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  • Review Article
  • OPEN ACCESS

Gastroesophageal Reflux Disease: A Potentially Infectious Disease?

  • Kevin V. Houston1,
  • Ankit Patel2,
  • Michael Saadeh3,
  • Alejandra Vargas3,
  • Steve M. D’Souza3,
  • Byung Soo Yoo4 and
  • David A. Johnson3,* 
 Author information  Cite
Journal of Translational Gastroenterology   2023;1(1):30-39

doi: 10.14218/JTG.2023.00011

Abstract

The gastrointestinal microbiome remains an explosively increasing topic of study, assessing the potentially pivotal roles of the microbiome in maintaining health or causality in disease pathogenesis. Gastroesophageal reflux disease (GERD) has long been understood to be a result of direct acidic injury. However, emerging evidence suggests that GERD could also be caused by alterations in the esophageal microbiome, causing an induction of a submucosal inflammatory cytokine cascade, that has a retrograde effect on the luminal mucosa. This concept of a microbial shift/dysbiosis in the causality of GERD is clearly a paradigm shift and has led to possible treatment strategies beyond the traditional approach of acid-suppressive therapies. This review focuses on the current evidence surrounding GERD and the rationale for possible esophageal microbiome-directed treatment strategies.

Keywords

Gastrointestinal microbiome, Gastrointestinal reflux disease, Dysbiosis, Cytokines, Probiotics, Prebiotics

Introduction

Gastroesophageal reflux disease (GERD) has been traditionally described as a chronic gastrointestinal (GI) disorder in which gastric contents reflux retrograde into the esophagus. This can result in clinically significant symptoms and may progress to complications such as erosive esophagitis, eosinophilic esophagitis (EoE), Barrett’s esophagus (BE), and esophageal adenocarcinoma. It has been estimated that GERD is among the most prevalent GI diseases worldwide. The prevalence of GERD ranges from 18.1% to 27.8% in the United States, resulting in substantial direct and indirect economic costs.1–3 The pathogenesis of GERD is influenced by a number of factors, characterized by an imbalance between harmful factors (reflux frequency, acidity of refluxate, esophageal mucosal contact time) and protective factors (esophageal acid clearance, mucosal integrity, lower esophageal sphincter pressure, anti-reflux barrier).4 Recent studies suggest that this multifactorial process is influenced by the esophageal microbiome, which can induce an immune response that eventually triggers inflammation and subsequent GERD.5,6

The microbiome is a collection of microorganisms, primarily bacteria, fungi (mostly yeasts), archaea, and viruses, that live in specific environments, such as the skin, mouth, respiratory tract, and GI tract.7,8 A collection of microbes is called the microbiota, whereas a collection of genes is called the microbiome.7 In addition to regulating the immune system, synthesis of nutrients, and protection against harmful pathogens, the microbiome plays an invaluable role in promoting health and well-being.9,10 Microbial dysbiosis can result in tissue damage and contribute to inflammatory, autoimmune, metabolic, and neoplastic diseases.9,11–13 Focus has been placed on understanding how changes within the microbiota may contribute to disease manifestations, a process that can now be accomplished through the development of molecular tools and techniques (metagenomic, metabolomic, lipidomic, meta-transcriptomic).14–17 Clarifying and elucidating mechanisms by which the microbiota interacts with the underlying human physiology in the GI tract will enable the development of novel therapies and optimize clinical practices. Advances in medical science are evolving towards the ideal goal of individualizing disease management to provide more personalized directed treatment of each patient, to improve clinical outcomes.18,19 Although the intestinal (colonic) microbiome has been extensively studied, the microbiome of the esophagus and oropharynx and its relation to GERD has not been studied to the same extent.20 An overview of the role of the esophageal microbiome in GERD, cytokine expression, and possible mitigation strategies will be presented in this article.

GERD and cytokine expression

GERD has long been described as the result of direct esophageal mucosal inflammation/damage secondary to the reflux of gastric acid and/or duodenal bile salts.21 It was previously thought that the refluxed acid led to direct chemical contact damage to the esophageal mucosa, and therefore a linear relationship between mucosal damage and the pH of reflux. However, many patients with clinical symptoms of GERD do not have objective mucosal evidence (erosions) of reflux.6

An alternative pathophysiology to the direct acid contact and disruption of the esophageal mucosal barrier involves cytokine expression and subsequent submucosal directed inflammatory damage back to the mucosa. Lipopolysaccharide (LPS) is a cell wall constituent of gram-negative bacteria and is vital for bacterial cell integrity, viability, and defense against environmental stress.22 The toll-like-receptor (TLR)-4 protein site found on human cells is best characterized as a sensing receptor that mediates LPS-induced signal transduction.23 Various internal and external factors can affect the oropharyngeal and esophageal microbiome, in particular altering the proportion of gram-positive to LPS-containing, gram-negative microbes (Figs. 1 and 2).24 This leads to increased LPS-TLR-4 binding and activates production of interleukin (IL)-18, which induces a cascading inflammatory response (Fig. 3).6 Further TLR-based signaling promotes transcription of pro-inflammatory chemokines, including IL-1, IL-6, IL-8, and tumor necrosis factor-alpha (TNF-α), and mediators such as nitric oxide synthase. The result of this cascade is a retrograde inflammatory disruption from the submucosa back to the luminal esophageal barrier, as well as possible adverse relaxation of the lower esophageal sphincter and decreased esophageal motility. The resulting disruptions at the luminal esophageal mucosal barrier can subsequently result in propagation of the cytokine cascade, direct entry of acid through the mucosal barrier as well as possible further changes to the biome, and worsening of the clinical symptoms of GERD.

Internal factors that influence esophageal disease.
Fig. 1  Internal factors that influence esophageal disease.24
External factors that influence esophageal microbiome.
Fig. 2  External factors that influence esophageal microbiome.24
Proposed mechanism of microbiome-influenced erosive disease.
Fig. 3  Proposed mechanism of microbiome-influenced erosive disease.

A pivotal and seminal study examined the mechanisms of damage from acid reflux and found that reflux esophagitis does not develop as a chemical injury at the epithelial surface as one would expect with reflux acid-induced mucosal damage.25 Twelve patients with reflux esophagitis were treated with proton pump inhibitors (PPIs) to resolution of symptoms. Endoscopic evaluations at 1- and 2-weeks post-PPI interruption revealed that all patients had redeveloped reflux esophagitis. With traditional GERD etiology, the refluxed acid would be expected to break down the junctional proteins of esophageal epithelial cells and permeate across the basolateral membrane and lead to cell death. Over time, continued acid reflux would penetrate deeper into the lamina propria and submucosa. Following cell death, hyperplasia of basal progenitor cells and elongated and hyperplastic papillae would be expected. Instead, biopsies revealed that the damage begins with T-lymphocyte infiltration of the submucosa, followed by migration upwards towards the epithelial surface. Hyperplasia of basal progenitor cells was observed, however only in areas without surface erosion.25 Following this study, the same investigators examined an alternate GERD etiology hypothesis involving hypoxia-inducible factor (HIF) mediated inflammation.26 When exposed to hypoxic stress or reactive oxygen species, the lack of oxygen inhibits prolyl hydroxylases in the cytoplasm from signaling the degradation of HIF-α by proteasomes. These HIFs are then translocated to the nucleus and signal the transcription of pro-inflammatory cytokines. These investigators re-examined the biopsies from their previous study. Specifically, they immunostained for HIF-1α, HIF-2α, and phospho-p65 and measured mRNA levels of pro-inflammatory mediators. They also studied HIFs in the setting of acidic bile salts. They found that there was an increase in HIF-2α, phosphorylated nuclear factor-kappa B (NF-κB) subunit p65, and mRNA expression of IL-8, IL-1β, and TNF-α in the biopsies with redeveloped reflux esophagitis. Additionally, they observed that exposure to acidic bile salts stabilized HIF-2α in esophageal epithelial cells, assisting in the development of the subsequent pro-inflammatory state.27

The association between reflux-induced expression of HIF-2α and its effects on increasing pro-inflammatory cytokines further strengthens the argument that GERD-related esophageal luminal barrier disruptions are the result of more than just direct acid caustic damage.27 Additional studies on human esophageal squamous cell lines found similar results; noting that reflux stimulated epithelial cells and led to subepithelial cytokine-mediated and retrograde-directed mucosal damage of tissue.28

Clearly, there is increasing evidence that GERD involves, in at least some patients, cytokine-mediated pathophysiology. The main cytokines involved in the esophageal pathophysiological cascade of the esophagus are pro-inflammatory cytokines interleukin IL-8 and IL-1β, which recruit inflammatory cells such as leukocytes and neutrophils.6 This is primarily affected through calcitonin gene-related peptide (CGRP) and substance P expression via activation of transient receptor potential cation channel subfamily V member 1 on epithelial cells and neurons. CGRP and neutrophil activation initiate a cascade of cytokine expression, resulting in local submucosal inflammation, hydrogen peroxide production, and increased immune cells infiltration in the mucosa. In addition to mucosal damage, hydrogen peroxide can lead to smooth muscle relaxation of the lower esophageal sphincter, further contributing to reflux.6 This theory was further supported by a recent study that examined the relationship between acid exposure and inflammatory cytokines in the esophageal mucosa.29 Acid exposure time, defined as the time with pH < 4.0 per day at 5 cm above the upper border of the GI junction, was associated with increased gene expression of the inflammatory cytokines IL-1β and TNF-α. Expression of these cytokines, as well as TLR4, GATA3, and CD68, inversely correlated with mean pH values in the distal esophagus.30

Microbiome effects on motility

The microbiome also plays a role in gut motility, thereby possibly contributing to the pathogenesis of GERD. Local LPS–TLR4 activation results in inducible nitric oxide synthase and cyclooxygenase-2 (COX-2) expression, which results in the aforementioned inflammatory cascade. In addition, this process also affects local motility within the esophagus and stomach. Nitric oxide expression results in relaxation of the lower esophageal sphincter as well as decreased esophageal motility.31 COX-2 expression results in delayed gastric emptying.32 Inhibitors of both enzymes have demonstrated to reversal of the respective effects, offering a mechanism with therapeutic potential.

Recognizably, PPIs provide relief for symptomatic GERD. While previously thought to provide treatment solely via decreased gastric acid production, a new study suggests an anti-inflammatory effect.27 One study showed that when esophageal squamous cells were exposed to an acidic bile salt medium with or without PPIs, there was an increase in IL-8 mRNA levels in group that did not receive PPIs. Additionally, an acidic bile salt medium led to an increase in IL-8 via NF-κB and AP-1 DNA binding sites. However, PPIs blocked AP-1 and NF-κB subunits and immune cell migration in cells exposed to an acidic bile salt medium.31 These therapeutic effects, independent of their role on gastric acid, further support cytokine-mediated pathophysiology in GERD.33,34

Colonic flora may also play a role in gastric motility. Short chain fatty acids (SCFAs) are produced as the result of fermentation of undigested carbohydrates by colonic bacteria. The associated increased SCFA production has been shown to cause decreased gastric motility.35 One study investigating gastric emptying in healthy volunteers after oral lactulose intake found a transient decrease in gastric motility after intake.36 This result has been reproduced through investigations of intracolonic infusions of carbohydrates (lactose) and SCFAs. Both infusions also demonstrated that SCFAs and local colonic fermentation of carbohydrates into SCFAs are associated with decreased gastric tone through an increase in peptide YY and oxyntomodulin.35,36 These associated changes in gastric motility and tone may also reduce acid clearance and/or promote transient esophageal sphincter relaxations that are associated with GERD.37,38

GI microbiome in relation to GERD

The GI microbiome includes various organisms across segments of the GI tract depending on their function and is subject to changes, as mentioned previously, to intrinsic and extrinsic influences. The gastroesophageal microbiome comprises six major phyla: Firmicutes, Bacteroidetes, Actinobacteria, Proteobacteria, Fusobacteria, and Saccharibacteria.11 The “normal” (non-disease) esophageal microbiome demonstrates an abundant number of gram-positive organisms, with the most common genus being Streptococcus ssp, and this is referred to as a type I microbiome.39,40 The abnormal microbiome, type II microbiome, consists of more gram-negative organisms. Different disease states have been reported to influence the esophageal microbiota as a results of a multitude of factors (Table 1).6,24,41–44 For example, in GERD the increased acidic environment can reduce Prevotella ssp, Helicobacter ssp, and Moraxella ssp in the distal esophageal microbiome leading to dysbiosis.45 Normally, more gram-positive organisms are found in the proximal and mid-proximal esophagus, with increasing rates of gram-negative bacteria going more distal towards the stomach.46 This likely could be due to gram-negative bacteria possessing LPS, which allows for survivability in lower pH environments.

Table 1

Esophageal microbiome compared to diseased states6,24,41–44

Disease stateEsophageal Microbiome
Gastrointestinal reflux diseaseNon-erosive reflux disease: Increased Proteobacteria (Neisseria oralis, Moraxella spp.) and Bacteroidetes (Bacteroides uniformis, Capnocytophaga spp., and Prevotella pallens; Decreased Fusobactereia (Leptotrichia) and Actinobacteria (Rothia spp). Reflux esophagitis: Decreased Firmicutes (Mogibacterium spp., Streptococcus infantis, Solobacterium moorei); Increased Fusobacteria (Leptotrichia spp.) and Proteobacteria (Marivita spp., Nisaea spp., Mesorhizobium spp.)
Barrett’s esophagusIncreased Fusobacteria and Proteobacteria (Neisseria spp, Campylobacter spp.); Decreased alpha diversity as well as Bacteroidetes and Prevotella
Esophageal adenocarcinomaIncreased abundance of Proteobacteria; Decreased Firmicutes; relatively unchanged Streptococci abundance
Eosinophilic esophagitisIncreased Proteobacteria (Neisseria and Haemophiles) and Corynebacterium; Decrease in Clostridia spp.
Squamous cell cancer (of the esophagus)Increased Fusobacterium and Bacteroidetes; Decrease in relative abundance of Firmicutes; Consistently associated with Porphyromonas gingivalis and Fusobacterium nucleatum
Laryngopharyngeal refluxPrevotella ssp. was more common; Fusobacterium ssp. and Porphyromonas ssp. were less common

The presence of a bacterial biofilm can allow some bacteria, those not typically accustomed to increased pH, to thrive in certain locations. A biofilm is composed of an extracellular polymeric substance that encases microorganisms.47 These substances can withstand the extremes of certain environments, which allows microorganisms that typically do not reside within a specific area to grow and expand. Interestingly Helicobacter pylori (H. pylori), within the past decade, has been found within biofilms.48,49 This, along with other properties such as urease, could have allowed H. pylori to colonize other aspects of the GI tract.

H. pylori has been known for decades to modify gastric acid secretion, but the link to GERD had not been fully elucidated. More recently, it has been shown that there is an inverse relationship between H. pylori and risk of GERD. A meta-analysis concluded that there was an increased risk of GERD following H. pylori eradication.50H. pylori can reduce gastric acid secretion.50 It requires a mucus layer in order to survive in an acidic environment, which can explain why there is a lack of H. pylori in the luminal mucosa of the esophagus.51 Additionally, H. pylori can affect GERD by modulating hormones, such as gastrin, ghrelin, and leptin, that play a role in metabolism.52 Studies have demonstrated that individuals with non-erosive reflux disease (NERD) have a higher prevalence of H. pylori compared to those with erosive reflux disease.52,53 These findings suggest that the H. pylori found in NERD may prevent esophageal-gastric mucosal erosion.

Another study evaluated the esophageal microbiota in GERD as well as related complications of BE and esophageal adenocarcinoma.51 It was also found that Campylobacter spp., a common gram-negative bacteria found in the mouth, but not typically within a normal esophagus, was significantly increased in patients with GERD and BE compared to healthy individuals and those with carcinoma.49 Due to the presence of reflux, there may be changes in the mucosal lining that allow the growth of Campylobacter spp. These results suggest a strong relationship of Campylobacter spp, with diseases involving reflux in the esophagus.

EoE is another disease state that has recently been associated with alterations in the esophageal microbiome.41 EoE is characterized by chronic eosinophilic infiltration of the mucosa leading to mucosal barrier breakdown due to triggers such as genetic risk factors, environmental shifts, allergens, and even microbiota changes. In pediatric patients with EoE, genera Corynebacterium spp. and Neisseria spp. were increased compared to non-EoE patients.54 An overall elevation in gram-negative organisms correlated with increased inflammation, as evidenced by histopathologic abnormalities upon endoscopic biopsy. A principal component analysis showed that EoE patients were generally characterized by larger amounts of Haemophilus, Pasteurella, Fusobacterium, and Aggregatibacter spp. and smaller amounts of Actinomyces, Veillonella, and Rothia spp. The analysis further showed a significant increase in Haemophilus spp., which then normalized once EoE was treated.55 A systematic review and meta-analysis demonstrated that PPIs have been efficacious in leading to histological remission (defined as <15 eos/hpf) in 50.5% (confidence interval (CI) = 42–58.7%) and symptomatic improvement in 60.8% (CI = 48–72%) of patients.56–58 The likely mechanisms for these effects may involve downregulated expression of pro-inflammatory cytokines such as IL-5 and IL-3, similar to corticosteroids, and acid suppression leading to growth of additional gram-negative organisms in lower pH environments.59

Oral hygiene can influence the esophageal microbiome with downstream effects.6 Good oral hygiene is associated with a higher proportion of gram-positive cocci and rods, mostly comprised of Streptococcus spp., which contrasts with poor oral hygiene, which is associated with shifts to a higher proportion of anaerobic gram-negative bacteria such as Prevotella spp.60 The oral microbiome shift to a more gram-negative dominant flora may have distal effects of LPS-inducing TLRs and activation of an inflammatory cascade in the esophagus. A study analyzing the differences in bacteria taxa levels in untreated GERD patients found that there may be benefit in the oral cavity microbiome in patients with GERD who take PPI. This may be a result of a pH change and a subsequent effect on oral conditions.45 Further research and randomized controlled studies can help elicit the direct effect of the oral cavity on the distal esophageal microbiome.

Mitigation strategies for esophageal dysbiosis and GERD

Many current guidelines recommend PPIs as first line of treatment for GERD,61–63 although prolonged use may contribute to persistent symptoms, as the underlying etiology is not fully addressed. Thus, addressing the microbiome directly may be warranted. There are several mitigation strategies that have been proposed for treatment of GERD. Thus, focusing on a personalized regimen for each patient may be a better strategy than long-term PPI use (Table 2).64–69

Table 2

Potential Mitigation strategies for esophageal dysbiosis and GERD

ModalityPositive outcomeNo clear benefit
PrebioticsSelling et al64 in a case series reported a study of 24 patients with GERD that were given food-grade maltosyl-isomaltooligosaccharides (MIMO) soluble fiber supplements had improvement in symptoms after weeks of daily consumption.More studies needed to discern efficacy
ProbioticsGomi et al67 enacted a double-blind, randomized, placebo-controlled trial with 100 healthy Japanese adults that were randomly assigned to a YIT10347 group or placebo group and consumed 100 mL of YIT10347-fermented milk or placebo fermented milk, respectively, every day for 4 wk. The YIT10347 group had significantly higher relief rates of overall gastrointestinal symptoms, upper gastrointestinal symptoms, flatus, and diarrhea than the placebo group. Cheng et al66 in a systematic review analyzes the efficacy of probiotics in GERD. They found 13 prospective studies published in 12 articles and concluded probiotic use can be beneficial for GERD symptoms such as regurgitation and heartburn.Ostlund-Lagerstrom69 studied 290 older adults and failed to show any improvement in digestive health after daily intake of a probiotic supplement containing L. reuteri. Qing-Hua et al65 studied the effects of probiotic capsule supplement and found no significant change in reflux diagnostic questionnaire (RDQ) or GI symptom rating scale (GSRS)
Fecal microbiome transplantationZheng et al68 utilized a form of FMT called washed microbiota transplantation. They enrolled 27 adults and divided into WNT vs PPI groups, with outcomes showing WMT showed better GERDQ scores, which correlated with better improvement in symptoms of heartburn, acid regurgitation, chest pain, and sleep disturbances than the PPI group.More studies needed to discern efficacy

Prebiotics

Prebiotics are non-digestible food ingredients that selectively promote the growth of beneficial bacteria in the GI tract, primarily Lactobacilli and Bifidobacterium spp., which can improve gut barrier function and reduce inflammation.64 In addition to promoting selective fermentation by probiotics and interacting with pathogens to prevent colonization, prebiotics are also absorbed into the intestine and exert anti-inflammatory properties. These benefits, however, may not be universal for all patients and may have many factors which influence their potential effects, including diet, demographics, and genetics.70

A case series reported a study of 24 patients with GERD who were given food-grade maltosyl-isomaltooligosaccharides (MIMO) soluble fiber supplements.64 Orally ingested MIMOs have been shown to selectively increase populations of certain gram-positive organisms such as Bifidobacterium and Lactobacillus spp. Albeit a small sample size, they found that 88% of their study cohort had improved symptoms of GERD after weeks of daily consumption. Subgroup analysis showed that two of the patients who were previously PPI-dependent for symptom control were able to eliminate PPI therapy after prebiotic initiation. The authors proposed that the likely mechanism involves a change in the microbiome via restoration of the protective and balanced symbiotic relationship in the esophagus.

Probiotics

Probiotics are live microorganisms that are intended to alter the composition and function of the gut microbiome in a beneficial way.65 Studies have suggested that certain probiotics, such as Lactobacillus ssp. and Bifidobacterium ssp., can reduce acid reflux symptoms through modulating immune responses and inhibiting potential pathogens by producing short-chain fatty acids, such as lactic acid.66 Probiotics may also increase gastric emptying by interacting with mucosal receptors on the stomach, which may result in a transient relaxation of the lower esophageal sphincter, one of the pathophysiological mechanisms associated with GERD.71,72 Several probiotic supplements have demonstrated modest efficacy in reducing heartburn symptoms.66,67,73 An interesting study, still in progress, hypothesized that long-term PPI use and its effect on microbiome disturbances could affect concomitant probiotic use.74 In this randomized, double-blind, placebo control trial, Liu et al. plan to enroll 120 eligible patients with GERD and place them either in a PPI (rabeprazole) plus probiotic (LiHuo probiotic) arm or a PPI alone arm. Results of this study should provide new insight regarding the effects of concurrent probiotic administration with PPI on the determinantal effects of GI tract homeostasis.

Probiotics may be beneficial for small intestinal bacterial overgrowth, which can impair immunity and/or intestinal motility.75 Dietary intake or addition of probiotic-containing foods has also been evaluated as a means for microbiome manipulation as a symptom-mitigating mechanism for GI-related diseases, such as prevention of intestinal disorders, reduction in symptoms of irritable bowel syndrome, and protection against some cancers.76 Intake of probiotic-containing yogurt decreases symptom severity in functional dyspepsia.77 Thus, enrichment of foods with probiotics may be another effective mechanism to achieve this therapeutic effect.78,79

Fecal microbiome transplantation (FMT)

FMT involves introducing the feces of a healthy donor into a diseased individual in order to restore the normal microbial composition of the lower GI tract. It is particularly effective and has been extensively studied in conditions such as refractory Clostridium difficile infection, and to a lesser degree in other conditions including irritable bowel syndrome, inflammatory bowel disease, and constipation.80–83 However, according to a recent study, the same may apply to GERD.68 Zheng et al. utilized a form of FMT called washed microbiota transplantation (WMT), looking specifically at NERD. WMT is a microbiota transplantation method that is similar to traditional FMT but adds the safety measure of washed microbiota. WMT is prepared by an intelligent microorganism separation system, which subjects the sample to a multi-level filtration system, washing the bacterial solution prior to use. It has better safety, quality control for bacterial flora disorders, and effectiveness.84 Twenty-seven adults (aged 18-85) were divided into WNT (n = 15) and PPI (n = 12) groups. WMT was delivered via a transendoscopic enteral tubing through one of two routes; either into the jejunum via gastroscopy or into the caecum via enteroscopy. At 1 month after treatment, the total remission rate in the WMT and PPI groups was 93.3% and 41.7%, respectively. Compared with the PPI group, the WMT group showed better results in GERDQ scores (p = 0.004) and RDQ scores (p = 0.003), as well as in the remission months (p = 0.002); nine patients showed sustained remission for more than 6 months in the WMT groups, while there were only two in the PPI group. Furthermore, the patients in the WMT group achieved an associated, better improvement in symptoms of heartburn, acid regurgitation, chest pain, regurgitation, and sleep disturbance compared to the PPI group.

Diet and lifestyle changes

Diet and lifestyle play an extremely critical role in determining the composition of the gut microbiome. Based on a recent systematic review, dietary factors such as protein and fat intake, and lifestyle factors such as alcohol consumption (except beer and wine) and low mental state were all positively correlated with GERD.61 Citrus intake between meals, sweet and spicy foods, and poor eating habits were positively correlated with GERD. There were also correlations with non-dietary related factors such as higher education, less sleep time, sedentary and physical occupational activities, night work, and less exercise. Conversely, vegetarian diets, fruits, vegetables, vitamins, coffee, and fiber were negatively correlated with GERD.61,85,86

There also appears to be specific changes in the microbiome related to alterations in sugar. A recent small study evaluating obese individuals noted resolution of their GERD symptoms within two weeks after switching to a low-carbohydrate diet. Notably, there were no significant changes in body weight, thereby the authors suggested the benefit was through the dietary change alone.87 They did not, however, consider that these dietary changes may have had a beneficial effect on the esophageal microbiome, thereby promoting GERD improvement. Another study demonstrated that a very low-carbohydrate diet significantly reduced distal esophageal acid exposure and improved symptoms in obese individuals with GERD.88 An additional study looked at 12 patients who were enrolled to observe acid changes in GERD with varying types of food and found that high-carbohydrate diets could increase acid reflux in the lower esophagus and exacerbate reflux symptoms.89 Furthermore, a more recent randomized control trial enrolled 98 veterans with symptomatic GERD and randomly assigned them to either a high total/high simple, high total/low simple, low total/high simple, or low total/low simple carbohydrate diet for nine weeks to determine the effect of carbohydrate reduction on the symptoms of GERD. Reflux episodes and esophageal acid exposure time measured by pH monitoring were significantly improved and correlated with improvements in GERD symptoms. There was a significant main effect of diet treatment on acid exposure time (p = 0.001) and on the total number of reflux episodes (p = 0.003). These findings suggest that reducing simple sugars in the diet can be effective in improving GERD symptoms.90 Although likely causally associated at least to some degree, the effects of these dietary changes and related potential beneficial effects on the esophageal microbiome have not yet been studied.

Stress

Patients with NERD can have acute stress induced dilated epithelial intercellular spaces (DIS). Similarly, exposure of rats to acute stress was found to induce DIS and increase esophageal mucosal permeability to small molecules.91 Esophageal mast cells also appear to be closely related to stress, as stress-induced permeability occurs. One study showed that the stress response mediator corticotrophin-releasing hormone receptor subtype 2 was expressed in the rat esophageal mucosa.92 Lastly, patients with a diagnosis of GERD report a higher symptom burden with increased stress, suggesting the underlying mechanism may involve not only increased central sensitization to acid, but peripheral sensitization driven by permeability changes at the level of the esophageal mucosa.91 These studies further demonstrate that GERD-related symptoms and mucosal changes may be related to factors beyond direct acid esophageal contact. Stress may have multiple effects on the microbiome via alterations in diet, inflammatory processing, sleep, and immune function, among other adverse functional changes. The specific effects of stress on the esophageal and GI microbiome, however, have yet to be defined.

Conclusion

We reviewed the current evidence regarding GERD and the GI microbiome. There is emerging data to suggest a paradigm shift in focus from GERD as a result of direct contact-mediated acidic injury towards an altered microbiome and induction of an inflammatory cytokine cascade. The effects of this microbiome cytokine cascade can have clinically significant consequences involving inflammatory changes in the esophagus. The emerging data implicate an ever-increasing spectrum of esophageal diseases ranging from GERD, BE, esophageal carcinoma, EoE, esophageal dysmotility, and laryngopharyngeal reflux. This review serves to suggest a translational message with clinical implications. Clearly, more robust studies and randomized controlled trials are necessary to better elicit the mechanisms involved in the microbiome-GERD relationship and to help elucidate mitigation strategies where appropriate. There is, however, emerging evidence that there may be a paradigm shift from the traditional treatment of GERD using acid-reducing medications towards focusing on treating the dysbiotic microbiome.

Abbreviations

BE: 

Barrett’s esophagus

CGRP: 

calcitonin gene-related peptide

CI: 

confidence interval

COX-2: 

cyclooxygenase-2

DIS: 

dilated epithelial intercellular spaces

EoE: 

eosinophilic esophagitis

FMT: 

fecal microbiota transplantation

GERD: 

gastroesophageal reflux disease

GI: 

gastrointestinal

H. pylori: 

Helicobacter pylori

HIF: 

hypoxia-inducible factors

IL: 

interleukin

LPS: 

lipopolysaccharide

MIMO: 

maltosyl-isomaltooligosaccharides

NERD: 

non-erosive reflux disease

NF-κB: 

nuclear factor-kappa B

PPI: 

proton-pump inhibitors

SCFA: 

short-chain fatty acids

TLR: 

toll-like-receptor

TNF-α: 

tumor necrosis factor-alpha

WMT: 

washed microbiota transplantation

Declarations

Acknowledgement

None.

Funding

None.

Conflict of interest

Dr. David A Johnson is the consultant/clinical investigator of ISOThrive. The authors have no other conflict of interests related to this publication.

Authors’ contributions

Design and outline: KVH and DAJ. All authors contributed to the writing and reviews of this manuscript.

References

  1. Howden CW, Manuel M, Taylor D, Jariwala-Parikh K, Tkacz J. Estimate of Refractory Reflux Disease in the United States: Economic Burden and Associated Clinical Characteristics. J Clin Gastroenterol 2021;55(10):842-850 View Article PubMed/NCBI
  2. Park CH. Cost-effective Management of Severe Gastroesophageal Reflux Disease: Toward an Improved Understanding of Anti-reflux Surgery. J Neurogastroenterol Motil 2020;26(2):169-170 View Article PubMed/NCBI
  3. Maret-Ouda J, Markar SR, Lagergren J. Gastroesophageal Reflux Disease: A Review. JAMA 2020;324(24):2536-2547 View Article PubMed/NCBI
  4. Zhang ML, Ran LQ, Wu MJ, Jia QC, Qin ZM, Peng YG. NF-κB: A novel therapeutic pathway for gastroesophageal reflux disease?. World J Clin Cases 2022;10(24):8436-8442 View Article PubMed/NCBI
  5. Okereke I, Hamilton C, Wenholz A, Jala V, Giang T, Reynolds S, et al. Associations of the microbiome and esophageal disease. J Thorac Dis 2019;11(Suppl 12):S1588-S1593 View Article PubMed/NCBI
  6. D’Souza SM, Houston K, Keenan L, Yoo BS, Parekh PJ, Johnson DA. Role of microbial dysbiosis in the pathogenesis of esophageal mucosal disease: A paradigm shift from acid to bacteria?. World J Gastroenterol 2021;27(18):2054-2072 View Article PubMed/NCBI
  7. Marchesi JR, Adams DH, Fava F, Hermes GD, Hirschfield GM, Hold G, et al. The gut microbiota and host health: a new clinical frontier. Gut 2016;65(2):330-339 View Article PubMed/NCBI
  8. Sender R, Fuchs S, Milo R. Revised Estimates for the Number of Human and Bacteria Cells in the Body. PLoS Biol 2016;14(8):e1002533 View Article PubMed/NCBI
  9. Ogunrinola GA, Oyewale JO, Oshamika OO, Olasehinde GI. The Human Microbiome and Its Impacts on Health. Int J Microbiol 2020;2020:8045646 View Article PubMed/NCBI
  10. de Vos WM, Tilg H, Van Hul M, Cani PD. Gut microbiome and health: mechanistic insights. Gut 2022;71(5):1020-1032 View Article PubMed/NCBI
  11. Pei Z, Bini EJ, Yang L, Zhou M, Francois F, Blaser MJ. Bacterial biota in the human distal esophagus. Proc Natl Acad Sci U S A 2004;101(12):4250-4255 View Article PubMed/NCBI
  12. Martin Z, Spry G, Hoult J, Maimone IR, Tang X, Crichton M, et al. What is the efficacy of dietary, nutraceutical, and probiotic interventions for the management of gastroesophageal reflux disease symptoms? A systematic literature review and meta-analysis. Clin Nutr ESPEN 2022;52:340-352 View Article PubMed/NCBI
  13. Brusilovsky M, Bao R, Rochman M, Kemter AM, Nagler CR, Rothenberg ME. Host-Microbiota Interactions in the Esophagus During Homeostasis and Allergic Inflammation. Gastroenterology 2022;162(2):521-534.e8 View Article PubMed/NCBI
  14. Gao B, Chi L, Zhu Y, Shi X, Tu P, Li B, et al. An Introduction to Next Generation Sequencing Bioinformatic Analysis in Gut Microbiome Studies. Biomolecules 2021;11(4):530 View Article PubMed/NCBI
  15. Wensel CR, Pluznick JL, Salzberg SL, Sears CL. Next-generation sequencing: insights to advance clinical investigations of the microbiome. J Clin Invest 2022;132(7):e154944 View Article PubMed/NCBI
  16. Gomaa EZ. Human gut microbiota/microbiome in health and diseases: a review. Antonie Van Leeuwenhoek 2020;113(12):2019-2040 View Article PubMed/NCBI
  17. Davidson RM, Epperson LE. Microbiome Sequencing Methods for Studying Human Diseases. Methods Mol Biol 2018;1706:77-90 View Article PubMed/NCBI
  18. Malla MA, Dubey A, Kumar A, Yadav S, Hashem A, Abd Allah EF. Exploring the Human Microbiome: The Potential Future Role of Next-Generation Sequencing in Disease Diagnosis and Treatment. Front Immunol 2018;9:2868 View Article PubMed/NCBI
  19. May M, Abrams JA. Emerging Insights into the Esophageal Microbiome. Curr Treat Options Gastroenterol 2018;16(1):72-85 View Article PubMed/NCBI
  20. Park CH, Lee SK. Exploring Esophageal Microbiomes in Esophageal Diseases: A Systematic Review. J Neurogastroenterol Motil 2020;26(2):171-179 View Article PubMed/NCBI
  21. Winkelstein A. Peptic esophagitis. JAMA 1935;104(11):906-909 View Article
  22. Sweet MJ, Hume DA. Endotoxin signal transduction in macrophages. J Leukoc Biol 1996;60(1):8-26 View Article PubMed/NCBI
  23. Soares JB, Pimentel-Nunes P, Roncon-Albuquerque R, Leite-Moreira A. The role of lipopolysaccharide/toll-like receptor 4 signaling in chronic liver diseases. Hepatol Int 2010;4(4):659-672 View Article PubMed/NCBI
  24. Houston K, Elmahdi A, Davis I, Vilela A, Yoo BS, D’Souza SM, et al. Esophageal Disease and the Role of the Microbiome, First Edition. London, UK: Academic Press an imprint of Elsevier; 2023, 177-190
  25. Dunbar KB, Agoston AT, Odze RD, Huo X, Pham TH, Cipher DJ, et al. Association of Acute Gastroesophageal Reflux Disease With Esophageal Histologic Changes. JAMA 2016;315(19):2104-2112 View Article PubMed/NCBI
  26. Souza RF, Bayeh L, Spechler SJ, Tambar UK, Bruick RK. A new paradigm for GERD pathogenesis. Not acid injury, but cytokine-mediated inflammation driven by HIF-2α: a potential role for targeting HIF-2α to prevent and treat reflux esophagitis. Curr Opin Pharmacol 2017;37:93-99 View Article PubMed/NCBI
  27. Huo X, Zhang X, Yu C, Zhang Q, Cheng E, Wang DH, et al. In oesophageal squamous cells exposed to acidic bile salt medium, omeprazole inhibits IL-8 expression through effects on nuclear factor-κB and activator protein-1. Gut 2014;63(7):1042-1052 View Article PubMed/NCBI
  28. Souza RF, Huo X, Mittal V, Schuler CM, Carmack SW, Zhang HY, et al. Gastroesophageal reflux might cause esophagitis through a cytokine-mediated mechanism rather than caustic acid injury. Gastroenterology 2009;137(5):1776-1784 View Article PubMed/NCBI
  29. Mönkemüller K, Wex T, Kuester D, Fry LC, Kandulski A, Kropf S, et al. Role of tight junction proteins in gastroesophageal reflux disease. BMC Gastroenterol 2012;12:128 View Article PubMed/NCBI
  30. Morozov S, Sentsova T. Local inflammatory response to gastroesophageal reflux: Association of gene expression of inflammatory cytokines with esophageal multichannel intraluminal impedance-pH data. World J Clin Cases 2022;10(26):9254-9263 View Article PubMed/NCBI
  31. Yang L, Francois F, Pei Z. Molecular pathways: pathogenesis and clinical implications of microbiome alteration in esophagitis and Barrett esophagus. Clin Cancer Res 2012;18(8):2138-2144 View Article PubMed/NCBI
  32. Keshavarzi Z, Khaksari M, Shahrokhi N. The effects of cyclooxygenase inhibitors on the gastric emptying and small intestine transit in the male rats following traumatic brain injury. Iran J Basic Med Sci 2014;17(6):406-410 PubMed/NCBI
  33. Calatayud S, García-Zaragozá E, Hernández C, Quintana E, Felipo V, Esplugues JV, et al. Downregulation of nNOS and synthesis of PGs associated with endotoxin-induced delay in gastric emptying. Am J Physiol Gastrointest Liver Physiol 2002;283(6):G1360-G1367 View Article PubMed/NCBI
  34. Fan YP, Chakder S, Gao F, Rattan S. Inducible and neuronal nitric oxide synthase involvement in lipopolysaccharide-induced sphincteric dysfunction. Am J Physiol Gastrointest Liver Physiol 2001;280(1):G32-G42 View Article PubMed/NCBI
  35. Ropert A, Cherbut C, Rozé C, Le Quellec A, Holst JJ, Fu-Cheng X, et al. Colonic fermentation and proximal gastric tone in humans. Gastroenterology 1996;111(2):289-296 View Article PubMed/NCBI
  36. Piche T, Zerbib F, Varannes SB, Cherbut C, Anini Y, Roze C, et al. Modulation by colonic fermentation of LES function in humans. Am J Physiol Gastrointest Liver Physiol 2000;278(4):G578-G584 View Article PubMed/NCBI
  37. Kim HI, Hong SJ, Han JP, Seo JY, Hwang KH, Maeng HJ, et al. Specific movement of esophagus during transient lower esophageal sphincter relaxation in gastroesophageal reflux disease. J Neurogastroenterol Motil 2013;19(3):332-337 View Article PubMed/NCBI
  38. Iwakiri K, Hoshino S, Kawami N. Transient lower esophageal sphincter relaxation (in Japanese). Nihon Rinsho 2016;74(8):1343-1348 PubMed/NCBI
  39. Yang L, Lu X, Nossa CW, Francois F, Peek RM, Pei Z. Inflammation and intestinal metaplasia of the distal esophagus are associated with alterations in the microbiome. Gastroenterology 2009;137(2):588-597 View Article PubMed/NCBI
  40. Lv J, Guo L, Liu JJ, Zhao HP, Zhang J, Wang JH. Alteration of the esophageal microbiota in Barrett’s esophagus and esophageal adenocarcinoma. World J Gastroenterol 2019;25(18):2149-2161 View Article PubMed/NCBI
  41. Katzka D. Esophageal Disease and the Role of the Microbiome. 1st Ed. London, UK: Academic Press an imprint of Elsevier; 2023, 115-121
  42. Johnson D. Esophageal Disease and the Role of the Microbiome, 1st ed. London, UK: Academic Press an imprint of Elsevier; 2023
  43. Yoo B, Elmadhdi A, Vilela A, et al. Esophageal Disease and the Role of the Microbiome. 1st Ed. London, UK: Academic Press an imprint of Elsevier; 2023, 163-173
  44. Sarker A, Vaezi M. Esophageal Disease and the Role of the Microbiome, 1st Ed. London, UK: Academic Press an imprint of Elsevier; 2023, 125-133
  45. Kawar N, Park SG, Schwartz JL, Callahan N, Obrez A, Yang B, et al. Salivary microbiome with gastroesophageal reflux disease and treatment. Sci Rep 2021;11(1):188 View Article PubMed/NCBI
  46. Okereke I, Hamilton C, Reep G, Krill T, Booth A, Ghouri Y, et al. Microflora composition in the gastrointestinal tract in patients with Barrett’s esophagus. J Thorac Dis 2019;11(Suppl 12):S1581-S1587 View Article PubMed/NCBI
  47. Hall-Stoodley L, Costerton JW, Stoodley P. Bacterial biofilms: from the natural environment to infectious diseases. Nat Rev Microbiol 2004;2(2):95-108 View Article PubMed/NCBI
  48. Carron MA, Tran VR, Sugawa C, Coticchia JM. Identification of Helicobacter pylori biofilms in human gastric mucosa. J Gastrointest Surg 2006;10(5):712-717 View Article PubMed/NCBI
  49. Servetas SL, Carpenter BM, Haley KP, Gilbreath JJ, Gaddy JA, Merrell DS. Characterization of Key Helicobacter pylori Regulators Identifies a Role for ArsRS in Biofilm Formation. J Bacteriol 2016;198(18):2536-2548 View Article PubMed/NCBI
  50. Mou WL, Feng MY, Hu LH. Eradication of Helicobacter Pylori Infections and GERD: A systematic review and meta-analysis. Turk J Gastroenterol 2020;31(12):853-859 View Article PubMed/NCBI
  51. Blackett KL, Siddhi SS, Cleary S, Steed H, Miller MH, Macfarlane S, et al. Oesophageal bacterial biofilm changes in gastro-oesophageal reflux disease, Barrett’s and oesophageal carcinoma: association or causality?. Aliment Pharmacol Ther 2013;37(11):1084-1092 View Article PubMed/NCBI
  52. Zhou J, Shrestha P, Qiu Z, Harman DG, Teoh WC, Al-Sohaily S, et al. Distinct Microbiota Dysbiosis in Patients with Non-Erosive Reflux Disease and Esophageal Adenocarcinoma. J Clin Med 2020;9(7):2162 View Article PubMed/NCBI
  53. Sugihartono T, Fauzia KA, Miftahussurur M, Waskito LA, Rejeki PS, I’tishom R, et al. Analysis of gastric microbiota and Helicobacter pylori infection in gastroesophageal reflux disease. Gut Pathog 2022;14(1):38 View Article PubMed/NCBI
  54. Benitez AJ, Hoffmann C, Muir AB, Dods KK, Spergel JM, Bushman FD, et al. Inflammation-associated microbiota in pediatric eosinophilic esophagitis. Microbiome 2015;3:23 View Article PubMed/NCBI
  55. Harris JK, Fang R, Wagner BD, Choe HN, Kelly CJ, Schroeder S, et al. Esophageal microbiome in eosinophilic esophagitis. PLoS One 2015;10(5):e0128346 View Article PubMed/NCBI
  56. Gutiérrez-Junquera C, Fernández-Fernández S, Cilleruelo ML, Rayo A, Echeverría L, Quevedo S, et al. High Prevalence of Response to Proton-pump Inhibitor Treatment in Children With Esophageal Eosinophilia. J Pediatr Gastroenterol Nutr 2016;62(5):704-710 View Article PubMed/NCBI
  57. Gómez-Torrijos E, García-Rodríguez R, Castro-Jiménez A, Rodríguez-Sanchez J, Méndez Díaz Y, Molina-Infante J. The efficacy of step-down therapy in adult patients with proton pump inhibitor-responsive oesophageal eosinophilia. Aliment Pharmacol Ther 2016;43(4):534-540 View Article PubMed/NCBI
  58. Lucendo AJ, Arias Á, Molina-Infante J. Efficacy of Proton Pump Inhibitor Drugs for Inducing Clinical and Histologic Remission in Patients With Symptomatic Esophageal Eosinophilia: A Systematic Review and Meta-Analysis. Clin Gastroenterol Hepatol 2016;14(1):13-22.e1 View Article PubMed/NCBI
  59. Molina-Infante J, Rivas MD, Hernandez-Alonso M, Vinagre-Rodríguez G, Mateos-Rodríguez JM, Dueñas-Sadornil C, et al. Proton pump inhibitor-responsive oesophageal eosinophilia correlates with downregulation of eotaxin-3 and Th2 cytokines overexpression. Aliment Pharmacol Ther 2014;40(8):955-965 View Article PubMed/NCBI
  60. Socransky SS, Haffajee AD. Periodontal microbial ecology. Periodontol 2000 2005;38:135-187 View Article PubMed/NCBI
  61. Zhang M, Hou ZK, Huang ZB, Chen XL, Liu FB. Dietary and Lifestyle Factors Related to Gastroesophageal Reflux Disease: A Systematic Review. Ther Clin Risk Manag 2021;17:305-323 View Article PubMed/NCBI
  62. Iwakiri K, Fujiwara Y, Manabe N, Ihara E, Kuribayashi S, Akiyama J, et al. Evidence-based clinical practice guidelines for gastroesophageal reflux disease 2021. J Gastroenterol 2022;57(4):267-285 View Article PubMed/NCBI
  63. Katz PO, Dunbar KB, Schnoll-Sussman FH, Greer KB, Yadlapati R, Spechler SJ. ACG Clinical Guideline for the Diagnosis and Management of Gastroesophageal Reflux Disease. Am J Gastroenterol 2022;117(1):27-56 View Article PubMed/NCBI
  64. Selling J, Swann P, Madsen LR, Oswald J. Improvement in Gastroesophageal Reflux Symptoms from a Food-grade Maltosyl-isomaltooligosaccharide Soluble Fiber Supplement: A Case Series. Integr Med (Encinitas) 2018;17(5):40-42 PubMed/NCBI
  65. Sun QH, Wang HY, Sun SD, Zhang X, Zhang H. Beneficial effect of probiotics supplements in reflux esophagitis treated with esomeprazole: A randomized controlled trial. World J Gastroenterol 2019;25(17):2110-2121 View Article PubMed/NCBI
  66. Cheng J, Ouwehand AC. Gastroesophageal Reflux Disease and Probiotics: A Systematic Review. Nutrients 2020;12(1):132 View Article PubMed/NCBI
  67. Gomi A, Yamaji K, Watanabe O, Yoshioka M, Miyazaki K, Iwama Y, et al. Bifidobacterium bifidum YIT 10347 fermented milk exerts beneficial effects on gastrointestinal discomfort and symptoms in healthy adults: A double-blind, randomized, placebo-controlled study. J Dairy Sci 2018;101(6):4830-4841 View Article PubMed/NCBI
  68. Zheng YM, Chen XY, Cai JY, Yuan Y, Xie WR, Xu JT, et al. Washed microbiota transplantation reduces proton pump inhibitor dependency in nonerosive reflux disease. World J Gastroenterol 2021;27(6):513-522 View Article PubMed/NCBI
  69. Östlund-Lagerström L, Kihlgren A, Repsilber D, Björkstén B, Brummer RJ, Schoultz I. Probiotic administration among free-living older adults: a double blinded, randomized, placebo-controlled clinical trial. Nutr J 2016;15(1):80 View Article PubMed/NCBI
  70. Davani-Davari D, Negahdaripour M, Karimzadeh I, Seifan M, Mohkam M, Masoumi SJ, et al. Prebiotics: Definition, Types, Sources, Mechanisms, and Clinical Applications. Foods 2019;8(3):92 View Article PubMed/NCBI
  71. Foster JP, Dahlen HG, Fijan S, Badawi N, Schmied V, Thornton C, et al. Probiotics for preventing and treating infant regurgitation: A systematic review and meta-analysis. Matern Child Nutr 2022;18(1):e13290 View Article PubMed/NCBI
  72. Indrio F, Riezzo G, Raimondi F, Bisceglia M, Filannino A, Cavallo L, et al. Lactobacillus reuteri accelerates gastric emptying and improves regurgitation in infants. Eur J Clin Invest 2011;41(4):417-422 View Article PubMed/NCBI
  73. Beckett JM, Singh NK, Phillips J, Kalpurath K, Taylor K, Stanley RA, et al. Anti-Heartburn Effects of Sugar Cane Flour: A Double-Blind, Randomized, Placebo-Controlled Study. Nutrients 2020;12(6):1813 View Article PubMed/NCBI
  74. Liu W, Xie Y, Li Y, Zheng L, Xiao Q, Zhou X, et al. Protocol of a randomized, double-blind, placebo-controlled study of the effect of probiotics on the gut microbiome of patients with gastro-oesophageal reflux disease treated with rabeprazole. BMC Gastroenterol 2022;22(1):255 View Article PubMed/NCBI
  75. Zhong C, Qu C, Wang B, Liang S, Zeng B. Probiotics for Preventing and Treating Small Intestinal Bacterial Overgrowth: A Meta-Analysis and Systematic Review of Current Evidence. J Clin Gastroenterol 2017;51(4):300-311 View Article PubMed/NCBI
  76. Dahiya D, Nigam PS. The Gut Microbiota Influenced by the Intake of Probiotics and Functional Foods with Prebiotics Can Sustain Wellness and Alleviate Certain Ailments like Gut-Inflammation and Colon-Cancer. Microorganisms 2022;10(3):665 View Article PubMed/NCBI
  77. Nakae H, Tsuda A, Matsuoka T, Mine T, Koga Y. Gastric microbiota in the functional dyspepsia patients treated with probiotic yogurt. BMJ Open Gastroenterol 2016;3(1):e000109 View Article PubMed/NCBI
  78. Ianiro G, Pizzoferrato M, Franceschi F, Tarullo A, Luisi T, Gasbarrini G. Effect of an extra-virgin olive oil enriched with probiotics or antioxidants on functional dyspepsia: a pilot study. Eur Rev Med Pharmacol Sci 2013;17(15):2085-2090 PubMed/NCBI
  79. Ohtsu T, Takagi A, Uemura N, Inoue K, Sekino H, Kawashima A, et al. The Ameliorating Effect of Lactobacillus gasseri OLL2716 on Functional Dyspepsia in Helicobacter pylori-Uninfected Individuals: A Randomized Controlled Study. Digestion 2017;96(2):92-102 View Article PubMed/NCBI
  80. Browne AS, Kelly CR. Fecal Transplant in Inflammatory Bowel Disease. Gastroenterol Clin North Am 2017;46(4):825-837 View Article PubMed/NCBI
  81. Tian H, Ge X, Nie Y, Yang L, Ding C, McFarland LV, et al. Fecal microbiota transplantation in patients with slow-transit constipation: A randomized, clinical trial. PLoS One 2017;12(2):e0171308 View Article PubMed/NCBI
  82. El-Salhy M, Patcharatrakul T, Gonlachanvit S. Fecal microbiota transplantation for irritable bowel syndrome: An intervention for the 21(st) century. World J Gastroenterol 2021;27(22):2921-2943 View Article PubMed/NCBI
  83. Wang JW, Kuo CH, Kuo FC, Wang YK, Hsu WH, Yu FJ, et al. Fecal microbiota transplantation: Review and update. J Formos Med Assoc 2019;118(Suppl 1):S23-S31 View Article PubMed/NCBI
  84. Zhang T, Lu G, Zhao Z, Liu Y, Shen Q, Li P, et al. Washed microbiota transplantation vs. manual fecal microbiota transplantation: clinical findings, animal studies and in vitro screening. Protein Cell 2020;11(4):251-266 View Article PubMed/NCBI
  85. Newberry C, Lynch K. The role of diet in the development and management of gastroesophageal reflux disease: why we feel the burn. J Thorac Dis 2019;11(Suppl 12):S1594-S1601 View Article PubMed/NCBI
  86. Tosetti C, Savarino E, Benedetto E, De Bastiani R, Study Group for the Evaluation of GERD Triggering Foods. Elimination of Dietary Triggers Is Successful in Treating Symptoms of Gastroesophageal Reflux Disease. Dig Dis Sci 2021;66(5):1565-1571 View Article PubMed/NCBI
  87. Yancy WS, Provenzale D, Westman EC. Improvement of gastroesophageal reflux disease after initiation of a low-carbohydrate diet: five brief case reports. Altern Ther Health Med 2001;7(6):120 PubMed/NCBI
  88. Austin GL, Thiny MT, Westman EC, Yancy WS, Shaheen NJ. A very low-carbohydrate diet improves gastroesophageal reflux and its symptoms. Dig Dis Sci 2006;51(8):1307-1312 View Article PubMed/NCBI
  89. Wu KL, Kuo CM, Yao CC, Tai WC, Chuah SK, Lim CS, et al. The effect of dietary carbohydrate on gastroesophageal reflux disease. J Formos Med Assoc 2018;117(11):973-978 View Article PubMed/NCBI
  90. Gu C, Olszewski T, King KL, Vaezi MF, Niswender KD, Silver HJ. The Effects of Modifying Amount and Type of Dietary Carbohydrate on Esophageal Acid Exposure Time and Esophageal Reflux Symptoms: A Randomized Controlled Trial. Am J Gastroenterol 2022;117(10):1655-1667 View Article PubMed/NCBI
  91. Ustaoglu A, Nguyen A, Spechler S, Sifrim D, Souza R, Woodland P. Mucosal pathogenesis in gastro-esophageal reflux disease. Neurogastroenterol Motil 2020;32(12):e14022 View Article PubMed/NCBI
  92. Söderholm JD. Stress-related changes in oesophageal permeability: filling the gaps of GORD?. Gut 2007;56(9):1177-1180 View Article PubMed/NCBI
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