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Microbiome and gastroesophageal disease: Pathogenesis and implications for therapy

Steve M D’Souza

Department of Internal Medicine, Eastern Virginia Medical School, Norfolk VA, USA

E-mail : bhuvaneswari.bibleraaj@uhsm.nhs.uk

Lindsey B Cundra

Department of Internal Medicine, Eastern Virginia Medical School, Norfolk VA, USA

Byung S Yoo

Department of Internal Medicine, Eastern Virginia Medical School, Norfolk VA, USA

Parth J Parekh

Department of Internal Medicine, Eastern Virginia Medical School, Norfolk VA, USA

Gastroenterology Division, Eastern Virginia Medical School Norfolk VA

David A Johnson

Gastroenterology Division, Eastern Virginia Medical School Norfolk VA

DOI: 10.15761/GHE.1000199

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Abstract

There is growing evidence that gastroesophageal disease is significantly influenced by the microbiome of the esophagus. Additionally, the commensal microbiome of the oropharynx, stomach, and colon have a role in its pathogenesis. Changes to the composition of the normal esophageal flora, notably a transition from Gram-positive to predominantly Gram-negative, is thought to promote disease susceptibility.

Diseases of the esophagus, which include gastroesophageal reflux, Barrett's esophagus, esophageal cancer, esophageal dysmotility, as well as eosinophilic esophagitis. These are all characterized by an inflammatory-mediated cascade thought to be propagated, in part, potentially by an imbalance of commensal microbes.

In addition to activation of the inflammatory cascade, potentiation of dysbiosis itself may be a consequence of dysbiotic changes in bacterial composition. Bacteriocins are inhibitory polypeptides produced by bacteria, which may play an integral role in further progression to dysbiotic states by inhibiting growth of commensal flora. Accordingly, this may present an avenue for disease mitigation by shifting the composition of the microbial community towards an eubiotic state.

Therapeutic options targeting the microbiome, including prebiotics, probiotics, antibiotics, as well as bacteriocins have been studied. This review focuses on the current knowledge of the involvement of the microbiome in esophageal diseases (most notably GERD/Barrett’s esophagus/esophageal cancer) and identifies emerging new concepts for treatment.

Key words

microbiome, GERD, probiotics, prebiotics, bacteriocins, dysbiosis, Barrett’s esophagus, esophageal cancer, esophagitis

Introduction

Gastroesophageal disease is a major source of health and economic cost worldwide that is estimated at $18.1B annually. Gastroesophageal reflux disease (GERD) is the most common esophageal pathology, with 31% of the United States population reporting heartburn or reflux symptoms within the past week [1,2]. Esophageal cancer also poses a significant burden of disease, with >18,000 new diagnoses and >16,000 deaths estimated in 2020 [3]. Changes in understanding of the molecular pathway-driven pathogenesis of the esophageal disease have contributed to the development of many therapeutic options.

There has been a recent meteoric rise in the literature demonstrating the significance of the gut microbiome and dysbiosis, defined as microbial imbalance or maladaptation, in the pathogenesis of gastrointestinal (GI) disease [4]. This review aims to review the current literature for microbiome-related pathogenesis of gastroesophageal disease and to discuss disease-mitigation strategies and future research.

Normal gastroesophageal microflora

The esophageal microbiome is shaped by the oral cavity, oropharynx, and stomach due to migration of oral bacteria to the esophagus and reflux of gastric microbiota. There have been multiple attempts to classify the healthy esophageal flora into different cluster types. One study that evaluated healthy and GERD patients demonstrated two microbiome types, referred to as Type I and Type II [5]. Type I microbiomes consisted primarily of Gram-positive microbes, dominated by those within the Streptococcus genus. Type II microbiomes were dominated by Gram-negative flora and were at higher risk of developing reflux-related esophageal disease. One hypothesis for this effect is the activation of Toll-like receptors (TLRs) by Gram-negative bacterial products and a subsequent propagation of the inflammatory cascade [6]. Another study further classified esophageal biomes into three community types: one type dominated by Streptococcus spp., one by Prevotella spp., and one with intermediate predominance of Streptococcus, Prevotella, Haemophilus, and Rothia spp [7].

The composition of esophageal flora is closely linked to the gastric and oral flora. There is a notable similarity of prevalent genera such as Streptococcus, Prevotella, Haemophilus, Fusobacterium, and Neisseria, which are highly prevalent in both the stomach and oral cavity [8]. One major difference in composition between areas is the presence of Helicobacter pylori in the stomach. This organism, causally linked to gastroduodenal ulceration and inflammation, colonizes the gastric mucosa due to its ability to survive within the strong acidic conditions and is thereby less likely to be found in the esophageal compartment [9,10].

Dysbiosis in disease states

Gastroesophageal reflux disease

It is well recognized that GERD is an inflammatory disease state affecting the lower esophagus related to transient or chronic lower esophageal sphincter insufficiency. Retrograde reflux of gastric acid with or without bile causes symptoms and inflammatory changes associated with GERD. The most frequent treatment for GERD is directed at gastric acid reduction via acid suppressors such as proton-pump inhibitors (PPIs) or histamine-2 receptor antagonists (H2RAs), antacids as well as lifestyle modification [11]. Untreated GERD may progress further and manifest with complications of erosive esophagitis, esophageal stricture, or Barrett’s esophagus (BE) [11].

Inflammatory pathogenesis of GERD

The mucosal inflammation seen histologically in GERD was classically thought of as a consequence of direct chemical injury from gastric acid reflux, however, literature has demonstrated an inflammatory-cascade mediated pathogenesis. The specific factors contributing to epithelial insult are mainly gastric acid and duodenal bile salts. There are also many protective factors against the subsequent inflammatory response, such as a barrier of stratified squamous epithelium, paracellular adhesion, and intracellular buffering [12]. Bypassing or overwhelming these protective mechanisms leads to cellular injury and an inflammatory cascade [12]. In-vitro and in-vivo exposure of lower esophageal keratinocytes to duodenal acidified-bile salts such as those from duodenogastric reflux promotes local cytokine production and migration of lymphocytic cells, primarily T-cells [13]. Progression of exposure leads to inflammation of mucosa but preservation of the epithelial cell layer, implying that the main insult to the mucosa is deep rather than superficial. This suggests that the pathogenesis of reflux esophagitis is primarily inflammation-driven rather than chemically driven. A study examining biopsies from patients with GERD before and after treatment with PPIs confirmed proliferation of T-cells, hyperplasia of basal cells, and papillary elongation without damage to surface cells [14]. This study also confirmed the role of PPIs in the reversibility of these histological changes.

Following acid exposure, various inflammatory mediators produced by the mucosa also contribute to lower esophageal sphincter (LES) relaxation. Production of IL (Interleukin)-8, among other induced factors including transient receptor potential channel vanilloid subfamily member-1, substance P, calcitonin gene related peptide, and platelet activating factor, stimulates migration of immune cells. These factors also induce further IL activation and subsequent NADPH oxidase production of hydrogen peroxide. This peroxide effect on local smooth muscle leads to LES relaxation [15]. IL-8 production is also found to be inhibited by PPIs such as omeprazole through a mechanism involving nuclear factor kappa-light-chain-enhancer of activated B cells (NF-κB) and activator protein-1, and this may be a contributing factor to the therapeutic effect of PPIs in GERD [16].

Role of the microbiome in GERD

Recognizably, lipopolysaccharide (LPS) is the most abundant in the cell wall of Gram-negative bacteria [17]. The TLR-4 protein site in humans is the sensing receptor that mediates LPS-induced signal transduction. Following disruption of the epithelial barrier, increased LPS-TLR-4 binding activates production of IL-18, which induces a cascading inflammatory response [6]. This activation of TLR-4 is pivotal for both infectious and noninfectious (e.g. allergic or autoimmune) related inflammation and is a major mechanism for pathogenesis of inflammatory disease states by Gram-negative flora [18]. 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 chemokines and mediators promote slower esophageal sphincter relaxation and cyclooxygenase (COX)-2 activity, which leads to delayed gastric emptying [19]. This is exemplified in literature discussing Campylobacter spp., specifically Campylobacter concisus, which is observed only in patients with esophageal pathology [20]. C. concisus, a common oral flora, is not often found in the healthy esophagus. However, colonization by the organism was observed at the site of histologic changes due to GERD and BE in addition to a strong correlation between C. concisus and an increased level of IL-18 [20,21].

This association suggests the presence of a biofilm, a structurally organized community of flora that stimulate local microbial secretion of an environmentally protective coating and adhesion molecules. Biofilms have been observed in association with GI disease, most notably in oral and colonic pathology [22,23]. Biofilm-associated proliferation may present a framework for understanding esophageal pathology although further research into not just the composition of native flora, but their three-dimensional organization is needed [20].

Therapeutic regimens, especially PPIs, have been demonstrated to alter both the gastroesophageal as well as colonic microbiomes. The use of PPIs in GERD patients has been demonstrated to decrease diversity of gastric, esophageal, and fecal flora [24-26]. It is unclear if this is a protective or injurious effect although this could be a contributing factor for increased infection risk and may play a role in the association with fecal microbiome-related disease such as Clostridium difficile infection [27].

The role of H. pylori colonization or infection and association with GERD has been controversial. Although patients who are H. pylori positive may not demonstrate clinical signs of disease and fall within the “healthy” category, colonization may be associated with reduction of gastric microbial diversity [28-29]. The significance of this effect on esophageal disease is unclear. Several studies have demonstrated an inverse correlation with H. pylori infection and severity of reflux-related disease, with support from work suggesting that eradication of H. pylori is associated with worsening of GERD [30-33]. This effect appears to be limited to specific pro-inflammatory subtypes, including strains associated with gastritis and strains expressing inflammatory cytotoxin-associated gene A (cagA) [34]. It is theorized that decreased acid production in H. pylori gastritis-associated strains may contribute to decrease in GERD symptoms. There is some conflicting data as there are several analyses that suggest no association of H. pylori infection with symptoms or pathologic changes associated with GERD nor eradication of infection with increase in GERD symptoms [35-37]. Given the significant morbidity associated with H. pylori related peptic ulcer disease, eradication remains the current recommendation [33]. Further research into the inflammatory mechanism behind the protective effects of specific subtypes, however, may play a role in future therapeutic approaches to GERD.

It has been theorized that metabolic activity of the colonic biome may further contribute to GERD progression [38]. Colonic breakdown of fermentable oligo-, di-, monosaccharides and polyols (FODMAPs) produces short-chain fatty acids (SCFAs) that contribute to lower esophageal sphincter (LES) relaxation [39,40]. The mechanism for this may be through stimulation of Peptide YY (PYY) production [41]. Both SCFA as well as PYY act to inhibit gastric motility as well as to relax lower esophageal sphincter tone, resulting in retention of gastric contents as well as susceptibility to reflux, which has implications for dietary intake and colonic microbiome alteration within the scope of GERD [40].

Barrett’s esophagus

Barrett’s esophagus (BE) is an intestinal metaplasia of the distal esophageal epithelium characterized by transition from normal stratified squamous epithelial composition to columnar mucosa [42,43]. This occurs in response to chronic inflammation of mucosa secondary to reflux, and it carries a premalignant risk for esophageal adenocarcinoma (EAC) [5,9,44].

Inflammatory pathogenesis of BE

As seen in the pathogenesis of GERD, cytokines IL-1B, IL-6, and IL-8 have a close causational relationship with the metaplasia in BE. A mouse model of BE demonstrated that IL-1B and IL-6 are overexpressed at the squamocolumnar junction of the esophagus and promote an inflammation of gastric cardiac stem cells [45]. The inflammation further leads to alteration of stem cell niche and provides a pathway for progression to dysplasia. Another mouse model of Barrett’s esophagus has revealed that a high fat diet (HFD) is associated with esophageal dysplasia through alteration of the microbiome [46]. HFD increases production of IL-8/C-X-C Motif Chemokine Receptor 1 chemokines, known to be upregulated in a pro-inflammatory state, and the cytokines stimulate the migration of immature granulocytic cells in the esophagus promoting local inflammatory responses [46].

With the predominance of Gram-negative species in the distal esophagus via the increased LPS ligands, as seen in GERD, there is a consequent pro-inflammatory response through an increased release of chemokine/cytokine. The host’s response to the increased Gram-negative LPS results in NF-κB activation of the epithelial cells. NF-κB molecular pathway serves as an initial responding step from noxious stimuli (chemical, bacterial, and viral) and assumes a role of upregulating inflammation, innate immune responses, adaptive responses, apoptosis inhibition, cell proliferation and differentiation. IL-1B and IL-8 are increased as a result of NF-κB activation and the secreted cytokines create a positive feedback loop eliciting a more robust innate immune response in BE [19].

Role of the microbiome in BE

As seen in patients with GERD, patients with BE have a distinct microbiome composition [47]. Type II microbiomes, as described earlier, are associated with progression of GERD to BE [48]. The species in dominance are Veillonella, Prevotella, Haemophilus, Neisseria, Fusobacterium, Rothia, Granulicatella, Campylobacter, Porphyromonas, Fusobacterium, and Actinomyces spp. Type II microbiomes demonstrate a decrease in Streptococcus spp. and an increase in Gram-negative anaerobes/microaerophiles including Veillonella, Prevotella, Haemophilus, Neisseria, Rothia, Granulicatella, Campylobacter, Porphyromonas, Fusobacterium, and Actinomyces spp [5]. This transition from Gram-positive to Gram-negative predominance is what is believed to be a contributing factor to pathogenesis of esophagitis as well to drive metaplastic progression to BE [48,49]. It is also possible that gastric acid could contribute to conversion from Type I to Type II microbiome by killing acid-sensitive bacteria in the esophagus [50].

Molecular products secreted by these flora or components of the bacterial wall such as LPS interact with TLRs and continue the inflammatory cascade seen in reflux esophagitis, preventing resolution of mucosal changes. During the ongoing inflammatory process of reflux esophagitis, changes in the local flora predispose the local squamous epithelial tissue towards metaplasia to columnar epithelium. Wild-type murine models given an HFD demonstrated increase in goblet cell prevalence and relative neutrophil presence compared to germ-free models [46]. This suggests that local microbe-epithelium interactions, presumed to be through microbe product-TLR binding, is a possible mechanism for the metaplastic process. Furthermore, there may be a role of the colonic microbiome in this process as an increase of the Firmicutes:Bacteroidetes ratio within the colon is seen in BE [46]. Firmicutes spp. metabolize FODMAPs and dietary fiber into SCFAs. As previously described, SCFA production is associated with decreased LES tone as well as decreased gastric motility through stimulation of PYY mediated smooth muscle effects [40].

There is considerable overlap between periodontal and esophageal flora, with a similar high Firmicutes/Bacteroidetes ratio [51]. It is presumed that this similarity in composition is mainly from movement of microbes in an aboral direction. However, a recent study found a distinct oral microbiome that is associated with presence of BE.47 This case-control study analyzed the oral microbiome using a three-taxon model, Lautropia, Streptococcus, and unspecified genus in the order of Bacteroidales and distinguished the microflora of patients with BE from healthy individuals. This model of clustering predicted patients with BE with a sensitivity of 97% and specificity of 88%.47 Larger investigations are needed to further evaluate the role of oral dysbiosis and diagnostic implications for BE as various environmental factors including diet can influence the oral microbiome and larger sample size is needed to isolate the predictive effect [52].

Esophageal cancer

Esophageal cancer is one of the most frequent cancers worldwide. Squamous cell carcinoma and adenocarcinoma comprise the two major histological subtypes [53]. Globally, esophageal squamous cell carcinoma (ESCC) is the most common of the two, making up approximately 88% of esophageal cancers, with an unchanging global incidence [53,54]. Risk factors for both malignancies overlap, their etiologies and incidence vary [55].

Inflammatory pathogenesis

Adenocarcinoma

The etiology of EAC has been associated with long standing inflammation or mucosal injury, such as that seen in reflux esophagitis. The pathophysiology contributing to this disease state is complex involving an interplay between environmental factors, genetic susceptibilities, and host dynamics. However, approximately 80% of cases can be attributed to GERD, cigarette smoking, obesity, and low fruit and vegetable consumption [56]. GERD is the strongest risk factor for EAC, correlating strongly with duration and frequency of symptoms. Other risk factors include BE, motor disorders of the esophagus, other malignancies, medications, and environmental exposures [57]. BE is the risk factor that has the strongest association with EAC with estimates that BE progresses to high-grade dysplasia at a rate of 0.5% to 0.9% per year [58]. However, EAC, like the complications of GERD discussed above, can arise without preceding symptoms. As discussed previously, the pathogenesis of GERD follows an inflammatory-mediated cascade rather than through direct mucosal injury. On the contrary, GERD is not a risk factor for ESCC, which is additionally associated with age, socioeconomic status, and human papillomavirus.

Recent epidemiological studies have observed that the incidence of esophageal adenocarcinoma to be on the rise in the Western world, with a 6-fold increase in the United States alone [59]. The recent rise in incidence in the Western world suggests an environmental etiology at play. Studies have explored factors such as diet, smoking, obesity, H. pylori infection, and antibiotics [50].

Squamous cell carcinoma

Esophageal squamous cell cancer is a complex disease, with many predisposing factors, involving both genetic as well as environmental components. Incidence of the disease is influenced by environmental exposure, but there is regional variation to the nature of exposure. The highest areas of incidence include East Asia, Southeastern Africa, and Southeastern South America [54]. Smoking and tobacco use are the most common risk factors in wealthier populations, while hot-liquid consumption, dietary carcinogens, and poor dentition contribute enough to incidence that poverty itself is a risk factor for pathogenesis [54,60,61]. There is a growing body of literature evaluating genetic susceptibility that may increase carcinogenesis following an environmental trigger [54].

Pathogenesis of ESCC is associated with overexpression of inflammatory mediators. Persistent production of NF-κB and activation of TLR-4 have both been demonstrated to be present in early stage ESCC and are decreasing with progression to advanced stages [62]. TLR-4 in particular activates an innate inflammatory response with subsequent activation of an acute to chronic inflammatory cascade [63]. This suggests that the presence of external factors that affect the local mucosa-microbe interaction leads to a localized inflammatory reaction, and that persistence of this inflammation coupled with a genetic predisposition triggers hyperproliferation of squamous tissue and progression to carcinoma.

Role of the microbiome in esophageal cancer

There is a growing body of evidence investigating the relationship between the microbiome and esophageal cancer [64]. The microbiome is altered in precursors to esophageal carcinoma, such as the abnormal Type II microbiomes with enriched gram-negative bacteria that are mainly associated with GERD and BE. This alteration of the microbiome is potentially involved toward carcinogenesis. The microbiota of cancerous esophageal tissue has been characterized to be profoundly affected by the oral microbiome and periodontopathic species derived from the oral cavity. Oral microbial composition has been associated with risk of EAC and ESCC [64]. In fact, a multitude of studies implicate oral bacteria in the etiology of oral, esophageal, gastric and other gastrointestinal cancers [65]. Due to bacteria migration, the oral and gastric microbiota shape the esophageal microbiome and therefore may contribute to esophageal carcinogenesis [64]. However, there are variations in microbiota even between ESCC and EAC.

Adenocarcinoma

The microbiome of EAC has been characterized predominantly by periodontopathic species derived from the oral microbiome: Treponema denticola, Streptococcus mitis, and Streptococcus anginosus [66]. This indicates periodontitis and inadequate oral hygiene may be associated with increased esophageal cancer risk [67]. In particular, fragments of S. anginosus has been isolated in head and neck carcinomas as well as in early dysplastic changes of esophageal and gastric cancer [68]. This implies that S. anginosus is associated with numerous malignancies of the upper digestive tract. The exact mechanism underlying this process has not been delineated. However, induction of inflammatory cytokines by infection of S. mitis and S. anginosus has been demonstrated [66]. Other periodontal species have been associated with esophageal cancer.64 For instance, it has been found that the periodontal pathogens Tannerella forsythia, Veillonella, Selenomonas, and Treponema denticola to be associated with higher risk of EAC [69,70].

On the contrary, several periodontal species were also associated with a reduced risk of EAC [64]. This implies that specific bacteria can lower malignant transformation. Further evidence of this inverse correlation is provided by lower EAC risk is associated with infection with H. pylori [64]. In one study, the microbiome in both normal subjects and EAC was characterized to be more alike than to BE comparisons, with an increased relative abundance of Bifidobacteria, Bacteroides, Fusobacteria, Veillonella, Staphylococcus and Lactobacilli and decreased relative abundance of Campylobacter when compared with BE samples [20]. Other protective factors such as bacterial biosynthesis of carotenoids were also associated with protection against EAC [64]. One possible explanation is that specific bacterial infection inhibits the metaplastic process via synthesis of vitamins or by preventing pathogen invasion in commensal species changes.

However, lower EAC risk has also been associated with depletion of certain bacteria. For instance, depletion of the commensal genus Neisseria64 and the species Streptococcus pneumoniae were associated with lower EAC risk [71]. This is corroborated by other studies wherein microbial diversity has also been shown to be decreased [70,72]. It has been postulated that once carcinogenesis has begun, Streptococcus leaves the cells to invade surrounding tissue [71]. Further, the microbiota associated with EAC may change depending on other risk factors such as obesity, complicating the findings.

Toll-like receptors (TLRs) are a class of proteins that play a key regulatory role within the innate immune system. A potential mechanism by which the microbiome participates in carcinogenesis, is via TLRs [70]. TLRs 1-3, 6, 7 and 9 are significantly upregulated in EAC [71]. Both TLR-4 and TLR-5 have also been suggested as potential mediators of the progression from reflux disorders to EAC. This suggests an association between the TLR signaling pathway and the altered microbiome. In tissue biopsies from the esophagus, TLR-4 (whose natural ligand is LPS) expression is significantly increased in EAC and BE when compared to normal esophagus [50]. Further, activation of the TLR-4-NF-κB pathway is evident in reflux disorders and may contribute to malignant transformation [19]. Therefore, in the abnormal Type II microbiomes, where there is a predominance of Gram-negative bacteria, overstimulation of TLR-4 may trigger a larger and more carcinogenic inflammatory cascade. Further, expression of the COX-2 isoform, an LPS-TLR-4-NF-κB pathway downstream gene, is elevated in esophageal carcinomas. It has been found that there is an increase of COX-2 that occurs along the progression from low-grade dysplasia to high-grade dysplasia in the EAC pathway [73]. This implies that the activation of the LPS-TLR-4-NF-κB pathway may contribute to malignant transformation. This theory has been experimentally tested in a murine model wherein the presence of E. coli induced activation of TLRs implicated in EAC [71].

Squamous cell carcinoma

As with esophageal adenocarcinoma, ESCC has been shown to be associated with periodontal pathogens and poor oral hygiene [54,63]. Specifically, the abundance of the periodontal pathogen Porphyromonas gingivalis trended with higher risk of ESCC [74]. In one study, poor oral health was reported as a risk factor for esophageal squamous dysplasia [75]. To this point, oral SCC, also associated with poor oral hygiene, has been linked to changes in the oral microbiome (Firmicutes, Streptococcus, Actinobacteria, and Rothia), which were substantially decreased in relation to normal tissue [76]. Oral SCC has been shown to be accompanied with other squamous cell carcinomas of the digestive tract [77]. It has been suggested that a region of epithelial cells can be affected by carcinogenic alterations [78].

Subjects with ESCC have also been shown to exhibit decreased microbial diversity [63]. Interestingly, this decrease in microbial diversity has been replicated in other anatomical sites of the gastrointestinal system such as the stomach with gastritis [65] and the colon with colorectal cancer [79]. Gastric microbiota changes have also been associated with ESCC, and Clostridiales and Erysipelotrichales orders have been particularly implicated [80].

Esophageal dysmotility

Inflammatory pathogenesis

Altered neuromotor function leading to gastrointestinal dysmotility in response to mucosal inflammation has been described in esophagitis and ulcerative colitis [81]. In patients with GERD, an increase in cytokines and chemokines such as IL-1B, IL-6, IL-8, IL-10, Interferon-γ, monocyte chemoattractant protein-1, and Regulated-upon-Activation, Normal-T-Cell-Expressed-and-Presumably-Secreted (RANTES) are observed [82]. IL-6, a cytokine released as a result of mucosal damage, affects the circular smooth muscle cells in the lower third of the esophagus and ultimately disturbs muscle contractility. Although the exact mechanism of cytokine effects on neuroafferent cells is unknown, it is proposed that the increased number of cytokines are produced in exposure to gastric refluxate in GERD and that cytokines such as IL-6 are able to alter the esophageal contractility leading to esophageal dysmotility [83].

Role of the microbiome in esophageal dysmotility

While there are no studies directly evaluating the role of the local microbiome in pathogenesis of esophageal motility disorders, there are some investigations that have characterized the microbiome in achalasia, Chagas disease and connective tissue diseases such as systemic sclerosis. Additionally, a large volume of literature characterizes the effects of local flora on smooth muscle elsewhere along the GI tract, particularly the colon.

Although Chagas disease is a well-recognized consequence of infection by a tropical parasitic disease caused by Trypanosoma cruzi, samples of flora grown from patients with Chagas related megaesophagus has demonstrated a predominance of nitrite- and nitrate-reducing bacteria [84]. Further investigation of patients with achalasia and megaesophagus demonstrate an overgrowth of Streptococcus spp., many of which may act as nitrite-/nitrate-fermenters [85]. As previously described, Type I esophageal microbiomes are typically seen as ‘normal’ flora and consist primarily of Streptococcus spp. It is possible that the decrease in interaction between esophageal and gastric flora in various megaesophagus states leads to overgrowth of these Type I flora, although this has not clearly been characterized. Furthermore, increase in nitrite-/nitrate- fermentation, coupled with increased esophageal retention of food products may contribute to development of squamous cell carcinoma and may explain the increased risk that is seen in these patients [60,85].

As described previously in relation to GERD and BE, increase in the fecal Firmicutes/Bacteroidetes ratio corresponds with an increase in Firmicutes spp. Fermentation products, specifically SCFAs. SCFA and associated PYY downstream effects on gastric smooth muscle lead to decreased contraction [40]. This SCFA mediated effect following change in colon Firmicutes:Bacteroidetes ratio has also been demonstrated in cases of decreased colonic motility leading to constipation [86]. While their effect in the terminal ileum appears to be mainly stimulation of peristalsis following ileocolic reflux, effects elsewhere in the GI tract mainly appear to be decrease in motor tone [87]. More investigation is needed to isolate the effect of SCFA production on esophageal peristalsis.

Connective tissue diseases are associated with gut dysbiosis [88]. Most notably, systemic sclerosis, which can lead to fibrosis of the muscular layers of the GI tract and subsequent dysmotility, most frequently manifests in the esophagus [89]. Multiple studies investigating compositional changes in colonic flora have demonstrated decrease in commensal flora such as Bacteroides, Clostridium, and Faecalibacterium, and increase in invasive flora [90-93]. While the mechanism for dysbiotic contribution to fibrosis still requires more investigation, it is believed that epithelial barrier dysfunction leading to microbial inflammatory cascade activation may play a role [93].

Eosinophilic esophagitis

Eosinophilic Esophagitis (EoE) is a chronic immune mediated disorder that is characterized endoscopically by fixed esophageal rings, esophageal narrowing, and mucosal friability and diagnosed by biopsy findings of eosinophilic infiltration of the esophageal mucosa [94]. It is frequently associated with atopic disease, most frequently in male patients, and initially treated with a combination of an anti-inflammatory regimen, most often topical corticosteroids, and dietary modification to remove potential allergens.94

Inflammatory pathogenesis

EoE is a multifactorial disease, with several genetic components, frequently atopic condition associations, as well as environmental factors that are presumed to affect pathogenesis. The role of these various factors in development of EoE is still being characterized, and there are several explanations for its inflammatory origins. One theory is that repeat allergen exposure in susceptible individuals may contribute to eosinophil-driven inflammation [95]. This is highlighted in some data that demonstrates childhood PPI use with EoE as theoretically decreasing allergen digestion and prolonging exposure [96].

The progression of EoE is believed to be following genetic or environmental disruption of the epithelial barrier exposing the underlying mucosal tissue to local allergens and bacterial products. These products stimulate secretion of IL-1, IL-8, and migration of T-helper 2 (Th2) cells, which produce IL-5 and stimulate recruitment and activation of eosinophils, as well as IL-13, which stimulates downregulation of desmoglein-1, a cell adhesion molecule integral to the maintenance of the epithelial barrier [97,98]. Local activation of eosinophils leads to toxic degranulation that further simulated local inflammation as well as transforming-growth factor (TGF) expression, which mediates structural protein deposition and leads to the characteristic endoscopic and histologic fibrotic findings [97,99].

Role of the microbiome in EoE

Esophageal mucosal eosinophilia and its associated diseases are characterized by a change in the local microbiome [100]. For instance, it has been reported that in patients with active EoE, the microbiome contains a significant increase in Haemophilus spp [100]. Further, this change was mitigated following standard of care EoE treatment to a microbiome found in GERD and healthy subjects. Further, the bacterial load but not the diversity was increased in subjects with EOE and GERD as compared to healthy controls [100]. However, in another study, patients with active EoE had a significant increase in Neisseria spp. and Corynebacterium spp. compared with controls with mitigation of effect following standard of care EoE treatment [101].

Composition of more proximal flora may also contribute to pathogenesis of EoE. A study of the salivary microbiome in pediatric patients demonstrated significant differences in bacterial composition in EoE patients compared to non-EoE controls [102]. Most specifically, there was an association with Haemophilus spp. with active disease, similar to the changes seen in esophageal samples. This suggests a close interaction between the flora of both locations, and that characterization of salivary dysbiosis may be a surrogate marker for EoE disease activity [100,102].

Role of bacteriocins

Bacteriocins are small peptide molecules that are expressed by bacteria in response to stress. Their primary role is presumed to be inhibition of competitive local flora, but they play a larger role in regulation of the microbiota within the human GI tract. They have been traditionally used with the food industry internationally for preservation, but their role in combination with antibiotics as well as their role in inhibition of carcinogenesis are still developing [103]. These bacterial products are typically classified by nature of bactericidal activity, genetic structure, size, and method of production, and they can separately be classified by expression from Gram-positive or Gram-negative flora [104].

A clear direct effect of bacteriocins would include direct antibiotic effect or incorporation as adjuvants into the current antibiotic generation. These inhibitory effects lead to changes in composition of the local flora. The local stress on the commensal flora may induce Gram-negative bacteriocin production and drive the local flora composition to be more Gram-negative dominant, or towards a Type II microbiome. This may contribute to the esophageal dysbiosis that is associated with progression of reflux-related disease.

Another potential role of bacteriocins is in their antineoplastic effect. Thus far, the majority of research regarding their role has been on the colorectal adenoma-adenocarcinoma pathway. In this pathway, increase in bacteriocins from Gram-negative bacteria, specifically microcins and colicins, has been documented to correlate with progression of disease. This increased bacteriocin concentration consists primarily of specific expression of Gram-negative derived colicins and microcins [103]. These small polypeptides are both protective against competitive flora as well as promote direct cytotoxic effect on local tumor cells, though this effect is still being clarified.103 In the EAC pathway, it is possible that a similar shift in bacteriocin production may contribute to local cytotoxic effect, though a specific cytokine mediated pathway is still being identified.

Implications for therapy

Prebiotics

There is increasing evidence that dietary intake has a profound effect on microbiome balance. This effect plays a key role in reducing dysbiosis related induction of inflammatory signaling cascades [105-107]. Due to the developing understanding of the role of the microbiota, especially Gram-positive/Gram-negative ratio, in the pathogenesis of gastroesophageal disease, this presents a promising avenue for therapeutic intervention through utilization of bacteriocin based therapies. Bacteriocins, as mentioned in earlier sections, are bacterial polypeptide products that target a narrow spectrum of competitive flora and inhibit growth. They are also inactivated by enzymatic degradation, decreasing toxicity and limiting diffuse inhibitory effects. Prebiotics, including Maltosyl-isomaltooligosaccharide (MIMO), are aimed at improving Gram-positive/Gram-negative ratio. Isomaltooligosaccharides have been demonstrated at increasing the number of Gram-positive flora, especially Lactobacillus spp. It is theorized that this increase in Gram positives coincides with an increase in bacteriocins that inhibit proliferation of Gram-negative flora. This intervention type has been evaluated with some potential in reducing or eliminating GERD symptoms in case series [108].

Probiotics

The use of probiotics to modify the gut microbiome has been trialed in a variety of GI disease states, and there are several investigations into usage to decrease GERD symptoms. Probiotic formulations that include strains mainly within the genera Lactobacillus and Bifidobacterium have been studied and have demonstrated reduction in symptoms when used as monotherapy [109-112]. However, many studies are limited by quality due to limitations in experimental design such as producing an adequate placebo for control [113]. A randomized-controlled study utilizing Bacillus subtilis and Enterococcus faecium with PPI demonstrated decrease in diarrhea symptoms and small intestinal bacterial overgrowth but did not reduce GERD symptoms or healing rate compared to PPI alone [114]. Additionally, recent evidence demonstrated that although orally administered probiotics can remain viable, there may be a marked mucosal colonization resistance by the host [115].

Antibiotics

Antibiotics are also a possible therapeutic option for modifying the microbiome, given their efficacy in the treatment of GI infectious diseases. While routine use of antibiotics for the treatment of esophageal disease has not been investigated, it has been used with success elsewhere in the GI tract for dysbiosis related disease states. In patients with small intestinal bacterial overgrowth (SIBO), a condition characterized by proliferation of commensal flora within the small bowel, antibiotics with poor oral bioavailability such as rifaximin have been used with efficacy, though data on the use of systemic antibiotics is limited [116]. Given the implications of emerging bacterial resistant pathogens and risk for C. difficile colitis, it is not likely that this approach will be viable for esophageal diseases [117,118].

Bacteriocins

Another possible avenue for intervention is direct bacteriocin utilization and delivery. As previously mentioned, bacteriocins have a potential use through two mechanisms, direct antibiotic effect as well as cytotoxic effect towards neoplastic cells. While this is an active area of research, and inhibitory isolates that target Methicillin-resistant Staphylococcus aureus [119] and Vancomycin-resistant Enterococcus [120] have been isolated, more research is needed regarding products that target primarily Gram-negatives as well as subsequent literature to evaluate for efficacy and safety [120]. Two potential weaknesses that bacteriocins as therapeutic agents may have is decreased efficacy due to early digestion of products prior to reaching the target site as well as cytotoxic effects on non-target tissues. Fortunately, one promising solution is utilization of similar methods for target drug delivery, encapsulation or attachment to bacteriocins to macromolecule-based, metal, or polymer-based nanoparticles [121]. This has the added potential for modulating or increasing intended effect through attachment of adjuvants to the same nanodelivery particles.

Conclusions

Dysbiosis of the local flora within the esophagus is associated with progression to various gastroesophageal disease states, including the gastroesophageal reflux disease, reflux esophagitis, Barrett’s esophagus, esophageal adenocarcinoma pathway, as well as esophageal squamous cell carcinoma, dysmotility, and eosinophilic esophagitis. This dysbiosis manifests through various mechanisms, including upregulation of inflammatory pathways through altered gut-microbe interaction as well as changes in composition through secretion of bacteriocins and subsequent local bactericidal and cytotoxic effects. Further understanding of these interactions may suggest potential therapeutic options. At present, prebiotics and perhaps direct bacteriocin therapies have the most promising potential for esophageal disease.

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Editorial Information

Editor-in-Chief

Marcel CC Machado
University of Brazil

Article Type

Review Article

Publication history

Received date: March 02, 2020
Accepted date: March 19, 2020
Published date: March 23, 2020

Copyright

©2020 D’Souza SM. This is an open-access article distributed under the terms of the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited.

Citation

D’Souza SM, Cundra LB, Yoo BS, Parekh PJ, Johnson DA (2020) Microbiome and gastroesophageal disease: Pathogenesis and implications for therapy. Gastroenterol Hepatol Endosc 5: doi: 10.15761/GHE.1000199

Corresponding author

David A. Johnson

Gastroenterology Division, Eastern VA Medical School, Norfolk VA, USA

E-mail : bhuvaneswari.bibleraaj@uhsm.nhs.uk

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