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Home / The Role of B Cells in Colitis Review

The Role of B Cells in Colitis Review

  • Journal List
  • Therap Adv Gastroenterol
  • five.half-dozen(iv); 2013 Jul
  • PMC3667473

Therap Adv Gastroenterol. 2013 Jul; half-dozen(4): 295–308.

Part of the gut microbiota in health and chronic gastrointestinal affliction: understanding a hidden metabolic organ

Caitriona 1000. Guinane

Teagasc Food Inquiry Centre, Moorepark, Fermoy, Co. Cork, Ireland

Paul D. Cotter

Teagasc Food Inquiry Centre, Moorepark, Fermoy, Co. Cork, Ireland The Alimentary Pharmabiotic Center, University College Cork, Cork, Ireland

Abstruse

The human gut microbiota has become the subject of extensive inquiry in recent years and our noesis of the resident species and their potential functional capacity is quickly growing. Our gut harbours a complex community of over 100 trillion microbial cells which influence human physiology, metabolism, nutrition and immune role while disruption to the gut microbiota has been linked with gastrointestinal conditions such equally inflammatory bowel disease and obesity. Here, nosotros review the many meaning recent studies that have centred on further enhancing our understanding of the complexity of intestinal communities every bit well every bit their genetic and metabolic potential. These have provided important information with respect to what constitutes a 'salubrious gut microbiota' while furthering our understanding of the office of gut microbes in intestinal diseases. We also highlight recently adult genomic and other tools that are used to study the gut microbiome and, finally, nosotros consider the manipulation of the gut microbiota as a potential therapeutic option to treat chronic gastrointestinal disease.

Keywords: gastrointestinal disease, gut wellness, microbial multifariousness, microbial manipulation

Introduction

The human abdominal tract harbours a diverse and circuitous microbial community which plays a central role in human wellness. It has been estimated that our gut contains in the range of yard bacterial species and 100-fold more genes than are institute in the homo genome [Ley et al. 2006a; Qin et al. 2010]. This community is commonly referred to equally our hidden metabolic 'organ' due to their immense impact on homo wellbeing, including host metabolism, physiology, nutrition and immune function. It is at present credible that our gut microbiome coevolves with u.s.a. [Ley et al. 2008] and that changes to this population can have major consequences, both beneficial and harmful, for human being wellness. Indeed, it has been suggested that disruption of the gut microbiota (or dysbiosis) can be meaning with respect to pathological intestinal weather such every bit obesity [Ley et al. 2006b; Zhang et al. 2009] and malnutrition [Kau et al. 2011], systematic diseases such as diabetes [Qin et al. 2012] and chronic inflammatory diseases such as inflammatory bowel disease (IBD), encompassing ulcerative colitis (UC) and Crohn's disease (CD) [Frank et al. 2007].

The office of the gut microbiome in human health and disease is becoming clearer thank you to high throughput sequencing technologies (HTS) too as parallel contempo developments in nongenomic techniques. The purpose of this review is to summarize the very significant major developments that accept occurred with respect to revealing the microbial variety of the human being gut and how this intestinal microbiota impacts on gastrointestinal (GI) disease. We besides discuss the state-of-the-fine art tools that can be used to study the gut microbiome and await to future therapeutic options, such as the manipulation of the gut microbiota, to accost GI atmospheric condition.

Tools for studying the gut microbiome

Understanding the limerick and functional capacity of the gut microbiome represents a major challenge. Still, research in this area is ever expanding and currently a number of different approaches are being used and developed to determine gut microbial composition, genetic content and function.

Traditionally, civilisation-based techniques were used to determine the composition of the gut microbiota. These approaches accept mostly focused on the 'easy-to-culture' microbes of the gut and accept become less popular due to indications that just 10–50% of the gut bacteria are culturable [Eckburg et al. 2005]. Culturing-based methods certainly take their limitations and exercise not readily provide an overview of the gut microbial limerick. Information technology should be noted, even so, that in that location have been some advances in this surface area through the increased availability of specialized media to cultivate more fastidious organisms [Goodman et al. 2011]. A recent written report constitutes a further evolution in this expanse and has resulted in the coining of the term 'microbial culturomics' [Lagier et al. 2012]. Microbial culturomics introduces an array of new culturing techniques, coupled with matrix-assisted light amplification by stimulated emission of radiation desorption/ionization–time of flight mass spectrometry (MS), to identify a range of previously uncultivated microbiota from the gut. This strategy includes the elimination of the 'easy-to-culture', or more abundant, populations that are nowadays in high numbers to facilitate the enrichment of the more hard to culture organisms past methods such as diverse filtration or the utilise of antibiotics and phage cocktails, leading to the identification of 174 species not previously described in the human gut [Lagier et al. 2012].

Despite these recent successes, it is clear that civilization-independent approaches are ameliorate suited to providing a more rapid insight into the gut microbiota. In particular, the development and awarding of fast and depression-toll DNA sequencing methods has been revolutionary. HTS has been widely used to examine the complication of the gut microbiome due to the speed, calibration and precise information provided. For compositional analysis, the 16S rRNA gene has been most oft targeted due to its presence in all prokaryotes and the existence of variable domains that allow different taxa to exist distinguished. Although the bulk of HTS studies to engagement accept relied on the Roche 454 pyrosequencing platforms, other sequencing technologies, such every bit those provided past Illumina (San Diego, CA, U.s.), are becoming more popular [Caporaso et al. 2011b]. Other HTS technologies that can exist applied include the SOLid system (Applied Biosystems, Foster Urban center, CA, USA), the Ion platforms (Life Technologies, Carlsbad, CA, United states) and SMRT system (Pacific Biosystems, Menlo Park, CA, The states), while additional platforms, such as those that rely on nanopore applied science, are in development [Clarke et al. 2009; Rosenstein et al. 2012; Schadt et al. 2010].

While 16S rRNA studies provide information in relation to the microbial composition of an ecosystem, these exercise not provide direct data regarding the microbial viability or the functional potential of the populations present. Metagenomic (or shotgun sequencing) studies go beyond the 16S rRNA cistron to characterize the total genetic content of a customs, thereby providing an insight into the potential functional capacity of the microbes nowadays [Kurokawa et al. 2007; Qin et al. 2010; Turnbaugh et al. 2009b]. Regardless of the arroyo taken, it is of import to annotation that these sequencing technologies require detailed bioinformatic analyses to deal with the big volumes of data generated (for a review, meet Kuczynski and colleagues) [Kuczynski et al. 2012]. Indeed, increasingly, the major bottleneck has moved from being the generation of information to the storage of these information and the availability of scientists with the advisable specialist bioinformatic skills. Furthermore, although these gene-centric approaches take provided much information regarding the content of the gut, we also need to sympathise the action of these genes and the affect on the metabolic networks inside the gut. To further make up one's mind specific microbial activity, it is necessary to analyse cistron expression (metatranscriptomics), poly peptide products (metaproteomics) and metabolic profiles (metabolomics). These techniques can be complex and, to different extents, are notwithstanding somewhat in their infancy. To date, metatranscriptomics, based on large-scale sequencing of 16S rRNA transcripts, has been used to expect at the composition of the active microbiota in salubrious individuals and has revealed that the transcriptional contour beyond individuals is more than like than indicated by the associated taxonomic multifariousness [Gosalbes et al. 2011, 2012]. The faecal metaproteome of healthy adults was also recently investigated using liquid chromatography–tandem MS [Kolmeder et al. 2012]. Metaproteomics has an advantage over RNA-based studies as it analyses a more stable gene product. This study showed that the metaproteome retained considerable temporal stability over time and contained a proteome core that included metabolic enzymes, chaperones and stress proteins [Kolmeder et al. 2012]. The field of metabolomics has advanced dramatically and developments with respect to nuclear magnetic resonance (NMR) and MS make it possible to analyze 1000s of metabolites simultaneously [Nicholson et al. 2005]. NMR has been used to investigate metabolite compositions of the gut microbiota in very many instances [Marchesi et al. 2007; Mestdagh et al. 2012; Saric et al. 2008]. Although an extremely valuable tool, NMR tin be limited by resolution and sensitivity. In some cases, ion cyclotron resonance–Fourier transform MS, which has an extremely high mass resolution and which tin can detect small variations between metabolite signals [Rossello-Mora et al. 2008], may merit consideration.

Large-calibration studies of the gut microbiome

In contempo years a number of large funding initiatives were undertaken with a view to understanding the complexity of the human microbiome, including the gut surroundings. The European Metagenomics of the human intestinal tract (MetaHIT) [Arumugam et al. 2011; Qin et al. 2010] and the US human Microbiome Projection (HMP) [HMP Consortium, 2012a, 2012b] have both, through big-calibration sequencing, worked towards establishing the baseline healthy gut microbiota and how this is altered in a disease state.

MetaHIT focused on investigating the correlation between the gut microbiome and abdominal pathologies, particularly obesity and IBD [Qin et al. 2010]. In 1 case, this consortium sequenced faecal DNA from a cohort of 124 individuals, including healthy subjects and those with IBD or obesity, to establish a catalogue of nonredundant genes from the intestinal tract [Qin et al. 2010]. This project indicated that xl% of genes were shared amongst the majority of individuals and therefore represented a core metagenome. It was besides institute that 99.1% of genes were of bacterial origin, with the majority of the remaining genes belonging to the archeal kingdom, with a relatively pocket-sized number of eukaryotic and viral genes also being detected [Qin et al. 2010].

The HMP assessed the variety of the microbiota across multiple body sites in salubrious subjects, including the GI tract, to decide the baseline composition of the healthy human microbiome [HMP Consortium, 2012a]. Large-scale sequencing for meta-analyses has produced 16S rRNA data from 690 samples from 300 subjects and across 15 body sites [Turnbaugh et al. 2007]. The HMP likewise generated a catalogue of microbial genomes from the human microbiome, which consists of approximately 800 reference genomes from multiple body sites to engagement [HMP Consortium, 2012b] (see too http://hmpdacc.org). Both consortia provided a hugely valuable microbial catalogue that highlights the substantial variation in microbial species and genes in the gut. In addition, together with others, this piece of work helps our understanding of what constitutes a 'good for you' gut microbiota while revealing novel potential associations betwixt the gut microbiota and GI diseases [Qin et al. 2010, Arumugam et al. 2011; HMP Consortium, 2012a, 2012b].

The 'healthy' gut microbiota

The abdominal microbiota of salubrious individuals is known to confer a number of health benefits relating to, for case, pathogen protection, nutrition, host metabolism and immune modulation [O'Hara and Shanahan, 2006; Sekirov et al. 2010] (Figure 1). Historically, culture-based analysis has indicated that the gut of a salubrious adult share bacterial species that are common amid the bulk of individuals. In dissimilarity, however, the application of more recently developed technologies, which facilitate the culture-independent test of the gut microbiota, have indicated that there is large interindividual microbial diverseness, with merely a small phylogenetic overlap between people [HMP Consortium, 2012a]. Information technology should as well exist noted that the many HTS-based studies undertaken to describe the normal GI microbial customs have differed with respect to the health, age, location and diet of the individuals included [Qin et al. 2010, 2012; Tap et al. 2009; Turnbaugh et al. 2009a], in the specific molecular methods used [Claesson et al. 2009; Hamady and Knight, 2009] and in how the data have been analysed [Wooley and Ye, 2009]. Information technology has been established, however, that there is a high overall temporal stability of the microbial community inside an individual, which suggests the existence of an individual core microbial population [Caporaso et al. 2011a; Costello et al. 2009; Jalanka-Tuovinen et al. 2011]. Even hither, a number of factors including crumbling, diet, antibiotic use and environmental factors can cause changes.

An external file that holds a picture, illustration, etc. Object name is 10.1177_1756283X13482996-fig1.jpg

The gut microbiota in health and intestinal disease. The gastrointestinal microbiota play a role in host physiology, metabolism and nutrition. An amending in the gut microbial community is linked to a number of intestinal weather, including cancer, obesity and a variety of bowel disorders. The contribution of beneficial components of the gut microbiome to host physiology, metabolism and immune function has become the focus of e'er more attention, and will undoubtedly lead to new therapeutic approaches.

Infants are mostly thought to exist built-in with intestines that are sterile or that, at most, contain a very low level of microbes [Jimenez et al. 2008]. However, the infant GI tract is rapidly colonized following commitment. The composition of the infant gut tin can vary significantly based on a number of factors, including mode of commitment, feeding blazon, or due to antibiotic, prebiotic or probiotic utilise (for a review see Fouhy and colleagues) [Fouhy et al. 2012]. Despite this, the baby intestinal microbiota remains less complex than that of adults. Early colonizers include enterobacter and enterococci followed by anaerobic organisms such as bifidobacteria, clostridia, Bacteroides spp. and anaerobic streptococci [Adlerberth and Wold, 2009]. These populations continue to evolve and by age two the infant gut microbiota is thought to brandish a community structure similar to the adult gut [Palmer et al. 2007].

Equally noted in a higher place, interindividual variation within the adult gut microbiota is very large. Turnbaugh and colleagues established that the faecal microbiome of identical twins share less than 50% of species phylotypes [Turnbaugh et al. 2010]. However, based on HTS 16S rRNA-based, studies, it is credible that in general the developed gut is dominated past two bacterial phyla, Firmicutes and Bacteroidetes, with other phyla including Actinobacteria, Proteobacteria, Verrucomicrobia and Fusobacteria being present in lower proportions [Eckburg et al. 2005; Tremaroli and Backhed, 2012]. Greater variations exist below the phylum level, although certain butyrate-producing leaner, including Faecalibacterium prausnitzii, Roseburia intestinalis and Bacteroides uniformis, accept been identified equally key members of the developed gut microbiota [Qin et al. 2010]. Further knowledge relating to the species and functional composition of the gut was gleaned through the analysis of sequence data from 22 faecal metagenomes from individuals across 4 countries. This has led to a suggestion that the human gut microbiome consists of 3 enterotypes that vary with respect to the associated microbial species and their functional potential [Arumugam et al. 2011]. These clusters were named to reflect their dominant members, that is, Bacteroides (enterotype 1), Prevotella (enterotype 2) and Ruminococcus (enterotype three). Information technology was claimed that the most frequent of these was enterotype 3, which is enriched in Ruminococcus in addition to the co-occurring Akkermansia [Arumugam et al. 2011]. It has since been indicated, however, that the 3 enterotype divisions are not equally distinct as starting time thought and in particular the Ruminococcus-ascendant enterotype appears less axiomatic than initially claimed [Jeffery et al. 2012a; Wu et al. 2011].

The elderly intestinal microbiota has also been the discipline of a number of studies in recent years. This is particularly timely every bit an ageing population is now condign a full general characteristic of Western countries [Biagi et al. 2010; Claesson et al. 2011, 2012]. It has been noted that there are age-related physiological changes in the GI tract of older people that are characterized by a chronic low-form inflammation (inflammageing) [Franceschi, 2007] which tin can lead to a microbial imbalance in the intestine [Guigoz et al. 2008]. HTS assay has indicated that the composition of the gut microbiota of older people (>65 years) is distinct from that of younger adults and, although extremely variable between individuals, has a general dominance of the phylum Bacteroidetes [Claesson et al. 2011]. Claesson and colleagues further established a relationship between diet, the wellness status and the gut microbial population of older people [Claesson et al. 2012]. In summary, taxonomic assignments showed that the microbiota of people in a long-stay intendance surroundings had a high proportion of Bacteroidetes, whereas individuals living in the community had a loftier level of Firmicutes. Notably, the microbiota of individuals in long-stay care was significantly less diverse and a loss of the customs-associated microbiota correlated with increased frailty [Claesson et al. 2012]. This and other work has strongly implied that the GI microbiota is extremely of import to the health and in the progression of disease and frailty in older people [Claesson et al. 2012; Guigoz et al. 2008]. Regardless of age, the evolution of a clearer understanding of what constitutes a healthy microbiota allows one to establish what, if anything, is unusual inside the microbiota of those with various diseases.

The gut microbiota and disease

Equally the volume of data relating to the limerick and functional potential of the gut microbiota increases, the number of diseases that have been linked with alterations in our gut microbial customs has also expanded. Indeed, the many instances of such potential associations are too great to summarize in this review and thus here the focus is on associations that accept been the focus of greatest attention, that is, the possibility of a link betwixt the gut microbiota and chronic GI diseases, including irritable bowel syndrome (IBS) and IBD, systemic diseases such as type 2 diabetes (T2D) and obesity, as well every bit the onset of colorectal cancer (CRC) (Table 1 and Figure 1).

Table 1.

Microbial associations with chronic intestinal diseases.

Condition Microbial clan* References $
IBS Increased:
Firmicutes:Bacteroidetes ratio
Ruminococcus
Dorea
Clostridium
Gammaproteobacteria (pIBS)
Haemophilus influenzae (pIBS)
Decreased:
Bifidobacterium
Faecalibacterium
Bacteroides 		Ghoshal et al. [2012]; Jeffery et al. [2012b]; Rajilic-Stojanovic et al. [2011]; Saulnier et al. [2011]
IBD (incl. CD and UC) Increased:
bacterial numbers in mucosa (CD)
Gamma–proteobacteria
Enterobacteraceaeastward
adherent invasive Escherichia coli (CD)
Clostridium spp.
Decreased:
bacterial diversity
Firmicutes
Bacteroidetes
Lachnospiracheae
Clostridium leptum and coccoides group
(Faecalibacterium prausnitzii)
Roseburia
Phascolarctobacterium 		Frank et al. [2007]; Garrett et al. [2010]; Li et al. [2012]; Manichanh et al. [2006]; Morgan et al. [2012]
CRC Increased:
Fusobacterium spp.
East. coli (pks+)		 Arthur et al. [2012]; Castellarin et al. [2012]; Kostic et al. [2012]; McCoy et al. [2013]
Obesity Increased:
Firmicutes:Bacteroidetes ratio ‡
Actinobacteria
Bacteroides ‡
Prevotellaceae
Decreased:
bacterial diversity
C. leptum grouping
(Ruminococcus flavefaciens)
Bifidobacterium
Methanobrevibacter 		Clarke et al. [2012]; Duncan et al. [2007]; Ley et al. [2005]; Schwiertz et al. [2009]; Turnbaugh et al. [2006, 2009a]; Zhang et al. [2009]
T2D Increased:
Opportunistic pathogens
(Clostridium spp., Eastward. coli, Eggerthella lenta)
Akkermansia muciniphilia
Bacteroides spp.
Decreased:
Butyrate-producing organisms
(Roseburia spp., Faecalibacterium spp., Eubacterium spp.)
Firmicutes 		Qin et al. [2012]; Larsen et al. [2010]

Irritable bowel syndrome

Functional bowel disorders such as IBS are defined solely on symptom-based diagnostic criteria. IBS is characterized by abdominal hurting or discomfort and contradistinct bowel habits. Although the aetiology is multifactorial, recent understanding of the pathophysiology of IBS has revealed that variations in the normal gut microbiota may have a office to play in the low-grade intestinal inflammation associated with the syndrome [Brint et al. 2011; Ponnusamy et al. 2011]. Microbial dysbiosis in the gut is thought to be involved in IBS pathogenesis through facilitating adhesion of pathogens to the bowel wall (for a review, see Ghoshal and colleagues [Ghoshal et al. 2012]). Specifically, a study involving phylogenetic microarrays and quantitative polymerase chain reaction (qPCR) analysis revealed a articulate separation between the GI microbiota of patients with IBS and that of the controls, that is, IBS was characterized past an increment in Firmicutes and, more than specifically, in the numbers of Ruminococcus, Clostridium and Dorea, in add-on to a marked reduction in Bifidobacterium and Faecalibacterium spp. [Rajilic-Stojanovic et al. 2011]. In a like study of paediatric patients with the syndrome, an alteration in members of Firmicutes and Proteobacteria, also with a higher abundance of Dorea, Ruminococcus and Haemophilus parainfluenzae, was noted. Furthermore, members of the genus Bacteroides were establish to exist present at a lower level in paediatric patients with IBS than in the healthy controls and an increase in Alistipes was linked with a greater frequency of pain [Saulnier et al. 2011]. Other work past Jeffery and colleagues institute subgroups among the patients with IBS with varying microbial signatures, however generally an increase in the Firmicutes to Bacteroidetes ratio was axiomatic in patients with IBS who differed from normal populations [Jeffery et al. 2012b, 2012c]. These HTS studies suggest that a link betwixt the gut microbiota and IBS may be, which could, in time, lead to the blueprint of therapeutic options.

Inflammatory bowel disease

IBD, encompassing both UC and CD, is characterized by a chronic and relapsing inflammation of the GI tract. UC and CD are generally described as chronic IBDs, although are distinct diseases that differ both in their symptoms and inflammation pattern. Specifically CD is a chronic, segmental inflammation of the GI tract [Loftus, 2004] and although the aetiology is non withal clear, it is defined as a circuitous trait that results from the interaction between the host genetics and the gut microbial population [Elson, 2002]. UC is more often than not characterized past inflammation and ulceration of the lining of the colon. The onset of both conditions is, in general, not idea to be due to a single causal organism but past a general microbial dysbiosis in the gut [Lepage et al. 2011; Martinez et al. 2008]. Yet, this continues to be the subject field of much debate. A role for gut microbes in the manifestation of IBD has been indicated by a number of studies and the gut microbiota are idea to be essential components in the development of mucosal lesions (for a review see Manichanh and colleagues) [Manichanh et al. 2012]. Abdominal inflammation is by and large believed to be associated with a reduced bacterial diversity and, in particular, a lower abundance of, and a reduced complexity in, the Bacteroidetes and Firmicutes phyla with a specific reduction of abundance in the Clostridium leptum and Clostridium coccoides groups [Manichanh et al. 2006; Sokol et al. 2006]. Information technology has also been indicated that while Firmicutes are reduced there is an increase in gammaproteobacteria in patients with CD [Li et al. 2012]. In contrast to the general microbial dysbiosis theory, some researchers accept suggested the involvement of specific taxa, for example the Enterobacteriaceae have been associated with the microbiota of patients with UC [Garrett et al. 2010] and adherent invasive East. coli have been identified in the ileal mucosa of patients with CD [Darfeuille-Michaud et al. 2004]. There take been a number of studies that accept also highlighted a lower abundance of F. prausnitzii (a fellow member of the C. leptum group) in patients with CD and UC [Frank et al. 2007; Martinez-Medina et al. 2006; Sokol et al. 2009] and a part for this microorganism in combating bacterial dysbiosis in CD has been suggested [Sokol et al. 2008]. In add-on, recent work analyzing abdominal biopsies and stool samples from patients with IBD and healthy subjects documented an association of the disease status of IBD with alterations in the abundances of Enterobacteriaceae, Ruminococcaceae and Leuconostocaceae, while at genus level, Clostridium levels increased whereas butyrate producer Roseburia and succinate producer Phascolarctobacterium were significantly reduced in both UC and CD conditions [Morgan et al. 2012]. Regardless of the microbial population or pathogen in question, and although specific causality has not yet been clarified, these and other studies accept certainly outlined a link between the gut microbiota and IBD.

Colorectal cancer

A role for the gut microbiome in the pathogenesis of CRC has been suggested in a number of contempo publications [Arthur et al. 2012; Kostic et al. 2012; Plottel and Blaser, 2011]. Although a single causative organism has not been identified, a number of studies have implicated an association for Fusobacterium members with CRC [Castellarin et al. 2012; Kostic et al. 2012; McCoy et al. 2013]. More than specifically, a recent study using fluorescent in situ hybridization assay indicated a link between Fusobacteria and CRC, with higher numbers identified in tumours compared with control samples [Kostic et al. 2012]. This ascertainment was supported by 16S rDNA sequencing assay of the colorectal microbiome that revealed members of the Fusobacterium genus, including Fusobacterium nucleatum, Fusobacterium mortiferum and Fusobacterium necrophorum sequences, were enriched in neoplasm tissue. These changes were plant to be accompanied by broad phylum-level changes, including a significant reduction in Firmicutes and Bacteroidetes. This may suggest that Fusobacterium spp. contribute to tumourigenesis through an inflammatory mechanism [Kostic et al. 2012]. Chronic inflammation is an established risk factor for carcinogenesis [Balkwill and Mantovani, 2001] and a tumour-associated or 'tumour-elicited' inflammation can be a feature of CRCs [Grivennikov et al. 2010]. Notably, another report, which relied on the use of metagenomic sequence and qPCR data, confirmed the association between this genus and CRC, revealing an overabundance of Fusobacterium sequences in tumour tissue compared with normal contr-ols [Castellarin et al. 2012]. Members of Fusobacterium, interestingly, have besides been associated with a number of other abdominal pathologies including IBD [Strauss et al. 2011] and acute appendicitis [Guinane et al. 2013; Swidsinski et al. 2011].

The link between microbially induced inflammation and CRC has too been highlighted in a number of other studies. Indeed it has been established that microbial products can enter barrier-defective colonic tumours, trigger inflammation through a host immune response and, in turn, increase tumour growth [Grivennikov et al. 2012]. HTS studies have also revealed a link between inflammation and the gut microbial composition in colitis-susceptible, interleukin-x deficient mice [Arthur et al. 2012]. This study revealed that mice with colitis had a less diverse gut microbial composition, which was accompanied past an increase in Proteobacteria, and particularly in E. coli levels, in the presence of intestinal inflammation [Arthur et al. 2012]. Ultimately, the role of some E. coli in CRC was linked to a polyketide synthase (pks) pathogenicity island encoding a genotoxin (colibactin). This was supported past the observations that isogenic mutants lacking the pks island brought about decreased tumour growth and invasion in mice than their wild-blazon pks + counterparts [Arthur et al. 2012]. Although these studies suggest that a combination of host inflammation and specific microorganisms contribute to CRC tumourigenesis, information technology is evident that further research in this area is needed.

Obesity and type 2 diabetes

Obesity and related disorders, such as T2D and metabolic syndrome, accept get increasingly common in recent decades. Obesity is a circuitous syndrome that develops from a prolonged imbalance of free energy intake and energy expenditure. Although lifestyle factors, diet and exercise contribute largely to the modern epidemic, it has likewise been indicated by an e'er-increasing body of piece of work that the microbial communities within the human intestine play an important role in obesity [Ley, 2010; Ley et al. 2005; Tilg and Kaser, 2011; Turnbaugh et al. 2006]. Although it has been suggested that increased energy harvest due to the presence of specific microbial populations contributes to obesity [Ley et al. 2005; Turnbaugh et al. 2006], this has not e'er been found to be the instance [Murphy et al. 2010] and, indeed, it is becoming increasingly apparent that there tin can be very many other ways in which the microbiota can influence weight gain and host metabolism (for a review meet Clarke and colleagues) [Clarke et al. 2012]. The identity of the central populations/taxa that may be associated with weight gain has also been the subject area of much debate. Although a number of studies of the microbiota of lean and obese mice accept indicated that genetically (ob/ob) and diet-induced obese mice contain higher proportions of Firmicutes and lower levels of Bacteroidetes than their lean counterparts [Ley et al. 2005], the situation in humans is less clear despite the fact that there have been a number of studies that accept focused on the gut microbiota of lean and obese individuals (for a review see Clarke and colleagues) [Clarke et al. 2012]. Indeed, Ley and colleagues, plant a subtract in the Firmicutes to Bacteroidetes ratio post-obit weight loss in homo subjects [Ley et al. 2006b]. Farther work by Turnbaugh and colleagues indicated a lower proportion of Bacteroidetes in obese individuals, an increased abundance of Actinobacteria while the levels of Firmicutes remained unaltered [Turnbaugh et al. 2009a]. The importance of the Firmicutes to Bacteroidetes ratio in obesity, however, is still non clear with some conflicting studies published to date in this area [Duncan et al. 2007; Schwiertz et al. 2009].

T2D has, in contempo years, go a health upshot worldwide. T2D is principally linked with obesity-related insulin resistance. All the same, several genetic and environmental factors are thought to influence the condition. Here again, alterations in the composition of the gut microbiota of adults with T2D, relative to that of healthy controls, has been noted. Although in many instances the question as to whether these changes represent a crusade or an effect remains unresolved, it is anticipated that farther research in this expanse will clarify this issue. Regardless, a considerable number of fascinating studies have recently appeared. Larsen and colleagues employed 16S rRNA compositional sequencing to reveal that the proportions of the Firmicutes, and specifically the Clostridia class, were reduced, while the Bacteroidetes and the class Betaproteobacteria were enriched in a group with T2D compared with controls [Larsen et al. 2010]. More than recently, an impressive large metagenome-wide association study identified gut microbial markers which might be useful in classifying T2D [Qin et al. 2012]. Overall, this study institute a moderate degree of gut dysbiosis in patients with T2D. Of the idenitifiable bacterial species in this study it was indicated that control samples were enriched in various butyrate-producing bacteria, while patients with T2D were characterized by an increase in sure opportunistic pathogens, such as a number of Clostridium spp. in addition to important gut microbes including Akkermansia muciniphilia, Bacteroides spp. and Desulfovibrio spp. [Qin et al. 2012]. The identification of these gut microbial markers may exist important in classifying T2D or perhaps other obesity or metabolic-related diseases.

Strategies to manipulate the gut microbiota

As shown in the above, there is growing evidence that the gut microbiota plays a primal function in human GI health and disease. It is therefore logical that modulating the gut microbiota should be considered every bit a therapeutic strategy to care for chronic affliction. The approaches investigated include the employ of prebiotics, supplementation with probiotics, reconstitution of bacterial populations by faecal transplantation or past employing antimicrobials to eliminate pathogens or dispense the gut microbiota in a mode that volition benefit host health.

Prebiotics and probiotics are becoming increasingly popular (for a review encounter Vyas and Ranganathan) [Vyas and Ranganathan, 2012]. Prebiotics are nutritional compounds used to promote the growth of beneficial commensals and thus have the potential to improve GI health. Employ of oral probiotic cultures to restore the gut microbiota has led to promising results in the treatment of abdominal disorders such as UC and obesity [Andreasen et al. 2010; Bibiloni et al. 2005; Kadooka et al. 2010]. While information technology tin be argued, however, that oral probiotic doses do not provide sufficient microbial numbers to fully influence the populations of the colon, information technology may be that these microbes exert their influence through complex means, such equally the production of an antimicrobial or a modulation of the allowed organization. Faecal microbial transplantation (FMT) is becoming a more unremarkably used approach to replenishing the GI microbiota (for reviews see Borody and Khoruts, and Floch) [Borody and Khoruts, 2011; Floch, 2012]. The aim of FMT is to reintroduce a stable community of GI microbes from a healthy donor to supplant the disrupted populations in a diseased individual. In particular, FMT has been used in the treatment of recurrent Clostridium difficile infection when standard treatment has failed. FMT has been found to exist successful in C. difficile treatment, with illness remission reported in up to 92% of cases [Gough et al. 2011].

In addition to being a viable therapeutic option, antibiotics tin have potentially damaging furnishings through the perturbation of the gut microbiota. In particular, wide spectrum antibiotics can inflict pregnant 'collateral damage', as has been revealed recently by HTS technologies (for a review see Cotter and colleagues) [Cotter et al. 2012]. As a upshot, a number of investigations have focused on antimicrobials other than classical antibiotics. It is thus peculiarly notable that the ability to produce bacteriocins is a mutual feature among gut microbes. Bacteriocins are ribosomally synthesized modest antimicrobial peptides produced by bacteria with either a broad or narrow spectrum and to which the producing bacterium is immune [Cotter et al. 2005]. Bacteriocins with a narrow spectrum of action against a target microorganism can offer a therapeutic alternative to traditional antibiotics. Gut-associated bacteriocin producers besides have the reward of producing the antimicrobial in situ, and therefore, in these situations, the antimicrobial peptide is not afflicted by proteolysis during gastric transit or does not need to exist encapsulated. Bacteriocins take been shown to be useful in controlling a number of GI pathogens in vivo, including Listeria monocytogenes [Corr et al. 2007], Salmonella spp. [Casey et al. 2004], Campylobacter jejuni [Stern et al. 2006] and C. difficile [Rea et al. 2011].

In addition to employing antimicrobials with a view to decision-making pathogens in the GI tract, it has likewise been suggested that antimicrobials could exist employed to dispense the microbiota to treat other GI disorders, such as obesity [Murphy et al. 2013a, 2013b]. In one case, Murphy and colleagues explored the concept of targeting the gut microbiota nutrition-induced obese mice through 2 different antimicrobial strategies with a view to, in turn, assessing the touch on obesity-associated metabolic abnormalities [White potato et al. 2013a]. The 2 interventions employed involved oral administration of the antibody vancomycin and the Abp 118 bacteriocin-producing probiotic Lactobacillus salivarius UCC 118 respectively. Both strategies contradistinct the gut populations in distinct ways. For example, vancomycin assistants resulted in a dramatic increment in Proteobacteria levels accompanied with a decrease in the Firmicutes and Bacteroidetes phyla, merely only vancomycin resulted in an improvement in the metabolic abnormalities associated with obesity. These results further highlighted the link between the gut microbiota and wellness, and indicate the potential benefits of using gut microbiota-manipulating strategies to improve health [Potato et al. 2013a, 2013b].

Concluding remarks

Our gut microbiota evolves with us and plays a pivotal part in human wellness and illness. We now know that the resident microbiota influence host metabolism, physiology and allowed system evolution while perturbation of the microbial customs can issue in chronic GI affliction. While the revolution in molecular technologies has provided us with the tools necessary to more accurately study the gut microbiota, we now need to more than accurately elucidate the relationships between the gut microbiota and several intestinal pathologies. Agreement the office that microbial populations play in GI disease is central to the ultimate development of appropriate therapeutic approaches. The concept of altering our gut customs by microbial intervention in an effort to meliorate GI health is currently a topic that is receiving considerable involvement. The targeting of specific components of the gut microbiome volition potentially permit the removal of the harmful organisms and enrich the beneficial microbes that contribute to our health.

Footnotes

Funding: Enquiry in P.D.C. lab is supported by Science Foundation of Republic of ireland (SFI) funded Centre for Science, Applied science and Technology, the Comestible Pharmabiotic Middle (APC) and P.D.C. is too supported by a SFI PI honour "Obesibiotics" (11/PI/1137).

Disharmonize of interest statement: The authors declare no conflicts of interest in preparing this commodity.

Correspondent Data

Caitriona M. Guinane, Teagasc Food Research Centre, Moorepark, Fermoy, Co. Cork, Republic of ireland.

Paul D. Cotter, Teagasc Nutrient Research Center, Moorepark, Fermoy, Co. Cork, Ireland The Alimentary Pharmabiotic Centre, University College Cork, Cork, Ireland.

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Articles from Therapeutic Advances in Gastroenterology are provided here courtesy of SAGE Publications

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Source: https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3667473/