Microbiome changes associated with acute and chronic pancreatitis: A systematic review

BackgroundAltered intestinal microbiota has been reported in pancreatic disorders, however, it remains unclear whether these changes alter the course of disease in patients with acute (AP) and chronic pancreatitis (CP), or whether these disease states alter the environment to enable pathogenic microbial composition changes to occur. We undertook a systematic review to characterize the gut microbiome in pancreatitis patients.MethodsMEDLINE and EMBASE were searched for studies on microbiota in pancreatitis published from January 1, 2000 to June 5, 2020. Animal studies, reviews, case reports, and non-English articles were excluded. A frequency analysis was performed for outcomes reported in ≥2 studies and studies were analyzed for risk of bias and quality of evidence.Results22 papers met inclusion criteria; 15 included AP, 7 included CP. No studies were appropriately designed to assess whether alterations in the gut microbiome exacerbate pancreatitis or develop as a result of pancreatitis. We did identify several patterns of microbiome changes that are associated with pancreatitis. The gut microbiome demonstrated decreased alpha diversity in 3/3 A P studies and 3/3 C P studies. Beta diversity analysis revealed differences in bacterial community composition in the gut microbiome in 2/2 A P studies and 3/3 C P studies. Functionally, gut microbiome changes were associated with infectious pathways in AP and CP. Several studies suffered from high risk of bias and inadequate quality.ConclusionsDetecting differences in microbial composition associated with AP and CP may represent a diagnostic tool. Appropriately controlled longitudinal studies are needed to determine whether microbiome changes are causative or reactive in pancreatitis.     

Gut dysbiosis and heart failure: navigating the universe within

Alternations in gut microbial composition (i.e. loss of microbial diversity or ‘gut dysbiosis’) have been associated with heart failure with reduced ejection fraction (HFrEF). It has also been suggested that increased chronic low‐level inflammation and immune system dysregulation seen in patients with HFrEF could be related to gut dysbiosis and increased intestinal permeability. Hence, the concept of modulating gut microbial composition with the goal of reducing systemic inflammation and controlling HFrEF progression has generated a substantial interest in the scientific community. However, several challenges to the gut dysbiosis theory remain as the exact gut microbial composition in HFrEF patients in these studies is not the same and a common microbiome linked to HFrEF is not yet established. With the advances in culture independent sequencing techniques it has also become evident that the gut microbiome may be much more diverse than previously believed. Further, various ‘omic’ technologies have enabled us to appreciate the potential role of gut microbial metabolites in various physiological processes in the host. Hence, identification of specific gut microbial metabolites may offer an alternative approach at solving this gut microbiome‐HFrEF puzzle. In the current review, we evaluate the concept of gut symbiosis, the potential role of gut dysbiosis in systemic inflammation and HFrEF, and finally highlight the challenges faced by the gut dysbiosis theory in HFrEF and provide a framework for the possible solutions.     

The gut microbial influence on cholestatic liver disease

Patients with cholestatic liver diseases like primary sclerosing cholangitis (PSC) and primary biliary cholangitis (PBC) have a different gut microbiome composition than healthy controls. In contrast with PBC, PSC has a strong association with inflammatory bowel disease and is the prototypical disease of the gut‐liver axis. Still, there are some distinct overlapping microbial features in the microbiome of patients with PSC and PBC suggesting similarities in cholestatic diseases, although the possible pathogenetic involvement of these shared microbial changes is unknown. Herein, we present an overview of the available data and discuss the relevance for potential disease relevant host‐microbiota interactions. In general, the microbiome interacts with the host via the immunobiome (interactions between the host immune system and the gut microbiome), the endobiome (where the gut microbiome contributes to host physiology by producing or metabolizing endogenous molecules) and the xenobiome (gut microbial transformation of exogenous compounds, including nutrients and drugs). Experimental and human observational evidence suggest that the presence and functions of gut microbes are relevant for the severity and progression of cholestatic liver disease. Interestingly, the majority of new drugs that are currently being tested in PBC and PSC in clinical trials act on bile acid homeostasis, where the endobiome is important. In the future, it will be paramount to perform longitudinal studies, through which we can identify new intervention targets, biomarkers or treatment‐stratifiers. In this way, gut microbiome‐based clinical care and therapy may become relevant in cholestatic liver disease within the foreseeable future.     

Gut inflammation and microbiome in spondyloarthritis

Spondyloarthritis (SpA) is chronic inflammatory disease involving joints and the spine. Bowel inflammation is common in SpA, which may be classified as acute or chronic. Chronic gut inflammation is most common in SpA patients with axial involvement as compared to those presenting with peripheral involvement alone. The pathogenesis of gut inflammation in SpA could be explained by two factors—over-activation of immunological cells and altered gut microbiome. This is exemplified by SpA animal models, namely HLA-B27-expressing transgenic animals and SKG mice models. Immunological mechanisms include homing of activated T cells from gut into synovium, excess pro-inflammatory cytokines secretion by immune cells such as IL-23 and genetic variations in immunological genes. The evidence for role of gut microbiome in SpA is gradually emerging. Recently, metagenomic study of gut microbiome by sequencing of microbial nucleic acids has enabled identification of new microbial taxa and their functions in gut of patients with SpA. In SpA, the gut microbiome could emerge as diagnostic and prognostic marker of disease. Modulation of gut microbiome is slated to have therapeutic potential as well.     

Gut Immunity and Type 1 Diabetes: a Mélange of Microbes,Diet, and Host Interactions?

Type 1 diabetes (T1D) is a complex autoimmune disease, and first stages of the disease typically develop early in life. Genetic as well as environmental factors are thought to contribute to the risk of developing autoimmunity against pancreatic beta cells. Several environmental factors, such as breastfeeding or early introduction of solid food, have been associated with increased risk for developing T1D. During the first years of life, the gut microbial community is shaped by the environment, in particular by dietary factors. Moreover, the gut microbiome has been described for its role in shaping the immune system early in life and early data suggest associations between T1D risk and alterations in gut microbial communities. In this article, we discuss environmental factors influencing the colonization process of the gut microbial community. Furthermore, we review possible interactions between the microbiome and the host that might contribute to the risk of developing T1D.     

Diet and Gut Microbial Function in Metabolic and Cardiovascular Disease Risk

Over the past decade, the gut microbiome has emerged as a novel and largely unexplored source of variability for metabolic and cardiovascular disease risk, including diabetes. Animal and human studies support several possible pathways through which the gut microbiome may impact health, including the production of health-related metabolites from dietary sources. Diet is considered important to shaping the gut microbiota; in addition, gut microbiota influence the metabolism of many dietary components. In the present paper, we address the distinction between compositional and functional analysis of the gut microbiota. We focus on literature that highlights the value of moving beyond surveys of microbial composition to measuring gut microbial functioning to delineate mechanisms related to the interplay between diet and gut microbiota in cardiometabolic health.     

The interplay between the gut microbiota and NLRP3 activation affects the severity of acute pancreatitis in mice

ABSTRACT

Early dysbiosis of the gut microbiota is associated with the severity of acute pancreatitis (AP), although the underlying mechanism is unclear. Here, we investigated the role of crosstalk between NLRP3 and the gut microbiota in the development of AP utilizing gut microbiota deficient mice, as well as NLRP3 knockout (KO) mouse models. Pancreatic damage and systemic inflammation were improved in antibiotic-treated (Abx) and germ-free (GF) mice, accompanied by weakened activity of the intestinal NLRP3 inflammasome. Interestingly, fecal microbiota transplantation (FMT) reactivated the intestinal NLRP3 inflammasome and exacerbated the disease in Abx and GF mice. Although the gut barrier in GF and Abx mice was disrupted, gut microbiota deficiency ameliorated the severity of AP, probably due to the reduction in bacterial translocation from the gut to the pancreas. The composition of the gut microbiota was significantly different between NLRP3 KO mice and wild-type (WT) mice at baseline, and there were alterations in response to the induction of AP. While a dramatic shift in the gut microbiota with overgrowth of Escherichia-Shigella was observed in WT mice suffering from AP, there was no significant change in NLRP3 KO mice with or without AP, suggesting that NLRP3 deficiency counteracts AP-induced microbial disturbance. With a strengthened gut barrier and decreased systemic inflammation, NLRP3 KO mice showed less severe AP, as revealed by reduced pancreatic neutrophilic infiltration and necrosis. Taken together, these results identified the bidirectional modulation between the gut microbiota and NLRP3 in the progression of AP, which suggests the interplay of the host and microbiome during AP.     

Gut microbiota and allergy/asthma: From pathogenesis to new therapeutic strategies

Asthma and atopy, classically associated with hyper-activation of the T helper 2 (Th2) arm of adaptive immunity, are among the most common chronic illnesses worldwide. Emerging evidence relates atopy and asthma to the composition and function of gut microbiota composition. Moreover, certain gut microbial strains have been shown to inhibit or attenuate immune responses associated with chronic inflammation in experimental models. Although still a relatively nascent field of research, evidence to date suggests that the gut microbiome may represent fertile targets for prevention or management of allergic asthma and other diseases in which adaptive immune dysfunction is a prominent feature. The oral probiotics/prebiotic represents a possible therapeutic for improving asthma and allergic disease. Especially, recent technological developments that permit identification of microbes and their products using culture-independent molecular detection techniques. In this review, we literaturely summarise the aggravation or improvement of metabolic diseases by role of gut microbiota, probiotics/prebiotic treatment.     

HLA risk alleles and gut microbiome in ankylosing spondylitis and rheumatoid arthritis

Human leukocyte antigen (HLA) alleles are associated with a variety of autoimmune diseases. The composition of gut microbiome can be influenced by host immunity, which is partially regulated by HLA. In this review, first we provide evidence from animal and human studies on: if and how HLA-B27, HLA-DRB1 (shared epitope (SE)), and other HLA alleles alter the gut microbiome, then we analyzed the data for several hypotheses to explain the mechanism(s) of HLA alleles influences on gut microbiome, and finally, we discussed several potential clinical implications of HLA alleles and microbial data, such as bacterial biomarkers for diagnosis, treatment, and the screening of high-risk population.     

Exercise has the guts: How physical activity may positively modulate gut microbiota in chronic and immune-based diseases

Limited animal and human research findings suggests that exercise might have a beneficial role for health gut. Cardiorespiratory fitness correlates with health-associated gut parameters such as taxonomic diversity and richness. Physical exercise may augment intestinal microbial diversity through several mechanisms including promotion of an anti-inflammatory state. Disease-associated microbial functions were linked to distinct taxa in previous studies of familial type 1 diabetes mellitus (T1D). An integrated multi-approach in the study of T1D, including physical exercise, is advocated. The present review explores how exercise might modulate gut microbiota and microbiome characteristics in chronic and immune-based diseases, given the demonstrated relationship between gut function and human health.     

Gut microbiome in multiple sclerosis: The players involved and the roles they play

The human gut contains trillions of bacteria (microbiome) that play a major role in maintaining a healthy state for the host. Perturbation of this healthy gut microbiome might be an important environmental factor in the pathogenesis of inflammatory autoimmune diseases such as multiple sclerosis (MS). Others and we have recently reported that MS patients have gut microbial dysbiosis (altered microbiota) with the depletion of some and enrichment of other bacteria. However, the significance of gut bacteria that show lower or higher abundance in MS is unclear. The majority of gut bacteria are associated with certain metabolic pathways, which in turn help in the maintenance of immune homeostasis of the host. Here we discuss recent MS microbiome studies and the possible mechanisms through which gut microbiome might contribute to the pathogenesis of MS.     

Therapeutic modulation of gut microbiota in inflammatory bowel disease: More questions to be answered

Patients with inflammatory bowel disease (IBD) exhibit impaired control of the microbiome in the gut, and ‘dysbiosis’ is commonly observed. Western diet is a risk factor for the development of IBD, but it may have different effects on gut microbiota between IBD and non‐IBD individuals. Exclusive enteral nutrition (EEN) can induce remission in pediatric Crohn's disease with a decrease in gut microbial diversity. Although there are some theoretical benefits, actual treatment effects of prebiotics and probiotics in IBD vary. High‐quality studies have shown that VSL#3 (a high‐potency probiotic medical food containing eight different strains) exhibits benefits in treating ulcerative colitis, and gut microbial diversity is reduced after treated with VSL#3 in animal models. The effect of fecal microbiome transplantation on IBD is controversial. Increasing microbial diversity compared with impaired handling of bacteria presents a dilemma. Antibiotics are the strongest factors in the reduction of microbiome ecological diversity. Some antibiotics may help to induce remission of the disease. Microbiome alteration has been suggested to be an intrinsic property of IBD and a potential predictor in diagnosis and prognosis. However, the effects of therapeutic modulations are variable; thus, more questions remain to be answered.     

急性胰腺炎微循环障碍的发生机制及其治疗进展

近年来,越来越多的研究表明,血管收缩、血液分流、灌注不足、血液黏滞度增加以及血液凝固等微循环障碍与急性胰腺炎(AP)的发病机制密切相关。缺血再灌注损伤及氧自由基的不断产生亦可加速AP的进程。介绍了胰腺微循环的解剖学特征、胰腺微循环障碍的病理生理学机制及相关的炎症介质,以及AP微循环障碍的治疗进展,提示胰腺及全身微循环障碍可能在AP发生发展中起着重要的作用。     

Role of gut microbiota in cardiovascular diseases

The human gut is colonized by a community of microbiota, primarily bacteria,that exist in a symbiotic relationship with the host. Intestinal microbiota-host interactions play a critical role in the regulation of human physiology.Deleterious changes to the composition of gut microbiota, referred to as gut dysbiosis, has been linked to the development and progression of numerous diseases, including cardiovascular disease(CVD). Imbalances in host-microbial interaction impair homeostatic mechanisms that regulate health and can activate multiple pathways leading to CVD risk factor progression. Most CVD risk factors, including aging, obesity, dietary patterns, and a sedentary lifestyle, have been shown to induce gut dysbiosis. Dysbiosis is associated with intestinal inflammation and reduced integrity of the gut barrier, which in turn increases circulating levels of bacterial structural components and microbial metabolites,including trimethylamine-N-oxide and short-chain fatty acids, that may facilitate the development of CVD. This article reviews the normal function and composition of the gut microbiome, mechanisms leading to the leaky gut syndrome, its mechanistic link to CVD and potential novel therapeutic approaches aimed towards restoring gut microbiome and CVD prevention. As CVD is the leading cause of deaths globally, investigating the gut microbiota as a locus of intervention presents a novel and clinically relevant avenue for future research.     

Microbiome and pancreatic cancer: A comprehensive topic review of literature

AIM To review microbiome alterations associated with pancreatic cancer, its potential utility in diagnostics, risk assessment, and influence on disease outcomes.METHODS A comprehensive literature review was conducted by allinclusive topic review from PubM ed, MEDLINE, and Web of Science. The last search was performed in October 2016.RESULTS Diverse microbiome alterations exist among several body sites including oral, gut, and pancreatic tissue, in patients with pancreatic cancer compared to healthy populations.CONCLUSION Pilot study successes in non-invasive screening strategies warrant further investigation for future translational application in early diagnostics and learn modifiable risk factors relevant to disease prevention. Pre-clinical investigations exist in other tumor types that suggest microbiome manipulation provides opportunity to favorably transform cancer response to existing treatment protocols and improve survival.     

Metagenomics: key to human gut microbiota

The human gastrointestinal tract harbors the most complex human microbial ecosystem (intestinal microbiota). The comprehensive genome of these microbial populations (intestinal microbiome) is estimated to have a far greater genetic potential than the human genome itself. Correlations between changes in composition and activity of the gut microbiota and common disorders, such as inflammatory bowel diseases, obesity, diabetes, and atopic diseases, have been proposed, increasing the interest of the scientific community in this research field. In this perspective, a comprehensive and detailed view of the human gut microbiota, in terms of phylogenetic composition as well as genetic and metabolic potential, is essential to understand the dynamics and possible mechanisms of the cause/effect relationships between gut microbiota and pathology. Metagenomics has emerged as one of the most powerful sequence-driven approaches to study the composition and the genetic potential of this complex ecosystem, and efforts in this direction have been smoothed by the implementation of next generation sequencing platforms. Here, we highlight the potential of the newest high-throughput, culture-independent approaches for the characterization of the human gut microbiome in health and disease. Recent and promising results in this field are presented, underlining the perspectives and future research direction of human gut microbial ecology.     

Overgrowth of the indigenous gut microbiome and irritable bowel syndrome

Culture-independent molecular techniques have demonstrated that the majority of the gut microbiota is uncultivable.Application of these molecular techniques to more accurately identify the indigenous gut microbiome has moved with great pace over recent years,leading to a substantial increase in understanding of gut microbial communities in both health and a number of disorders,including irritable bowel syndrome(IBS).Use of culture-independent molecular techniques already employed to characterise faecal and,to a lesser extent,colonic mucosal microbial populations in IBS,without reliance on insensitive,traditional microbiological culture techniques,has the potential to more accurately determine microbial composition in the small intestine of patients with this disorder,at least that occurring proximally and within reach of sampling.Current data concerning culture-based and culture-independent analyses of the small intestinal microbiome in IBS are considered here.     

Gut microbiome in primary sclerosing cholangitis: A review

Primary sclerosing cholangitis(PSC) is a chronic cholestatic liver disease characterized by biliary inflammation and stricturing. Exploration of the pathogenesis of PSC in light of its association with inflammatory bowel disease(IBD) and the "gut-liver" axis is an emerging area of interest. A growing number of studies have begun to elucidate the role of the gut microbiota, its metabolites and its influence on host immune responses in the development of PSC and PSCIBD. Studies of the fecal microbiota have highlighted enriched levels of certain species, including Veillonella, Streptococcus and Enterococcus, among others. A heightened immune response to enteric dysbiosis and bacterial translocation have also been implicated. For example, Klebsiella pneumoniae strains derived from gnotobiotic mice transplanted with PSC-IBD microbiota were found to induce pore formation in human intestinal epithelial cells and enhanced Th17 responses. Gut microbes have additionally been hypothesized to be implicated in PSC pathogenesis through their role in the synthesis of various metabolites,including bile acids(BAs), which function as signaling molecules with important gut and hepatic effects. An expanded knowledge of the gut microbiome as it relates to PSC offers critical insight into the development of microbe-altering therapeutic interventions, such as antibiotics, nutritional interventions and fecal microbial transplantation. Some of these have already shown some preliminary evidence of benefit. Despite exciting progress in the field, much work remains to be done; areas that are particularly lacking include functional characterization of the microbiome and examination of pediatric populations. In this review, we summarize studies that have investigated the microbiome in PSC and PSC-IBD as well as putative mechanisms, including the potential role of metabolites, such as BAs. We then briefly review the evidence for interventions with microbe-altering properties for treating PSC.     

Gut microbiota and irritable bowel syndrome

Irritable bowel syndrome (IBS) is a common gastrointestinal disorder that poses a significant health concern. Although its etiology remains unknown, there is growing evidence that gut dysbiosis is involved in the development and exacerbation of IBS. Previous studies have reported altered microbial diversity, abundance, and composition in IBS patients when compared to controls. However, whether dysbiosis or aberrant changes in the intestinal microbiota can be used as a hallmark of IBS remains inconclusive. We reviewed the literatures on changes in and roles of intestinal microbiota in relation to IBS and discussed various gut microbiota manipulation strategies. Gut microbiota may affect IBS development by regulating the mucosal immune system, brain–gut–microbiome interaction, and intestinal barrier function. The advent of high-throughput multi-omics provides important insights into the pathogenesis of IBS and promotes the development of individualized treatment for IBS. Despite advances in currently available microbiota-directed therapies, large-scale, well-organized, and long-term randomized controlled trials are highly warranted to assess their clinical effects. Overall, gut microbiota alterations play a critical role in the pathophysiology of IBS, and modulation of microbiota has a significant therapeutic potential that requires to be further verified.