology, recent advances have shown that FD may be caused by changes in the duodenum, such as minimal mucosal inflammation and impaired mucosal integrity (Miwa et al., 2019).

There is no consensus as to whether immune activation precedes barrier damage or vice versa, despite the repeated links between the two. Most likely, the two pathophysiological phenomena are amplified by one another, resulting in a vicious circle, making it even more complex to unravel these mechanisms (Ceulemans et al., 2022). The inflammatory infiltrate is likely to release granular components, resulting in barrier impairment. A barrier defect, however, can allow luminal substances, such as microbial components, food antigens, acids, bile acids, and lipids, to invade the intestinal tissue, triggering mucosal immune responses (Wauters et al., 2020b).

In FD, mucosal eosinophils are predominant, with mast cells infiltration often occurring alongside, despite reports of CD8⁺ cytotoxic T lymphocytes and CD68⁺CCR2⁺ macrophages as tissue cell populations (Gargala et al., 2007; Futagami et al., 2010; Burns et al., 2019a). There is therefore low-grade immune activation of the duodenum, which can be observed through elevated amounts and activation of eosinophils and mast cells (clustering and degranulation), resulting in greater duodenal epithelial permeability (Vanheel et al., 2014), challenging the notion that FD is purely psychosomatic. It was further observed that FD was associated with increased duodenal eosinophils in a majority, which do not exclusively represent either subtype of this disorder.

The initial report of duodenal eosinophil infiltration in FD has been presented in pediatric patients from the USA, although there are no controls included in this study (Friesen et al., 2002), as well as in a nested case-control study of Swedish adults (Talley et al., 2007). In this population-based study with 1,001 participants who underwent endoscopy, there was a significant positive correlation between eosinophil infiltration in the duodenum and early satiety, a defining symptom of FD and particularly PDS (Talley et al., 2007). This suggests that duodenal impairments may contribute to meal-related complaints.

Subsequent replication of these results in the UK (Walker et al., 2010) and Australia (Walker et al., 2014) confirmed a preponderance of duodenal eosinophilia in PDS. However, there is a similar prevalence between PDS and EPS in other cohorts (Walker et al., 2009; Vanheel et al., 2014; Tanaka et al., 2016).

In fact, it is estimated that up to 40% of FD patients have micro-inflammation, frequently in the form of eosinophil infiltration (Du et al., 2018). In contrast, few studies have demonstrated changes in stomach immune cell profiles, none of which are associated with symptoms of FD (Futagami et al., 2010; Li et al., 2010; Pasricha et al., 2021), confirming that dyspeptic symptoms do not directly correlate with gastric pathophysiology. Accordingly, this further strengthens the notion that the duodenum is likely to be the key pathogenic organ for FD in that impaired duodenogastric communication is induced by duodenal abnormalities therefore generating FD symptoms (Vanheel and Farré, 2013; Wauters et al., 2020a; Ceulemans et al., 2022). Furthermore, increased mast cells and degranulation was found in the duodenum of FD patients in addition to the eosinophilic infiltration (Vanheel et al., 2014; Cirillo et al., 2015; Taki et al., 2019), although these findings were not always consistent (Tanaka et al., 2016; Puthanmadhom Narayanan et al., 2021), nevertheless substantiating the concept of an eosinophil-mast-cell axis (Wechsler et al., 2021).

Chemokines regulate eosinophil recruitment into the gastrointestinal tract, with eotaxin-1 [C-C motif chemokine ligand (CCL) 11], which is constitutively expressed in the intestinal lamina propria, being one of the most important (Powell et al., 2010). Eotaxin-3 (CCL26) is another powerful eosinophil-recruiting chemokines (Weller and Spencer, 2017). Therefore, the expression of CC-chemokine receptor (CCR)-3, which binds eotaxins, is required for the recruitment of eosinophils to the intestine (Blanchard and Rothenberg, 2009).

As far as immune profiles are concerned, those of the proximal small intestine appear to be predominantly influenced by the T-helper (Th)-2 phenotype (Brown and Esterházy, 2021). IL-5 is a key component of eosinophil biology, as its expression acts as the strongest stimulator among the various Th-2 cytokines required for eosinophil activation (Keely et al., 2015). Further, increased production of IL-5 and IL-13 by stimulated lymphocytes in FD patients is consistent with the profile of a Th2-type immune response (Kindt et al., 2009). In this Belgian study, Kindt et al. (2009), specifically, reported systemic changes in both FD and IBS patients, including increased CD3⁺CD45RA⁺CD45RO⁺ lymphocytes, as compared with the control group, suggesting that naïve T cells may be in transition to a memory phenotype (Kindt et al., 2009). Further, increased levels of IL-5 and IL-13 and decreased interferon-γ (IFN-γ) production following lymphocyte stimulation was reported in the combined FD and IBS cohort when compared to controls (Kindt et al., 2009). A decrease in IL-12 production was also observed following stimulation of monocytes (Kindt et al., 2009). Therefore, there is a shift to a Th-2 cytokine response in FD, such as those observed in atopy and allergy.

Another study, by Liebregts et al. (2011), reported increased proportions of circulating gut-homing T helper cells (CD4⁺α4β7⁺CCR9⁺) and increased production of tumor necrosis factor-α (TNF-α), IL-1β, IL-6, and IL-10, despite no increase in overall Th cell levels, implying immune recruitment to the gastrointestinal tract in these patients. In addition, this study demonstrated that elevated serum cytokines and enhanced lymphocyte recruitment to the small intestine, both of which are indicative of active inflammatory states, were associated with symptoms (upper abdominal pain, cramps, nausea, vomiting, and delayed gastric emptying) in patients with FD (Liebregts et al., 2011).

Mechanistically, a compromised mucosal barrier allows pathogens and food antigens to penetrate the intestinal barrier, leading to a Th2 immune response, which then activates immune responses initiated by mast cells and eosinophils. Upon activation, mast cells and eosinophils further produce pro-inflammatory cytokines and transforming growth factors that contribute to Th1/Th2 polarization (Keely et al., 2015). In parallel, activated eosinophils function as antigen-presenting cells for Th2-lymphocytes with immunoglobulin (Ig) class-switching to IgE in B cells via IL-4 or IL-13. Importantly, eosinophils are the most widely recognized and influential effector cells during Th2 responses (Powell et al., 2010). In this regard, Th2-associated IL-5 can activate duodenal eosinophils, and the granular content released by eosinophils, such as major basic protein (MBP), may then act as a signal to activate mast cells. As a reciprocal mechanism, mast cells are also identified as recruiters of eosinophils in FD, when they are activated by IL-4 or IL-13 released from Th2 cells.

Further to this, evidence is also growing that group 2 innate lymphoid cells (ILC2s) may contribute to the recruitment of eosinophils by producing cytokines, including IL-5 and IL-13 (Larose et al., 2017). In terms of mechanism, the loss of duodenal homeostasis is accompanied by the switch from ILC3-mediated homeostasis to ILC2-dominant response (Larose et al., 2017). Expansion of ILC2 populations are therefore activated by cytokines such as IL-33, IL-25, IFN-γ, and IL-1β, as well as serine protease released by mast cells (Larose et al., 2017). In this cascading inflammatory response, IL-5 and IL-13 are secreted by ILC2s, subsequently promoting eosinophilic recruitment and further perpetuating the inflammatory events (Larose et al., 2017). In addition, IL-33 is shown to stimulate mast cell activation, which in turn triggers the recruitment of eosinophils (Larose et al., 2017).

A link between FD and atopy and allergy can, therefore, be explained by the presence of duodenal eosinophils (Wauters et al., 2020a); although the hypothesis has been proposed in the literature, there is no direct evidence that the duodenal eosinophilia observed in FD patients is due to a type-2 immune response (Burns et al., 2019a).

In contrast, increased levels of TNF-α and IL-1β production point toward a Th17-driven response, as IL-17 has been shown to trigger the production of these cytokines from human macrophages (Liebregts et al., 2011). Eosinophils are responsible for regulating Th17 responses (Sugawara et al., 2016). Furthermore, pre-clinical studies have shown that intestinal eosinophil recruitment involves IL-17-dependent mechanisms, implying that FD-associated eosinophilia may occur independently of type-2 responses (Griseri et al., 2015). In light of recent reports of increased mucosal Th17 density in pediatric FD patients with chronic gastritis (Singh et al., 2020), it may be possible to explain at least some of the symptoms of this condition by Th17 cytokine responses (Keely et al., 2015; Burns et al., 2019a). The most recent work by Burns et al. (2023) shows that FD patients have elevated Th2- and Th17-like cells localized to the duodenum, implying that dual lymphocyte response pathways are implicated in the generation of FD symptoms. In addition, the existence of effector and memory cells indicates that the microinflammation in FD is antigen driven (Burns et al., 2023). Taken together, the interplay between Th2- and Th17-signaling and ILC2-mediated inflammatory signals may be hallmarks of immune activation profile in the text of FD (Keely et al., 2015).

In addition to the stimulation of mast cells by MBP derived from eosinophils, IL-4 and IL-13 released by Th2 cells may also stimulate mast cell activation in a manner similar to that of eosinophils, resulting in high levels of mediators released, such as histamine, substance P, and tryptase (Powell et al., 2010). Consequently, a co-accumulation of eosinophils and mast cells is prevalent in disorders of gut-brain interaction, lending credence to the idea of an eosinophil-mast cell axis.

With growing interest in the duodenum, research on duodenal immune dysfunction in FD, as indicated by increased eosinophil and mast cell infiltration and degranulation, has confirmed its association with FD symptoms such as early satiation, postprandial fullness, and abdominal pain (Wang et al., 2015; Lee et al., 2019; Järbrink-Sehgal et al., 2021).

But how does the low-grade inflammation augment mucosal permeability and cause physiological abnormalities in the stomach (i.e., gastric motility dysfunction and gastric hypersensitivity) that directly result in dyspeptic symptoms?

Visceral hypersensitivity is a crucial factor in FGIDs, greatly influencing the occurrence and severity of symptoms. This is due to abnormal mucosal immune response activation in relation to the level of inflammatory response and the close proximity of immune cells and sensory neurons.

In particular, Tanaka et al. (2016) found increased glial cell line-derived neurotrophic factor expression in eosinophils and a correlation with epigastric burning in patients with FD. Additionally, eosinophils may interact with neuronal signaling via neurotrophins that they produce, such as brain-derived neurotrophic factor and nerve growth factor (Cirillo et al., 2015; Ceulemans et al., 2022). The neuro-immunological perspective thus adds to the understanding of the mechanism of gastrointestinal symptoms associated with immune activation, as seen in FD. Furthermore, cytotoxic granular proteins produced by eosinophil degranulation, such as MBP and eosinophil peroxidase, can act as antagonists of the muscarinic M2 receptor, potentially causing smooth muscle dysfunction, which is linked to disturbed intestinal motility (Walker et al., 2010; Zala et al., 2015). The mechanistic association between these immune cells, intestinal epithelium, and various nerves may therefore cause increased mucosal permeability and altered smooth muscle contraction, leading to gastroduodenal hypersensitivity and motor dysfunction, which are directly associated with FD symptoms.

In addition, since the findings reveal altered expression of proteins that comprise the cell junction, the paracellular pathway is likely to be involved in barrier dysfunction in FD. Trans-tight junction conductance occurs via two distinct pathways: pore and leak (Shen et al., 2011). There is thus evidence that tight junction dysregulation contributes to increased intestinal permeability, loss of intestinal barrier, and disorders of gut-brain interaction, including FD. The pathophysiology of FD is likely to be influenced, more specifically, by the paracellular leak pathway as opposed to the pore pathway, according to recent literature.

There is a paucity of research on the specific pathways that are responsible for the altered permeability seen in FD; however, it is likely that duodenal immune activation will occur as a result of and contribute to changes in duodenal permeability since eosinophils and mast cells have been linked to both epithelial cell damage and repair (Komori et al., 2019). Duodenal eosinophil counts were also correlated with the protein expression of intercellular tight junctions, including zonula occludens-1, occludin, and claudin-1 (Vanheel et al., 2014; Nojkov et al., 2020); these tight junctions have also been associated with altered gene expressions in the duodenum, including IL-1β and IL-6 (Stenfeldt and Wennerås, 2004), but a more comprehensive understanding of the cause-and-effect relationship between duodenal barrier defect and abnormal immune activation is still awaited.

Additionally, the promotion and sprouting of fine nerve fibers in the duodenum, a condition more prevalent in patients with EPS, was linked to the accumulation of mucosal eosinophils with degranulation (Lee et al., 2019). According to another study in FD patients, eosinophils were found to be more abundant near submucous plexus neurons and were associated with structural abnormalities (gliosis, altered ganglionic architecture, and neuronal abnormalities) as well as functional impairments (lower calcium response to depolarization and electrical stimulation) of the submucous nerve plexus, thereby affecting neuronal and muscular function (Cirillo et al., 2015). Since the submucous plexus is responsible for mediating local gut contractions and reflex responses (Fleming et al., 2020), it is possible that inflammatory mediators released by eosinophils contribute to abnormal stimulation of submucous plexus neurons, leading to altered duodenogastric feedback and, ultimately, results in the manifestations of FD, including disturbances in gastric motility and symptoms associated with it. The results of both studies thus provide further evidence that duodenal immune activation in FD is linked to altered submucous neuronal responsiveness, neuronal structural abnormalities and sensitization of the afferent nerves (Cirillo et al., 2015; Lee et al., 2019).

The expanding knowledge of immune activation in FD has not yet led to significant advances in anti-inflammatory medications targeting eosinophil infiltration. It is recommended that PPIs be used as the first line of treatment in accordance with consensus recommendations from North America, Europe, and Japan (Moayyedi et al., 2017; Wauters et al., 2021b; Miwa et al., 2022).

The expression of vascular cell adhesion molecule-1, which is recognized by eosinophil ligands, has been shown to be inhibited by the use of PPIs (Barthel et al., 2006), providing an explanation for the response of eosinophilia in an acid-independent manner. In addition, the release of IL-5 by Th2-lymphocytes can activate eosinophils via eotaxins through a mechanism involving the activation of signal transducer and activator of transcription 6 (STAT6) pathway (Zimmermann et al., 2003). It has been demonstrated that omeprazole prevents STAT6 from binding to the eotaxin-3 promoter, which in turn inhibits the expression of eotaxin-3 by esophageal cells in eosinophilic esophagitis (EoE) (Cheng et al., 2013). Even though these mechanisms are implicated in EoE, which is characterized by a substantial inflammation profile where there are an increased number of eosinophils present, certain mechanisms associated with eosinophil infiltration may also exist in FD; therefore, similar mechanisms may be at work in the duodenum of FD patients when taking PPIs for their anti-eosinophilic effects (Min et al., 2017).

PPI therapy was also evaluated clinically for its effect on suppression of duodenal eosinophilia in 20 FD patients in a case-control study (Potter et al., 2019). Patients who took PPIs had a lower descending duodenal eosinophil count than those who did not (p = 0.03) despite there being no difference between the groups in the eosinophil counts in the duodenal bulb or in gastric biopsies (Potter et al., 2019).

Furthermore, Wauters et al. (2021a) reported the first prospective evidence for PPIs reducing duodenal eosinophils. The study found that treatment with pantoprazole reduced the number of mast cells and duodenal eosinophils in patients with FD, along with the ameliorated intestinal permeability as well as severity of symptoms (Wauters et al., 2021a). Moreover, clinical efficacy was associated with reduced mucosal eosinophil counts in these patients (Wauters et al., 2021a). Due to the fact that this effect was not mediated by changes in duodenal pH, it appears to be a direct impact on inflammation, free of PPI’s acid suppressant properties (Wauters et al., 2021a). FD patients also showed duodenal changes that were not reversed once long-term PPI was withdrawn, suggesting that persistent changes may be at play (Wauters et al., 2021a).

In dyspeptic patients, gastric acid secretion is within the normal range (Collen and Loebenberg, 1989). It is not completely clear how acid-suppressive drugs ease dyspeptic symptoms when GERD and FD do not overlap significantly. The available evidence suggests that PPIs alleviate symptoms by suppressing eosinophils, which indeed supports the central role played by eosinophils in fueling and maintaining low-grade inflammation and altered brain-gut communication, thus in turn generating symptoms in FD.

Furthermore, other anti-inflammatory therapies for gastroduodenal disorders other than FD should be considered, as they may support the transferability of these results to FD patient cohorts. An excellent illustration of this is budesonide, which is efficient in treating diseases of the proximal small intestine, such as refractory celiac disease (Mukewar et al., 2017). In a pioneering study of assessing anti-inflammatory therapies for FD, Talley et al. (2021) conducted a randomized, double-blind, placebo-controlled trail in adults with FD and mucosal eosinophilia using steroids that are also known to be effective in treating EoE accompanied by a reversible over-expression of eotaxin-3 and IL-13 (Blanchard et al., 2007). Although there was no significant difference in symptomatic response between the treatment and placebo groups, a decrease in duodenal eosinophil counts from pre- to post-treatment was linked to improved postprandial fullness and early satiety (Talley et al., 2021). Although this study failed to demonstrate efficacy of steroids in the treatment of FD, it shows that duodenal immune dysfunction is linked to gastroduodenal symptoms.

Other anti-inflammatory treatments that target duodenal eosinophil recruitment and activation, such as monoclonal antibodies against Th2-derived cytokines (Stein et al., 2006; Straumann et al., 2010; Rothenberg et al., 2015; Hirano et al., 2020), anti-α4β7 integrin antibody (Bochner, 2000; Grandinetti et al., 2019), and Janus kinase/STAT6 pathway inhibitors (Cheng et al., 2016), are also anticipated for FD patients.

As a third component of the “gut-brain” axis, microbiota has been actively researched. The luminal contents, although separated by the intestinal barrier, are influential on mucosal homeostasis and immune activation, with the gut microbiome being an important factor (Peterson and Artis, 2014). It has been suggested that FD patients exhibit low-grade duodenal and systemic inflammation, specifically increased duodenal permeability and eosinophilia (Talley et al., 2007; Liebregts et al., 2011); hence, altered gut microbiota are relevant to these processes (Vanheel et al., 2014).

There is evidence that FD is associated with alterations in microbial communities throughout the gastrointestinal tract, not only at one location. There was a significant difference in the composition and total number of microbiota in gastric fluid of patients with FD compared to healthy subjects (Nakae et al., 2016). When compared to healthy subjects, there was a significant decrease in Prevotella abundance and an increase in Bifidobacterium and Clostridium abundance (Nakae et al., 2016). Furthermore, a negative correlation was found between the relative abundance of Prevotella and the severity of PDS symptoms (Nakae et al., 2016).

In addition, one study demonstrated that gastric fluid samples from patients with FD lacked Acidobacteria, and a higher ratio of Bacteroidetes to Proteobacteria was observed (Igarashi et al., 2017). Despite the ambiguity as to what constitutes a healthy microbiome, gastric fluid from healthy individuals normally contains Acidobacteria and typically has a low ratio of Bacteroidetes to Proteobacteria (Igarashi et al., 2017).

Mechanistically, gastric fluid has a higher species richness, which may indicate that the microbes present, as well as toxic bacterial components and metabolic mediators such as lipopolysaccharides, induce leukocytes to produce pro-inflammatory cytokines, leading to gastric inflammation and, potentially, increased mucosal permeability (Rupp and Stengel, 2022). The result could be a malfunctioning enteric nervous system manifesting as a disturbance in gastric motility (Rupp and Stengel, 2022). However, the gut microbiota is linked to immune cells, enteroendocrine cells, and the enteric nervous system via a complex circuit system that operates in a coordinated but still unclear fashion. In addition, as previously discussed, there have been very few studies reporting changes in gastric immune cell subpopulations, and none of these have been linked to FD symptoms (Futagami et al., 2010; Li et al., 2010; Pasricha et al., 2021). Given the preceding discussion, additional research is required to determine if the gastric fluid microbiota is sufficiently large and diverse for bacterial components and bacteria-derived molecules to affect the stomachs of FD patients, causing inflammation and mucosal permeability.

Further, in the FD group, luminal Streptococcus was found at higher abundance in the oral cavity, esophagus, stomach, and duodenum than in the control group, and its relative abundance was positively associated with upper gastrointestinal symptoms in both the PDS and EPS subtypes (Fukui et al., 2020). FD patients were also found to exhibit Streptococcus as the predominant genus within the duodenal mucosa (Zhong et al., 2017). Moreover, microbial load was found to be positively related to the severity of meal-related FD symptoms, but negatively correlated with QOL (Zhong et al., 2017). Despite the inconsistency of microbiota studies, which is largely due to differences in methodology used in assessing the microbiome as well as differences in sampling sites and sequencing targets, it appears that there is a consensus that a bacterial overgrowth of Streptococcus species (bacterium with acid producing abilities) is present in FD patients (Paroni Sterbini et al., 2016; Zhong et al., 2017; Fukui et al., 2020).

One example of gut microbiota abnormalities in the small bowel is a condition known as SIBO, which is defined as an increased concentration of small intestine bacteria as measured by quantitative culture (at least 10⁵ colony-forming units per milliliter of jejunal aspirate) (Ghoshal and Ghoshal, 2017). An association between SIBO and the FD has been demonstrated in several studies (Shimura et al., 2016; Tziatzios et al., 2021; Chuah et al., 2022). In addition, a recent systematic review and meta-analysis revealed that patients with FD are more likely to suffer from SIBO detected by breath tests than healthy controls, with no significant differences in SIBO prevalence between subtypes of FD (Gurusamy et al., 2021). These studies point to a potential link between dysbiosis and the pathogenesis of FD, with SIBO possibly being associated with the onset or worsening of symptoms in a subset of FD patients. However, there is no evidence that dysbiosis and FD are causally related to one another, and the specific microbiome that is pathognomonic for FD is also unknown.

Although FD microbial changes are not restricted to a single region in the gastrointestinal tract, low-grade duodenal inflammation may result from alterations to the gut microbiota of the small intestine. Future studies may benefit from this hypothesis. In particular, the duodenal microbiota is physiologically necessary for the maintenance of small intestinal digestive functions because it is responsible for the fermentation of food and the release of digestive enzymes such as bile salt hydrolase (Urdaneta and Casadesús, 2017; Duncanson et al., 2021). However, total dietary fat consumption and dietary fat profile alter the relative abundance and diversity of duodenal bacteria due to their role as substrate, with a high-fat diet associated with decreased Bacteroidetes and increased Firmicutes (Sandhu et al., 2017). Diet, therefore, is closely associated with the microbiota, contributing to immune and microbial interactions in FD. In fact, FGIDs, such as FD, were significantly more prevalent in obese compared to normal weight patients (Tambucci et al., 2019).

As microbiota, and thereby their functional repertoires are altered in the context of FD, the changes in the short-chain fatty acid (SCFA) profile, products of fermentation as well as the pool of bile acids follow (Pavlidis et al., 2015; Wei et al., 2021). As a result, these changes in bile acid composition may, in turn, promote alterations in gut microbial diversity, resulting in epithelial stress and damage (Banerjee et al., 2016; Beeckmans et al., 2020).

The link between bile acid biology and FD pathophysiology suggests that duodenal microbiota-mediated bile acid signaling might be involved. It has been observed that reduced duodenal primary bile salt amounts in FD are associated with decreased intestinal barrier function (Beeckmans et al., 2018, 2020). The mechanism for this phenomenon is thought to involve overgrowth of pro-inflammatory bacteria as a result of reduced primary bile salt concentrations in the duodenum, leading to cellular stress responses and barrier dysfunction, which also contributes to low-grade inflammation (Kakiyama et al., 2013; Pavlidis et al., 2015). Duodenal epithelial barrier dysfunction could occur as a result of these changes.

In addition to this, changes in bile acid may be the link between diet, the microbiota, and leaky gut, all of which may be factors that contribute to the development of FD (Keely and Talley, 2020). For example, excess dietary fats are likely to increase intestinal permeability through a variety of mechanistic pathways, including the modification of tight junction expression and distribution, the promotion of the transition to barrier-disruptive hydrophobic bile acids, and the induction of oxidative stress and apoptosis in enterocytes (Duncanson et al., 2021). Also, increased gut permeability associated with a high-fat diet may also result from the activation of pro-inflammatory signaling cascades directly, as well as indirect mediators, such as increased barrier-disruptive cytokines, decreased barrier-forming cytokines, negative modulation of intestinal mucus composition, and enrichment of gut microbiota with barrier-disruptive properties (Rohr et al., 2020). In general, disruption of bile acid-microbiota-epithelial barrier homeostasis is a crucial mechanism underlying FD pathophysiology.

The dysbiotic signature relating to symptomatology has not yet been definitively identified despite microbial changes being implicated in FD pathogenesis. Research is still underway to determine exactly how the duodenal dysbiosis, duodenal eosinophilia, and barrier dysfunction interact in FD. A recent study found that decreased duodenal mucosal Neisseria and Porphyromonas abundance in FD patients is associated with symptoms and duodenal eosinophils, implying a link between duodenal dysbiosis and immune activation (Wauters et al., 2021d). Inflammatory immune responses and microbial changes may lead to the dysfunctional regulation of cellular stress response pathways, disrupting gut homeostasis and causing loss of mucosal integrity, which in turn leads to the recruitment of eosinophils and the perpetuation of symptoms (Burns et al., 2019b). Furthermore, the studies summarized above highlight the importance of further research into the effects of primary and secondary bile salts on duodenal permeability, as well as the potential role of bile salts in the mucosal immune profile of FD (Beeckmans et al., 2020).

Aside from compositional imbalances, there may be a metabolomic dysregulation as well. Among the key functions of the gut microbiota is the processing of indigestible components of polysaccharides, producing SCFAs such as butyrate, which has anti-inflammatory properties (Silva et al., 2020). In colitis models, SCFAs have demonstrated beneficial effects by alleviating mucosal inflammation (Vieira et al., 2012); other studies have linked the SCFA profile with specific IBS subtypes as well as the disturbance of gut motility (Hurst et al., 2014; Dalile et al., 2019; Shaidullov et al., 2021). In light of the paucity of literature regarding the role of SCFAs in FD, the profile of SCFA in FD duodenum has yet to be defined. Nonetheless, evidence from IBS or colitis-related data, along with others, give a clue that altered SCFAs may, to some extent, be responsible for gut motility disturbances, increased duodenal permeability, and immune cell infiltration in FD.

There are no conclusive studies that have established whether dysbiosis itself is the cause or merely an outcome of the FD pathological process, but several studies have pointed to probiotics as a possible treatment alternative.

As reported by Igarashi et al. (2017), a markedly different bacterial composition in gastric fluid was found between FD patients and healthy controls, and the shift in the microbiota analysis of FD patients was restored to that seen in the control group after treatment with the probiotic Lactobacillus gasseri OLL2716 (LG21 strain). In this study, a probiotic product containing Lactobacillus strains was used, which produce SCFAs including acetate, propionate and butyrate (Markowiak-Kopeć and Śliżewska, 2020). In a RCT using LG21 strain in H. pylori negative FD, continuous intake of LG21 strain resulted in symptom resolution in PDS rather than EPS (Ohtsu et al., 2017). Therefore, LG21 may exhibit its beneficial effects mainly in conditions associated with abnormal gastric motility such as delayed gastric emptying and gastric dysaccommodation (Ohtsu et al., 2017).

In addition, a recent study showed that Bacillus spores were more effective than placebo in treating FD adults (Wauters et al., 2021c). Probiotic therapy may be beneficial for immunomodulation and microbial regulation in FD as patients taking spore-forming probiotics more frequently achieved clinical endpoints with decreased pro-inflammatory IL-17 and Th17 cytokines and increased concentrations of Faecalibacterium and Roseburia in stools (Wauters et al., 2021c). In addition to providing evidence for the positive effects of probiotics on symptom severity, microbiome composition, and immune regulation, additional research indicates that probiotic consumption is associated with the modulation of microbial metabolites, resulting in the increase of beneficial intestinal metabolites, such as pelargonic acid, benzoic acid, and SCFAs, and the decrease of harmful intestinal metabolites, such as hippuric acid (Sun et al., 2021).

It is currently unknown what exact mechanism may be responsible for the potential beneficial effects of probiotics on FD symptoms; however, SCFAs are hypothesized as potential mediators. As mentioned above, the addition of probiotics to FD may enrich beneficial bacteria or SCFA-producing bacteria, thereby restoring SCFA production (van Zanten et al., 2012; Sun et al., 2021). By virtue of their immunological, endocrine, vagal, and other actions, SCFAs have also been shown to modulate gut-brain interactions, as well as ameliorate gut-barrier injury, inhibit intestinal inflammation, and regulate gut motility (Ropert et al., 1996; Lewis et al., 2010). Given limited studies investigating these effects in humans, probiotic-mediated resolution of microbial dysbiosis through SCFAs and the related immune modulation in FD remains a hypothesis.

Further, it is interesting to note that in a recent study that analyzed the microbial profiles of FD patients, no distinct differences were observed between them and their healthy control counterparts (Vasapolli et al., 2021). Though, it is noted that the effects of PPI and prokinetic use, dietary modifications, and delayed gastric emptying on the microbiota composition in the stomach and duodenum of FD patients cannot be completely ruled out. Overall, the evidence presented thus far points to a link between FD and dysbiosis; additional research is necessary to gain a deeper understanding of the pathogenic microbiome and its mechanisms, as well as the mechanisms underlying probiotics’ potential beneficial effects. Further clues might be provided by the duodenal microbiota-mediated bile acid signaling and metabolites resulting from diet-microbiota interactions.

Psychological co-morbidities, such as stress, anxiety, or depression, are linked to FGIDs and contribute to the pathophysiology of the disorder. The prevalence of anxiety and depression has been found to be higher among those with FD, although the estimates of the co-morbidities are highly variable (Li Y. et al., 2002; Hartono et al., 2012). The results of a study in Sweden, which followed up 887 participants for 10 years, indicated that anxiety at baseline, but not depression, was associated with the newly onset FD (Aro et al., 2015). As evidenced by these observations, the pathogenesis of FD is strongly influenced by mental disorders. Further studies indicate that mental disorders and psychosocial factors may contribute to FD through modulation of cerebral processing of visceral afferent signals and pain perception mediated by stress hormones (Van Oudenhove and Aziz, 2013; Hannibal and Bishop, 2014).

The altered glycometabolism was studied in 40 FD patients and 20 controls during resting state (Nan et al., 2015). In FD patients, glucose metabolism in the insula, anterior cerebral cortex, middle cingulate cortex, and middle frontal cortex was higher after controlling dyspepsia (Nan et al., 2015). Among the subjects, the abnormalities were positively correlated with anxiety and depression scores, which suggests that the altered cerebral glycometabolism might result from the vicious cycle of psychopathology and gastrointestinal symptoms. Psychological vulnerabilities may affect glucose metabolism in these homeostatic afferents and sensory areas beyond simply influencing visceral afferent signaling (Nan et al., 2015). Also, other studies that used fluorodeoxyglucose positron emission tomography to assess resting brain glucose metabolism in FD patients found higher levels of metabolism in various brain regions thought to be involved in pain modulation circuits, including the anterior cingulate cortex, the insula, and the thalamus compared to healthy subjects (Zeng et al., 2011). However, these differences were not associated with anxiety levels, but rather with symptom severity (Zeng et al., 2011).

Furthermore, while not specifically identified in FD patients, psychological variables and stress hormones have been demonstrated to influence gastrointestinal motility, mucosal immune activation, intestinal permeability, and microbiota (Molina-Torres et al., 2019). Taken together, psychosocial disorders, such as anxiety and mood disorders, were found to be independently associated with the occurrence of FD and PDS, which suggests top-down communication between the brain and gut (Aro et al., 2009; Jones et al., 2017).

Alternatively, the symptoms of FD or the disease burden itself are thought to cause anxiety or depression as a result of low-grade intestinal inflammation. It has been noted that patients with high baseline anxiety levels are more likely to develop new onset gastrointestinal symptoms; additionally, patients with FD or IBS and no mood disorders at baseline were more likely to develop anxiety or depression symptoms (Koloski et al., 2016). A study conducted by Koloski et al. (2016) has suggested that mood disorders precede FGID in one-third of patients, whereas FGID precedes mood disorders in two-thirds, indicating that bottom-up pathway signaling is relevant to a subset of these patients.

A number of different pathways are involved in the interaction of the gut microbiota with the central nervous system, which could interfere with brain function via possible neurological (vagus nerve and spinal cord), endocrine [hypothalamus-pituitary-adrenal axis (HPA)], metabolic (SCFAs, bile acids, and others), and immunological (cytokines) pathways (Cryan and Dinan, 2012). This suggests that mental disorders may be the result of dysbiosis and, as such, might be contributing to the development of FD.

Furthermore, an increased number and rate of degranulation of mast cells in the duodenum is associated with anxiety and depression in FD (Yuan et al., 2015). In addition, a 10-year study found a correlation between baseline duodenal eosinophilia and anxiety at follow-up, suggesting that gastroduodenal inflammation may contribute to psychiatric symptoms in patients with gut symptoms (Ronkainen et al., 2021). However, to verify the bottom-up model of FD based on the view of duodenal subtle inflammation, large prospective controlled studies are required, since the limited number of patients with increased duodenal mucosa infiltration by mast cells and eosinophils has prevented firm conclusions regarding the interaction between symptoms, duodenal low-grade immune activation, and psychological distress (Wauters et al., 2021e).

It is also suggested that, apart from psychosocial factors such as anxiety and depression, activation of the HPA axis may bridge gut-brain-axis by producing both gut-derived and central mediators that induce stress, which, in turn, produces symptoms associated with FD (Ceulemans et al., 2022). There is evidence that stress may negatively affect mental health in a variety of ways. For its role in FD, occupational stress or burnout was found to be associated with FD among female employees (Nam et al., 2018). Additionally, patients with FD had higher levels of stress compared with healthy controls; there was also a positive correlation between preceding and concurrent stress and the severity of fullness, a cardinal symptom of the FD (Klaassen et al., 2022). The authors conclude that elevated stress levels may precede fullness sensations in patients with FD (Klaassen et al., 2022).

Hyperactivity of the HPA axis plays a role in the interaction between stress and immune activation. The HPA axis is activated in response to stress-related events, which is indicated by an increase in cortisol, adrenocorticotropin, and corticotropin-releasing hormone (CRH) production (Barden, 2004). It is important to note that CRH is not only produced by the hypothalamus during chronic restraint stress (Zheng et al., 2009). Intestinal eosinophils produce CRH and substance P locally, which activate mast cells and, consequently, increase intestinal permeability (Zheng et al., 2009). The release of CRH by eosinophils is stimulated by psychological stress, possibly through stimulation of the neurokinin receptor 1/2 purinergic receptors located on eosinophils by substance P derived from nerve endings. Further, these stress-induced changes in mucosal permeability have been linked to the eosinophil-mast cell axis in other studies (Wallon et al., 2008; Vanuytsel et al., 2014). This is demonstrated by peripheral administration of CRH, which activates both eosinophilic and mast cell receptors, increasing the permeability of the small intestine (Wallon et al., 2008; Vanuytsel et al., 2014). By pre-treating with cromoglycate, a mast cell stabilizer, the effect can be blocked (Wallon et al., 2008; Vanuytsel et al., 2014). Collectively, enteric permeability can be altered by stress-induced signaling between the central nervous system and immune activation or, more specifically, mucosal mast cells (Söderholm and Perdue, 2001; Teitelbaum et al., 2008; Rodiño-Janeiro et al., 2015). In support of the notion that a mast cell-mediated mechanism may increase mucosal permeability in response to psychological stress, Vanuytsel et al. (2014) conducted a study where healthy volunteers were exposed to psychological stress (public speeches), and the effects of this psychological stress on intestinal mucosal permeability were measured using lactulose-mannitol ratios. In response to this type of psychological stress, mucosal permeability increased (Vanuytsel et al., 2014). Moreover, the study showed that CRH administration increased mucosal permeability and that the mast cell stabilizer cromoglycate reduced the mucosal permeability increases caused by both speech and CRH (Vanuytsel et al., 2014).

It has recently been shown by Wauters et al. (2021a) that patients with FD exhibit higher subjective stress levels and salivary cortisol levels than controls. Additionally, patients with FD showed reduced awakening cortisol levels after taking PPIs; these changes were associated with PPI-related duodenal eosinophil reduction, but not with a decrease in mucosal hyperpermeability (Wauters et al., 2021a). There were, however, no associations between PPI-related changes in mast cells and cortisol in FD, and the reduction in higher awakening cortisol was observed in the absence of subjective stress-level changes (Wauters et al., 2021a). Accordingly, the exact role of mast cells in the increased mucosal permeability induced by stress is yet enigmatic.

Overall, a valuable insight is provided by these findings, which demonstrate that in response to psychological stress, the CRH-eosinophil-mast axis is activated, resulting in degranulation and the release of potentially damaging pro-inflammatory mediators such as tryptase, histamine, serotonin, and others, which potentiate duodenal low-grade inflammation and impaired mucosal barriers. Thus, the hyperactivity of the HPA axis also provides a pathway, which allows infiltrating antigens or components of microbiota to penetrate the epithelial barrier and influence immune cells and neurocytes directly through the intestinal mucosa, establishing a critical link between gut microbiota and brain function and leading to further stress induction (Teitelbaum et al., 2008). The suppression of stress-induced low-grade inflammation of the mucosa as evidenced by the infiltration and degranulation of eosinophils or mast cells could, therefore, be a therapeutically useful approach for restoring homeostatic brain-gut axis to these sufferers, as it may break the vicious circle of gut-brain communication resulting from stress stimulation by targeting pro-inflammatory signaling pathways in the intestine.

In addition, the vagus nerve’s role in chronic stress response cannot be neglected. There is evidence that stress can reduce the activity of the vagus nerve, which may contribute to gastrointestinal inflammation (Taché and Bonaz, 2007; Bonaz et al., 2016). It has been suggested that the vagus nerve’s efferents provide an anti-inflammatory effect in the gut as well as ameliorate the increased intestinal permeability, both of which might be linked to vagal activity mediated reinforcement of tight junctions (Zhou et al., 2013; Van Houten et al., 2015), although further research is needed to determine the exact mechanism. This suggests that reduced vagal activity induced by stress may have a weaker protective effect on the epithelial barrier, increasing epithelial permeability and, as a result, promoting bacterial translocation (Rupp and Stengel, 2022). In this regard, targeting vagal tone in FD patients with high stress levels may also have a positive effect on regulating brain-gut interactions (Bonaz et al., 2018).

The activation of the duodenal eosinophil-mast cell axis has been highlighted in emerging studies of subtle duodenal pathology in FD patients. It is still debated, though, how infiltrating eosinophils and mast cells contribute to increased intestinal mucosal permeability. A decrease in transepithelial electrical resistance and an increase in passage of a paracellular probe associated with reduced expression of tight junction proteins were observed in healthy volunteers after 30 min of acid perfusion of the duodenum (Vanheel et al., 2020). Additionally, duodenal acid perfusion may activate mast cells, as seen by enhanced tryptase expression (Vanheel et al., 2020). However, pretreatment with cromoglycate fail to abrogate acid-induced epithelial barrier impairment, suggesting that the compromised integrity after acid exposure is caused by acid exposure itself rather than by a mast cell-dependent event (Vanheel et al., 2020). Eosinophils in colonic mucosa, however, have been shown to express muscarinic acetylcholine receptors, releasing CRH when stimulated by cholinergic stimulation, disrupting intestinal epithelial barrier function by paracrinely acting on mast cells, whereas activated eosinophils alone had no effect on epithelial permeability (Wallon et al., 2011). Although these mechanisms have not been specifically studied in patients or animal models of FD, discrepancies in the association between immune activation and barrier dysfunction may be explained by the fact that barrier dysfunction may be secondary to other pathological process, such as luminal substances (e.g., changes in enteric bacteria, SCFA profile, and bile acid pool), in addition to factors released by the inflammatory infiltrate (Xu et al., 2014). Further research in the context of FD may be spurred by the potential triad of mental disorders, duodenal immune cell infiltrates, and barrier defects.

As previously mentioned, FD patients may initially develop mental disorders during the course of their illness. Thus, neuromodulators and phytotherapy may be of benefit to these patients. In an updated meta-analysis of RCTs of all drugs for FD, it was concluded that, compared with placebo, antipsychotics showed greater efficacy, followed by pregabalin and tricyclic antidepressants (Ford et al., 2021; Black et al., 2022). In this analysis, serotonin norepinephrine reuptake inhibitors, selective serotonin reuptake inhibitor, and serotonin-1A agonists did not provide any benefit (Black et al., 2022).

Furthermore, a wide range of psychological therapies have been investigated, but the four main modalities studied in FD are psychodynamic-interpersonal therapy, cognitive behavioral therapy, stress management and mindfulness, and gut-directed hypnotherapy (Black et al., 2022). Despite promising results for patients with FD in terms of decreased psychological distress, improved gastrointestinal symptoms, and enhanced QOL, the evidence base for these treatment approaches is scant, which makes it impossible to recommend any particular modality over another (Black et al., 2022).

Regarding the mechanisms by which psychological therapies benefit patients with FD, there is a hypothesis that psychotherapy alleviates mental disorders by altering the microbiome or modulating vagal tone (Rupp and Stengel, 2022), but further research is required to examine these intriguing effects of psychotherapy specifically on patients with FD.

There may be a pre-existing gut-driven syndrome in some FD patients that is related to the onset of brain-related symptoms, therefore necessitating a different treatment approach; however, this strategy is still debated. As discussed previously, two factors may be implicated in the pathogenesis of gut-to-brain bottom-up models: one is dysbiosis, and the other is activation of duodenal mast cells and eosinophils.

From the perspective of dysbiosis, although studies abound repeatedly demonstrating the efficacy of probiotics in improving mental health, leading to the coinage of the term “psychobiotics,” they are not specifically studied in the context of FD (Liu et al., 2019; Ansari et al., 2020). Fecal matter transplant (FMT) is also a proven method for restoring a balanced microbiota and may be a suitable treatment option for intestinal dysbiosis (Khoruts and Sadowsky, 2016). Still, it is unclear whether FMT treatment for FGIDs is a panacea or merely a placebo (Pulipati et al., 2020; Shanahan et al., 2021). Further, there is a paucity of FD-related data investigating whether FMT may pose potential therapeutic gains for patients with FD-associated dysbiosis and, simultaneously, mitigate or even prevent common mental disorders in those with FD.

Furthermore, an RCT of 86 FD patients without SIBO found that rifaximin provided significantly more relief of postprandial fullness or bloating than placebo; however, psychological co-morbidities were not assessed (Tan et al., 2017).

Nevertheless, little is known about this entity that lies at the intersection of FGIDs, depression, and anxiety. At least some evidence indicates that co-morbid patients cluster differently than those with FGID, depression, or anxiety alone (Zhang T. et al., 2022b). In this regard, the treatment strategies to ameliorate gut microbiota dysbiosis that is associated with improved mental function needs to be further examined with regards to whether these have been studied specifically among patients with mental disorders, co-morbid FD patients, or simple FD patients, as variability in symptom and subgroup characterization can skew interventional trial results and lead to falsely attributed positive effects to other patient cohorts. It is therefore paramount, not only to demonstrate a specific microbial signature for FD or mental disorders, but also to well characterize the gut microbiota species in patients who have both FD symptoms and established psychological co-morbidities.

The bottom-up model also allude to eosinophilic duodenitis and increased duodenal mast cells as therapeutic targets for improving mental health and psychological function. Thus, anti-inflammatory (Dellon et al., 2020; Wauters et al., 2021a) and anti-allergy therapies (Friesen et al., 2006; Potter et al., 2020) that target these immune infiltrates and demonstrate promising therapeutic efficacy in FD patient cohorts or those with eosinophilic gastrointestinal disorders are awaited in FD patients co-morbid with psychiatric conditions. As shown in the study by Wauters et al. (2021a), perceived stress was greater in FD patients compared to healthy controls, and was unaffected by PPI therapy. Further, ex vivo permeability in FD patients was higher with a significant decrease to levels of healthy controls following PPI therapy (Wauters et al., 2021a). Nonetheless, the PPI’s anti-inflammatory effects did not seem to be responsible for this effect (Wauters et al., 2021a). Thus, the role of duodenal eosinophils and mast cells as therapeutic targets in co-morbid FD sufferers requires further investigation.

As previously mentioned, dyspeptic symptoms are more likely to arise when multiple functional abnormalities are present (Vanheel et al., 2017). There may be multiple pathophysiological mechanisms responsible for symptoms, so agents targeting only one mechanism are unlikely to be effective (Lee, 2021).

In cases of refractory symptoms, acupuncture can be used as an alternative treatment to conventional therapies (Masuy et al., 2019). This treatment involves the use of solid metallic needles, which penetrate the skin and are then manually manipulated, such as lifting, twisting, and thrusting, in order to stimulate specific acupuncture points (Ko et al., 2016; Tomita et al., 2018).

Neuroimaging research has accumulated a growing body of evidence indicating significant functional and structural changes in multiple brain regions in FD sufferers, including the frontal cortex, somatosensory cortex, postcentral gyrus, precuneus, and caudate tail (Zeng et al., 2009; Nan et al., 2014; Lee et al., 2016; Qi et al., 2020). Interestingly, acupuncture can regulate, to a certain extent, some of the aforementioned abnormal functional activities (Zeng et al., 2012; Chen et al., 2021; Dong et al., 2022). Acupuncture and electroacupuncture have been studied extensively for their effects on gastric and intestinal motility impairments. However, more attention is now being focused on the effect of these techniques on the brain-gut interaction (Ye et al., 2018; Masuy et al., 2019).

Several systematic reviews and meta-analyses have confirmed acupuncture’s promising efficacy in treating FD patients (Kim et al., 2015; Pang et al., 2016; Zhou et al., 2016; Ho et al., 2017; Guo et al., 2020; Zhang J. et al., 2020). A Cochrane review, however, found no evidence of benefit (Lan et al., 2014). The inconsistent results of meta-analyses are likely to be attributed to the low levels of evidence (no explicit blinding or randomization and short follow-up periods), as well as the inherent characteristics of the acupuncture procedure (no single adequate sham intervention for acupuncture trials, impossibility of complete blinding, positive therapeutic effects produced by sham acupuncture, and operator dependence due to no standardized protocol) (Yoon et al., 2022). However, RCTs involving acupuncture therapy in FD research are typically subject to these limitations. In general, a number of RCTs have well documented acupuncture’s efficacy in patients with FD.

The physiological abnormalities known to directly cause FD symptoms are thought to be gastric motor and sensory dysfunction. There is evidence that acupuncture modulates gastric sensory-motor function, which accounts for its therapeutic effect on some FD patients (Tang et al., 2020; Zhang S. et al., 2020; Li Y. et al., 2022).

It is however possible that constant exposure to multiple factors (e.g., H. pylori infection, increased gastric acid, and altered microbiota) may lead to priming of the duodenum, as manifested by increased mucosal permeability and low-grade inflammation, thus modifying these sensory-motor abnormalities and ultimately resulting in the manifestation of symptoms (Miwa et al., 2019). Acupuncture’s alleviation of sensory-motor dysfunction may therefore be explained more explicitly in terms of its effects on the root cause, i.e., impaired intestinal permeability and duodenal micro-inflammation.

It is important to note, however, that although subtle duodenal inflammation characterized by increased eosinophils and mast cells with their degranulation has led to new insights into immune-mediated pathophysiology, there is limited evidence to support the effect of acupuncture on duodenal low-grade inflammation in FD, since most data come from studies that are not specifically targeted at this disease. The possible mechanism of action includes acupuncture’s immunomodulatory effects to maintain homeostasis under Th2-skewed conditions, inhibition of duodenal mast cell degranulation, and regulating inflammatory responses as well as modulating gastrointestinal function by stimulating distinct autonomic pathways through regional or heterotopic acupoints (Yang et al., 2022).

In the context of brain to gut interaction, abnormal brain activation or altered engagement of descending or ascending pathways may contribute to the pathophysiology. Greater levels of glycometabolism in the anterior cingulate cortex, insula, middle cingulate cortex, and cerebellum were found to have a positive correlation with Symptom Index of Dyspepsia (SID) scores, while having a negative correlation with SID scores (Zeng et al., 2011). As reported by Zeng et al. (2012), acupuncture treatment reduced glycometabolism in the brainstem, anterior cingulate cortex, insula, thalamus, and hypothalamus, resulting in a decrease in SID scores and an increase in NDI scores.

From the gut to brain perspective, intestinal microbiota plays a significant role in altering brain function by balancing host immune responses; immune responses are further considered to be a key regulator of the gut-brain axis. As evidence grows, altered microbiota may contribute to the pathophysiology and clinical course of FGIDs, rather than simply being an epiphenomenon. It appears, based on the IBS-related data (Song et al., 2020), that acupuncture may help by managing microbial dysbiosis, improving the interaction between the intestinal microbiota and the brain-gut axis, and decreasing pro-inflammatory cytokines. Thus, acupuncture may be able to suppress inflammation not only by inhibiting the release of inflammatory cytokines via the various somatic autonomic reflex pathways, as was discussed previously, but also by regulating the brain-gut axis through the intestinal microbiota. New approaches to FD can therefore be fostered by acupuncture’s ability to modulate gut microbiota, interrupting the gut-brain vicious cycle.

Several chemosensing receptors are found in the gastrointestinal mucosa that detect nutrients in the lumen (Farré and Tack, 2013; Depoortere, 2014). This avalanche-effect occurs as a result of gut peptides being released from enteroendocrine cells into the bloodstream due to the detection of nutrients in the duodenum and jejunum (Farré and Tack, 2013; Depoortere, 2014). These signals are either transmitted via the vagus nerve or directly by fenestrated endothelial cells within circumventricular organs, such as the area postrema (Farré and Tack, 2013; Depoortere, 2014). There has been recent evidence that intensities of symptoms in FD may be associated with nutritionally specific altered release of gut hormones.

The peptide ghrelin, which has been studied extensively in FD pathophysiology, was captured in the present study with a strong citation burst. Ghrelin is an appetite-stimulating hormone that is primarily produced by gastric X/A-like endocrine cells in rats and P/D1 type cells in humans (Cummings et al., 2001; Farré and Tack, 2013). Ghrelin is produced and released primarily by the stomach, but it is also produced and released in small amounts by the small intestine and the brain, where it regulates gastric motility and appetite via mammalian/mechanistic target of rapamycin (mTOR) signaling activation (Yagi et al., 2013). As a ligand for growth hormone secretagogue receptors, acyl ghrelin aids normal gastrointestinal motility by acting on the brain-gut axis (Yagi et al., 2013).

Since ghrelin and acyl ghrelin concentrations were found to be subnormal in FD patients, stimulating ghrelin receptors may be able to improve stomach emptying in these cohorts (Shindo et al., 2009; Kim et al., 2012). Electroacupuncture elevates ghrelin levels in the hypothalamus, stomach antrum, and small intestine and promotes adenosine 5′-monophosphate-activated protein kinase (AMPK)/Tuberous Sclerosis Complex 2 (TSC2)/Ras homolog enriched in brain (Rheb) signaling by inhibiting mTOR, resulting in dyspepsia relief (Tang et al., 2020).

There is evidence that ghrelin and acyl ghrelin alleviate depressive-like behavior in animal models of chronic stress (Fan et al., 2017; Huang et al., 2017) as well as suppress certain inflammatory responses (Ziko et al., 2018). Through ghrelin-AMPK signaling, electroacupuncture-induced ghrelin production improved gastrointestinal motility and suppressed stress-induced intestinal mucosal inflammation (Tang et al., 2020). Consequently, acupuncture may restore ghrelin expression in FD, which indicates a potentially dual therapeutic role for mood disorders and mucosal inflammatory cell infiltration, therefore improving gastrointestinal motility (Takeshita, 2020). It should be noted, however, that the enteroendocrine cells, epithelial cells, immune cells, autonomic nerve, and gut microflora are interdependent and operate in a convoluted circuit system by undefined mechanisms. In view of these difficulties in studying and comprehending such broad ranges of interactions, any comprehensive understanding of acupuncture in FD is presently imperceptible.

Overall, acupuncture has been shown to be an effective alternative treatment for patients suffering from FD. Mechanistically, investigations with patients and animal models have indicated that acupuncture may ameliorate intestinal inflammation, regulate the brain-gut axis via modulating brain processing of visceral pain, reforming intestinal microbiota, and restoring peptide hormones expression, and thereby alleviate FD symptoms.