microbiome in reflux disorders and esophageal adenocarcinoma pdf

Microbiome In Reflux Disorders And Esophageal Adenocarcinoma Pdf

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While intestinal microbiomes have been relatively well studied, upper gastrointestinal tract microbiomes have not been thoroughly evaluated. Especially, studies on esophageal microbiomes are relatively limited.

Metrics details. The esophageal microbiome has been proposed to be involved in a range of diseases including the esophageal adenocarcinoma cascade; however, little is currently known about its function and relationship to the host.

Ann Clin Gastroenterol Hepatol. DOI: ORCiD: orcid. This is an open access article distributed under the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited.

Microbiome in Reflux Disorders and Esophageal Adenocarcinoma

Ann Clin Gastroenterol Hepatol. DOI: ORCiD: orcid. This is an open access article distributed under the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited. FullText PDF. There is growing evidence that gastroesophageal disease is influenced by the esophageal microbiome, and that commensal bacteria of the oropharynx, stomach, and colon are thought to have a role in modulatiing pathogenesis.

There is an abundance of gram-positive bBacteria in the healthy esophagus. The esophageal bacterial population becomes increasingly gram negative with disease progression. Associated with this shift to a more gram negative prevalence is an increase in the potential for the presence of antigenic lipopolysaccharide LPS.

The immunoreactivity of LPS endotoxin thought to promote susceptibility to inflammation and disease. The pathogenesis of the more common diseases of the esophagus e. Emerging data suggest however, that these are all characterized by an immune-mediated inflammatory cascade, propogated by a dysbiotic state.

This dysbiosis thereby can create adverse inflammatory or immunoregulatory responses with progression of disease. In the normal healthy state, the esophageal microbiome is constituted in-part, by a multitude of gram positive bacteria, many of which produce antibacterial peptides called bacteriocins.

Bacteriocins are selective and used to maintain population integrity by killing off foreign bacteria. Therefore it seems rational that defining, perhaps that defining, perhaps cultivating, a protective bacterial community that could help prevent or mitigate inflammatory diseases of the esophagus.

Furthermore, in conjunction with evidence demonstrating that some bacteriocins are cytotoxic or antiproliferative toward cancer cell lines, further exploration might provide a rich source of effective peptide-based drug targets. Therapeutic options targeting the microbiome, including prebiotics, probiotics, antibiotics and bacteriocins, have been studied, albeit the attributable effects on the esophagus for the most part, have been unrecognized by clinicians.

Changes in understanding of the pathogenesis of the esophageal disease have contributed to the development of new possible 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 [5]. This article aims to review the current literature for microbiome-related pathogenesis of gastroesophageal disease and to discuss disease-mitigation strategies and areas for future research. 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.

Recognizably, this varies considerably from person to person, even in the apparently healthy population. There have been multiple attempts to classify the healthy esophageal flora into different cluster types. Type I microbiome associated with healthy subjects, consisted primarily of gram-positive microbes, dominated by those within the Streptococcus genus. Conceivably, the dysbiosis antedates the inflammation. In this hypothesis, there is a notable activation of Toll-like receptors TLRs by gram-negative bacterial products compounds produced by gram-negative bacterial, and a subsequent propagation of the inflammatory cascade [7] Figure 1.

Another study further classified esophageal biomes into three community types or clusters: one type dominated by Streptococcus spp. These clusters were associated with a variation in metabolic function.

The streptococcus cluster associated with pentose phosphate metabolism, the prevotella cluster was associated with lipopolysaccharide LPS production, and, the intermediate cluster was associated with glycolysis and short chain fatty acid SCFA production [8]. For all three clusters, progression to reflux-related esophageal disease was associated with increase in relative abundance of gram-negative flora.

The prevalent genera including streptococcus, prevotella, haemophilus, fusobacterium, and neisseria, appear similar in both the stomach and oral cavity, suggesting that the oronasal compartment is the primary source of bacteria in the aerodigestive tract [9].

Download Image. Gastroesophageal reflux disease: It is well recognized that GERD is an inflammatory disease state affecting the lower esophagus related to inappropriate transient relaxation or chronic hypotenisity, of the lower esophageal sphincter.

Retrograde reflux of gastric acid with or without bile causes symptoms and inflammatory changes associated with GERD [10]. The most frequent treatment medications are intended to buffer antacids or reduce gastric acid secretion are intended using proton-pump inhibitors PPIs or histamine-2 receptor antagonists [11].

Untreated GERD may progress and manifest with complications of erosive esophagitis, esophageal stricture, BE, or esophageal adenocarcinoma [11]. Inflammatory pathogenesis of GERD: Histologically, the mucosal inflammation observed in GERD is classically thought to be a consequence of direct chemical injury from gastric acid reflux. The specific factors contributing to epithelial insult were gastric acid and duodenal bile salts. Recent literature, has demonstrated that a concomitant immunogenic pathway exists.

It remains unclear however, whether erosive injury or cytokine-mediated inflammation via response to antigenic bacterial LPS occurs first. Biopsies of tissue from the distal esophagus in GERD patients frequently show submucosal cytokine-induced inflammation, but with intact epithelial cells. These findings are inconsistent with initial surface epithelial chemical injury erosion.

Therefore, a non-erosive mechanism is more likely, and would be the result of immunoreactivity to a foreign biomaterial. In this case, the literature implicates a pathway involving LPS, a well-recognized cell wall constituent of gram-negative bacteria.

This LPS is critical to maintain the bacterial cell integrity and viability, but also is a potent inducer of inflammatory responses and can directly modulate the immune system and susceptibility to disease [12]. There are however, also many protective factors against an inflammatory response, including the stratified squamous epithelial barrier, paracellular adhesion and intracellular buffering. Bypassing or overwhelming these protective mechanisms leads to cellular injury and an inflammatory cascade [10].

In vitro and in-vivo exposure of lower esophageal keratinocytes to 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 the 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 driven more by the innate immune system than by chemical insult.

A study examining biopsies from patients with GERD before treatment with PPIs confirmed histologic damage proliferation of T-cells, hyperplasia of basal cells, and papillary elongation without damage to surface epithelial cells [14]. Various inflammatory mediators produced by the mucosa also contribute to lower esophageal sphincter LES relaxation.

Production of interleukin IL -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 response cells.

This peroxide effect on local smooth muscle leads to LES relaxation [15]. It is also hypothesized that nitric oxide, another downstream result of cytokine-induced inflammation, is responsible for the relaxation of the LES and decreases gastric emptying [16].

It is vital for bacterial cell integrity, viability, and defense against environmental stress [18]. The TLR-4 protein site in humans is the best characterized of several sensing receptors which mediate LPS-induced signal transduction. Following disruption of the epithelial barrier, increased LPS-TLR-4 binding activates production of IL, which induces a cascading inflammatory response.

Used as a standard for inflammation in models of septic shock, LPS aka endotoxin is an intrinsic cell membrane component in gram-negative bacteria. It is a potent pathogen-associated molecular pattern PAMP which alerts the host immune system that something non-self is present [21]. The former induces nitric oxide synthase [22] and the latter affects the sensitivity to LPS [23].

The subsequent release of NO triggers both vasodilation and potentiates response by activated macrophages [24]. In smaller amounts, LPS triggers a localized inflammatory response. When the concentration of LPS is high, as it would be in septic shock, hypotension, thrombosis, and mortality can occur.

Chemokines also lead to production of nitric oxide and cyclooxygenase COX -2, which promote lower esophageal sphincter relaxation and delayed gastric emptying, respectively [26]. This is exemplified in literature discussing campylobacter spp.

However, colonization by the organism was observed at the site of histologic changes due to GERD and BE as well as inflammatory bowel disease [28]. Additionally, there is a strong correlation between C. The focal effects of bacterial colonization suggest a local bacterial adherence, facillitated by a biofilm formation. Biofilm, develops via a structurally organized community of flora that stimulate local microbial secretion of an environmentally protective coating frequently e.

Biofilms have been observed in association with GI disease, most notably in oral and colonic pathology [31,32]. Biofilm-associated proliferation may present a framework for understanding esophageal pathology although further research regarding the composition the composition of native flora, and their three-dimensional organization is needed [27]. Bacteria behave quite differently in bulk culture compared to when they are in an established biofilm.

Among other things, they are much harder to kill. Individual microbes are also much closer together than typical, which changes the quorum threshold and ultimately their behavior, including upregulation of bacteriocin synthesis [33]. 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 affect diversity of gastric, esophageal, and fecal flora, mainly by allowing more proximal organisms to populate more distal areas [].

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 [37].

Reduced diversity, e. The spores typical to all Clostridium spp. It has been theorized that metabolic activity of the colonic biome may further contribute to GERD progression [38].

The result is retention of gastric contents as well as susceptibility to reflux, which has implications for dietary intake and colonic microbiome as well as motility alteration within the scope of GERD [40].

These SCFAs, however, do not all have the same effect at least on the motility of the guinea pig colon. Butyrate increases frequency of propulsive colonic contraction, whereas propionate and acetate decrease this frequency [42]. Development is thought to be in response to chronic inflammation of the mucosa secondary to gastroesophageal reflux. The associated risks for esophageal adenocarcinoma EAC are well recognized [6,26,45]. A mouse model of BE demonstrated that IL-1B and IL-6 are overexpressed at the squamocolumnar junction of the esophagus and promote inflammation of gastric cardiac stem cells [46].

The inflammation provides a further pathway for progression to dysplasia. These type II microbiomes demonstrate a decrease in Streptococcus spp. This transition from gram positive to gram negative relative abundance is thought to be associated with the pathogenesis of esophagitis as well as the metaplastic progression to BE [50,51].

The levels of both are directly correlated with transition from metaplasia to dysplasia [52]. 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 [53].

Gram-negative organisms are more acid-resistant, and in many cases highly tolerant of bile, which is toxic for gram-positive organisms [54,55]. 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, changes in the local flora predispose the local squamous epithelial tissue towards metaplasia to columnar epithelium.

Wild-type murine models given a HFD demonstrated increase in goblet cell prevalence and relative neutrophil presence compared to germ-free models [47]. 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 [47].

Signatures within the esophageal microbiome are associated with host genetics, age, and disease

We explored the potential signature of esophageal microbiota and its predicted functional profile along the continuous spectrum from BE to EAC. We analyzed through 16S-based amplicon sequencing the mucosal microbiota and the microbiota-related functional predictions in 10 BE and 6 EAC patients compared with 10 controls, exploring also potential differences between the metaplastic mucosa BEM and the adjacent normal areas of BE patients BEU. Functional predictions identified peculiar profiles for each group with a high potential for replication and repair in BEM; an upregulated energy, replication and signaling metabolisms, with the fatty-acids biosynthesis and nitrogen and D-alanine pathways down-regulated in EAC. Our pilot study identifies a unique microbial structure and function profile for BE and EAC, as well as for metaplastic and near-normal areas. It proposes a new concept for BE, which could be intended not only as the histological, but, also, as the microbial closest precursor of EAC. This requires further larger follow-up studies, but opens intriguing horizons towards innovative diagnostic and therapeutic options for EAC. 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.

Keywords: microbiome; gastroesophageal reflux disease; proteome; esophageal adenocarcinoma; Barrett's esophagus; reflux esophagitis.

Microbiome in reflux disorders and esophageal adenocarcinoma.

The incidence of esophageal adenocarcinoma has increased dramatically in the United States and Europe since the s without apparent cause. Although specific host factors can affect risk of disease, such a rapid increase in incidence must be predominantly environmental. In the stomach, infection with Helicobacter pylori has been linked to chronic atrophic gastritis, an inflammatory precursor of gastric adenocarcinoma.

Many researchers have already identified some factors that may contribute to the development of BE and EAC, and the identified risks include gastroesophageal reflux GER , male sex, older age, central obesity, tobacco smoking, Helicobacter pylori H. The human gut harbors trillions of microorganisms, the majority of which are bacteria. These microorganisms benefit the human host in many ways, such as helping in digestion, assisting in the synthesis of certain vitamins, promoting the development of the gastrointestinal immune system, regulating metabolism and preventing invasion by specific pathogens. In contrast, microbial dysbiosis may play important roles in various diseases, such as inflammation and cancers. The composition of the microbiota located in the normal esophagus is relatively conserved without distinct microbial preferences in the upper, middle and lower esophagus.

Either your web browser doesn't support Javascript or it is currently turned off. In the latter case, please turn on Javascript support in your web browser and reload this page. Cancer Journal Sudbury, Mass. Review Free to read.

Microbiome and Gastroesophageal Disease: Pathogenesis and Implications for Therapy

Associations of the microbiome and esophageal disease

Several diseases of the esophagus have been increasing over the last few decades. While most other solid organ tumors have seen a decrease in incidence over the last 40 years, esophageal adenocarcinoma EAC has become more prevalent with time. This increase in the number of cases of EAC has been especially evident in Western countries and Asia.

 Вы знаете, кто. - Какая разница? - огрызнулся светловолосый. - Позвольте вам сразу кое-что объяснить, - сказал директор. Секунду спустя оба, залившись краской, делали доклад директору Агентства национальной безопасности. - Д-директор, - заикаясь выдавил светловолосый.

In the stomach, infection with Helicobacter pylori has been linked to chronic atrophic gastritis, an inflammatory precursor of gastric adenocarcinoma. However​, the.

Foregut microbiome in development of esophageal adenocarcinoma

Очевидно, там у него был адрес, который он сумел утаить. Это хорошо защищенный почтовый ящик, и мне лишь случайно удалось на него наткнуться.  - Он выдержал паузу.  - Итак, если Танкадо хотел, чтобы мы обнаружили его почту, зачем ему понадобился секретный адрес. Сьюзан снова задумалась.

Он еще не знает, что такое настоящая боль, подумал человек в такси. Девушка вытащила из кармана какой-то маленький предмет и протянула его Беккеру. Тот поднес его к глазам и рассмотрел, затем надел его на палец, достал из кармана пачку купюр и передал девушке.

Мне в самом деле пора идти, они связи, обещаю. - Дэвид! - крикнула.  - Что… Но было уже поздно.

Осколки посыпались вниз и попали ему в шею. Беккер рванулся влево, в другую улочку. Он слышал собственный крик о помощи, но, кроме стука ботинок сзади и учащенного дыхания, утренняя тишина не нарушалась ничем. Беккер почувствовал жжение в боку. Наверное, за ним тянется красный след на белых камнях.

Правильно ли она поняла. Все сказанное было вполне в духе Грега Хейла.

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    Esophageal adenocarcinoma EA , the type of cancer linked to heartburn due to gastroesophageal reflux diseases GERD , has increased six fold in the past 30 years.

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    Microbiome studies open a new avenue to the understanding of the etiology and pathogenesis of reflux disorders. Keywords: GERD, reflux esophagitis, Barrett's.

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