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.     

Cystic fibrosis transmembrane conductance regulator knockout mice exhibit aberrant gastrointestinal microbiota

The composition of the gastrointestinal microbiome is increasingly recognized as a crucial contributor to immune and metabolic homeostasis—deficiencies in which are characteristic of cystic fibrosis (CF) patients. The murine model (CFTR^−/−, CF), has, in previous studies, demonstrated characteristic CF gastrointestinal (GI) manifestations including slowed transit and significant upregulation of genes associated with inflammation. To determine if characteristics of the microbiome are associated with these phenotypes we used a phylogenetic microarray to compare small intestine bacterial communities of wild type and congenic CF mice. Loss of functional CFTR is associated with significant decreases in GI bacterial community richness, evenness and diversity and reduced relative abundance of putative protective species such as Acinetobacter lwoffii and a multitude of Lactobacilliales members. CF mice exhibited significant enrichment of Mycobacteria species and Bacteroides fragilis, previously associated with GI infection and immunomodulation. Antibiotic administration to WT and CF animals resulted in convergence of their microbiome composition and significant increases in community diversity in CF mice. These communities were characterized by enrichment of members of the Lactobacillaceae and Bifidobacteriaceae and reduced abundance of Enterobacteriaceae and Clostridiaceae. These data suggest that Enterobacteria and Clostridia species, long associated with small intestinal overgrowth and inflammatory bowel disease, may suppress both ileal bacterial diversity and the particular species which maintain motility and immune homeostasis in this niche. Thus, these data provide the first indications that GI bacterial colonization is strongly impacted by the loss of functional CFTR and opens up avenues for alternative therapeutic approaches to improve CF disease management.     

Bacteriophage Encapsulation in pH-Responsive Core-Shell Capsules as an Animal Feed Additive

Increasing antibiotic resistance in bacteria that cause zoonotic infections is a major problem for farmers rearing animals for food as well as for consumers who eat the contaminated meat resulting in food-borne infections. Bacteriophages incorporated in animal feed may help reduce carriage and infections in animals including chickens and pigs. There are, however, unmet challenges in protecting phages from processing stresses e.g., during animal feed pelleting operations and during transit of phages through the acidic gastric environment. Core-shell capsules were produced using a concentric nozzle and commercially available encapsulation equipment to fabricate capsules with phages formulated in an oil-in-water microemulsion in the core. pH-responsive capsules released the encapsulated phage cargo within 10–30 min triggered by changes in local environmental pH typically found in the lower gastrointestinal (GI) tract of animals. Acid stability of phages exposed to pH values as low as pH 1 was demonstrated. Encapsulated phages were able to withstand exposure to 95 °C wet heat thermal stress for up to 120 s, conditions typically encountered during feed pellet extrusion processing. Free phages were inactivated within 15 s under these conditions. The present study demonstrates that encapsulation of bacteriophages in core-shell pH-responsive capsules with water-in-oil emulsified phages in the core significantly improves phage viability upon exposure to processing and environmental stresses that require consideration during production of animal feed and application in animals for biocontrol. The results from this study should help guide future development of phage formulations suitable for use in animal feed for animal biocontrol applications.     

肠道菌群：功能性胃肠病的防治新靶点

功能性胃肠病（FGIDs）是一组无器质性改变但存在消化功能异常的疾病,是消化科门诊中常见疾病之一。在 最新的罗马Ⅳ标准中将功能性肠胃病定义为脑-肠互动异常疾病。肠道菌群在脑-肠互动中发挥重要作用,参与功 能性胃肠病发生的多种病理生理机制。肠道菌群失调主要通过增加肠道渗透及内脏高敏感性、改变肠道动力和激活 免疫反应参与FGIDs症状产生。因此,重塑肠道菌群稳态的策略在治疗FGIDs中显示出一定的前景。     

Microbiota in health and irritable bowel syndrome: current knowledge,perspectives and therapeutic options

Abstract

The gastrointestinal tract is a natural reservoir of microbiota. The gut is germ-free at birth, but rapidly becomes host to various bacteria establishing a progressively mutual relationship. The composition of gut microbiota is individual-specific and depends on the genotype of the host and environmental factors. Novel techniques have been used to characterize gastrointestinal microbiota, including genomic approaches. The bacterial profile shows that dominant and minor phyla are present in the gastrointestinal tract. From the proximal to the distal segments of the gut the bacterial density gradually increases, reaching an estimated 10¹¹ to 10¹² bacteria per gram of colonic content. Dynamic interactions between gut and microbiota play a physiological role in metabolic, protective and structural functions, while dysbiosis contributes to several diseases. Microbiota appear to play a role in IBS, where qualitative and quantitative changes of bacteriaoccur in IBS subtypes. Initial therapeutic approaches in IBS have focused on microbiota. The relationship between perturbations of the microbiota, mucosal inflammation and IBS remains to be further investigated.     

Ionic liquids as a class of materials for transdermal delivery and pathogen neutralization

Biofilm-protected microbial infections in skin are a serious health risk that remains to be adequately addressed. The lack of progress in developing effective treatment strategies is largely due to the transport barriers posed by the stratum corneum of the skin and the biofilm. In this work, we report on the use of Ionic Liquids (ILs) for biofilm disruption and enhanced antibiotic delivery across skin layers. We outline the syntheses of ILs, analysis of relevant physicochemical properties, and subsequent neutralization effects on two biofilm-forming pathogens: Pseudomonas aeruginosa and Salmonella enterica. Further, the ILs were also examined for cytotoxicity, skin irritation, delivery of antibiotics through the skin, and treatment of biofilms in a wound model. Of the materials examined, choline-geranate emerged as a multipurpose IL with excellent antimicrobial activity, minimal toxicity to epithelial cells as well as skin, and effective permeation enhancement for drug delivery. Specifically, choline-geranate was comparable with, or more effective than, bleach treatment against established biofilms of S. enterica and P. aeruginosa, respectively. In addition, choline-geranate increased delivery of cefadroxil, an antibiotic, by >16-fold into the deep tissue layers of the skin without inducing skin irritation. The in vivo efficacy of choline-geranate was validated using a biofilm-infected wound model (>95% bacterial death after 2-h treatment). This work establishes the use of ILs for simultaneous enhancement of topical drug delivery and antibiotic activity.Microorganisms that are protected in a biofilm pose a significant health risk due to their antibiotic resistance and recalcitrance to treatment. Biofilm-protected bacteria account for ∼80% of total bacterial infections in humans and are 50–1,000 times more resistant to antibiotics than their planktonic counterparts (1). The antibiotic resistance of many biofilms originates in a layer of extracellular polymeric substances (EPSs) comprising polysaccharides, humic acids, nucleic acids, and peptides (2) that serve as a transport barrier. Further, biofilms are able to grow and persist on living as well as nonliving surfaces and are routinely found in hospital settings where patients are at high risk (3, 4). For example, the opportunistic Gram-negative pathogen, Pseudomonas aeruginosa, is commonly associated with high rates of morbidity and mortality, including urinary tract infections, septicemia, and endocarditis (5).Biofilms are especially problematic when they establish on human skin because their presence serves to escalate the severity of pathology and slow wound healing (6). In addition, the sustained presence of dermal biofilms, which increases the severity and duration of bacterial infections, elevates the risk of contact transfer in home and hospital settings. Several common dermatological diseases, including atopic dermatitis, bullous impetigo, diabetic ulcers, and acne, routinely manifest biofilms of Staphylococcus aureus and other bacteria (7, 8).Effective treatment of skin-based bacterial biofilms has been identified as a serious and unmet medical need (1, 9). However, biofilms established on skin are inherently difficult to treat, largely due to the outermost layer of the skin, the stratum corneum (SC), being a natural barrier for drug delivery. The SC is an effective transport barrier and severely limits diffusion of drugs (10). Although the SC may sometimes be compromised at the site of the skin biofilm due to the presence of a wound, an effective treatment must deliver antibiotics to all areas of infection. Biofilms often persist in the periphery of the actual wound, beneath an intact, healthy skin barrier because they exhibit local deep-tissue invasion (11, 12). To address this pathological concern, several formulation- and device-based methods were developed to increase drug delivery into skin (10) and biofilms (13, 14); however, their utility is limited. Specifically, device-based methods are difficult to use on large skin areas. Further, the presence of wounds at the site of biofilms poses a challenge in the use of devices. Formulation-based approaches make use of penetration enhancers such as fatty acids and alcohols, which often disrupt the skin lipid bilayer, thus enhancing transport (15). This approach often suffers from the inability to simultaneously enhance transport across both the SC and the biofilm. In addition, biofilm formation often leads to skin inflammation, leading to keratinocyte apoptosis and inhibition of reepithelialization (16). Formulations that are designed to enhance transdermal transport often contain strong penetration enhancers that can further inflame the wound site and adversely affect wound healing (17).Here, we report the use of both ionic liquids (ILs) and deep eutectic solvents (DESs) as a dual-purpose strategy for both disruption and neutralization of biofilm-forming pathogens, as well as drug delivery into and across the skin. Briefly, ILs are organic salts comprised of an organic cation and an organic or inorganic anion that, when mixed in 1:1 molar ratio (true ionic liquid), give rise to a room-temperature ionic liquid (RTIL) (18). Conversely, DESs are broadly defined as a mixture of charged and neutral species, either in equimolar or imbalanced ratios, that, when combined, have a much lower melting point than the individual component. Taken together, both ILs and DESs have gained acceptance for their beneficial antimicrobial and antifungal properties as demonstrated in several reports over the last decade (19–22). More recently, both ILs and DESs were found to increase drug solubility and serve as a carrier for topical drug delivery (23–26). Our comprehensive approach is unique in that we examine a panel of in-house synthesized ILs and DESs (henceforth referred to as ILs for simplicity) for all of the following applications: (i) antimicrobial properties on two biofilm forming Gram-negative pathogenic bacteria, Pseudomonas aeruginosa ATCC15692 and Salmonella enterica serovar Typhimurium LT2; (ii) cytotoxicity effects on mammalian cell lines; (iii) skin irritation potential; (iv) transdermal drug delivery properties; and (v) treatment of biofilm on a skin-wound model. This comprehensive screening strategy enabled the discovery of one IL, choline-geranate (11), which emerged as a multipurpose formulation with excellent antimicrobial activity, minimal toxicity to epithelial cells as well as skin, and effective permeation enhancement for drug delivery.     

HIV-induced alteration in gut microbiota

Consistent with an important role for adaptive immunity in modulating interactions between intestinal bacteria and host, dramatic alteration in the composition of gut microbes during chronic HIV infection was recently reported by ourselves and independently by four other research groups. Here we evaluate our results in the context of these other studies and delve into the effects of antiretroviral therapy (ART). Although gut microbiota of HIV-positive individuals on ART usually does not resemble that of HIV-negative individuals, the degree to which ART restores health-associated prevalence varies across bacterial taxa. Finally, we discuss potential drivers and health consequences of gut microbiota alterations. We propose that understanding the mechanism of HIV-associated gut microbiota changes will elucidate the role of adaptive immunity in shaping gut microbiota composition, and lay the foundation for therapeutics targeting the microbiota to attenuate HIV disease progression and reduce the risk of gut-linked disease in people with HIV.     

Gut microbiota as a source of a surrogate antigen that triggers autoimmunity in an immune privileged site

Recent discoveries on the role of commensal microbiota have significantly changed our understanding of human physiology. The host-microbiota interplay is now an important aspect to take into account to understand immune responses and immunological diseases. Autoimmune uveitis is a sight-threatening disease that arises without a known infectious etiology. It is unknown where and how autoreactive T cells become primed to trigger disease in the eye, which is an immune privileged site. We recently reported data supporting the notion that retina-specific T cells receive a signal in the gut from commensal microbiota-derived cross-reactive antigen(s) and trigger autoimmune uveitis in the R161H mouse model. Here we discuss our published findings, as well as our recent attempts to identify the responsible microbe(s) by using different antibiotic treatments, 16S rDNA sequencing and homology searches for candidate antigenic mimic(s) of the retinal antigen.     

The intestinal microbiome,probiotics and prebiotics in neurogastroenterology

The brain-gut axis allows bidirectional communication between the central nervous system (CNS) and the enteric nervous system (ENS), linking emotional and cognitive centers of the brain with peripheral intestinal functions. Recent experimental work suggests that the gut microbiota have an impact on the brain-gut axis. A group of experts convened by the International Scientific Association for Probiotics and Prebiotics (ISAPP) discussed the role of gut bacteria on brain functions and the implications for probiotic and prebiotic science. The experts reviewed and discussed current available data on the role of gut microbiota on epithelial cell function, gastrointestinal motility, visceral sensitivity, perception and behavior. Data, mostly gathered from animal studies, suggest interactions of gut microbiota not only with the enteric nervous system but also with the central nervous system via neural, neuroendocrine, neuroimmune and humoral links. Microbial colonization impacts mammalian brain development in early life and subsequent adult behavior. These findings provide novel insights for improved understanding of the potential role of gut microbial communities on psychological disorders, most particularly in the field of psychological comorbidities associated with functional bowel disorders like irritable bowel syndrome (IBS) and should present new opportunity for interventions with pro- and prebiotics.     

Fecal microbiota transplantation in gastrointestinal disease: 2015 update and the road ahead

At its height, the Clostridium difficile infection epidemic caused approximately 7000 infections and 300 deaths per day in the USA. Fecal microbiota transplantation (FMT) has demonstrated extraordinary clinical resolution, C. difficile infection cure rates of over 90%, and low recurrence. In tandem with the rise of FMT, the gastrointestinal microbiome has emerged as a ‘vital’ organ armed with a wealth of microbe ‘soldiers’ more powerful than known antibiotics. FMTs’ reputation has diffused into many new ‘indications’ yet these appear to be merely the tip of the iceberg when considering its potential applications. FMT as a therapeutic tool has evolved from the original format of blended donor stool and moved towards a refined product comprising a myriad of microbial components, presented aesthetically as encapsulated lyophilized powder.     

Impact of probiotic supplements on microbiome diversity following antibiotic treatment of mice

Shifts in microbial populations of the intestinal tract have been associated with a multitude of nutritional, autoimmune, and infectious diseases. The limited diversity following antibiotic treatments creates a window for opportunistic pathogens, diarrhea, and inflammation as the microbiome repopulates. Depending on the antibiotics used, microbial diversity can take weeks to months to recover. To alleviate this loss of diversity in the intestinal microbiota, supplementation with probiotics has become increasingly popular. However, our understanding of the purported health benefits of these probiotic bacteria and their ability to shape the microbiome is significantly lacking. This study examined the impact of probiotics concurrent with antibiotic treatment or during the recovery phase following antibiotic treatment of mice. We found that probiotics did not appear to colonize the intestine themselves or shift the overall diversity of the intestinal microbiota. However, the probiotic supplementation did significantly change the types of bacteria which were present. In particular, during the recovery phase the probiotic caused a suppression of Enterobacteriaceae outgrowth (Shigella and Escherichia) while promoting a blooming of Firmicutes, particularly from the Anaerotruncus genus. These results indicate that probiotics have a significant capacity to remodel the microbiome of an individual recovering from antibiotic therapy.     

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.     

Systematic review: Gut microbiota in fecal samples and detection of colorectal neoplasms

ABSTRACT

Colorectal cancer (CRC) is a leading cause of cancer morbidity and mortality. Dysbiosis in the gut microbiota may be associated with CRC. This systematic review focuses on differences in gut microbial community between people diagnosed with CRC or adenoma and healthy individuals using fecal samples, emphasizing non-invasive fecal microbiome models for CRC early diagnosis.

Nineteen studies were identified in a systematic literature search of Pubmed, Web of Science and ScienceDirect. Several bacteria were reported to differ in abundance between CRC and adenoma cases and healthy controls, with Fusobacterium the most common. Fecal multi-bacterial predictive models used to distinguish CRC patients from healthy controls had reported areas under the receiver operating curve (AUCs) in external validation populations of 0.68–0.77.

Though advanced sequencing techniques could in the future complement current non-invasive methods for CRC early detection, more studies with high statistical power, comparable and reproducible methods and external validation of predictive models are needed.     

Gastrointestinal,vaginal, nasopharyngeal,and breast milk microbiota profiles and breast milk metabolomic changes in Gambian infants over the first two months of lactation: A prospective cohort study

Microbiota composition in breast milk affects intestinal and respiratory microbiota colonization and the mucosal immune system’s development in infants. The metabolomic content of breast milk is thought to interact with the microbiota and may influence developing infant immunity. One hundred seven Gambian mothers and their healthy, vaginally delivered, exclusively breastfed infants were included in our study. We analyzed 32 breast milk samples, 51 maternal rectovaginal swabs and 30 infants’ rectal swabs at birth. We also analyzed 9 breast milk samples and 18 infants’ nasopharyngeal swabs 60 days post-delivery. We used 16S rRNA gene sequencing to determine the microbiota composition. Metabolomic profiling analysis was performed on colostrum and mature breast milk samples using a multiplatform approach combining 1-H Nuclear Magnetic Resonance Spectroscopy and Gas Chromatography-Mass Spectrometry. Bacterial communities were distinct in composition and diversity across different sample types. Breast milk composition changed over the first 60 days of lactation. α-1,4- and α-1,3-fucosylated human milk oligosaccharides, and other 33 key metabolites in breast milk (monosaccharides, sugar alcohols and fatty acids) increased between birth and day 60 of life. This study’s results indicate that infant gut and respiratory microbiota are unique bacterial communities, distinct from maternal gut and breast milk, respectively. Breast milk microbiota composition and metabolomic profile change throughout lactation. These changes may contribute to the infant’s immunological, metabolic, and neurological development and could consist the basis for future interventions to correct disrupted early life microbial colonization.