The Human Gut Microbiome – A Potential Controller of Wellness and Disease

Interest toward the human microbiome, particularly catgut microbiome has flourished in recent decades owing to the quickly advancing sequence-based screening and humanized gnotobiotic model in interrogating the dynamic operations of commensal microbiota. Although this field is silent at a very preliminary stagecoach, whereby the functional properties of the building complex catgut microbiome remain less sympathize, several promising findings have been documented and parade big likely toward revolutionizing disease etiology and checkup treatments. In this review, the interactions between catgut microbiota and the host have been focused on, to provide an overview of the character of gut microbiota and their singular metabolites in conferring host protection against invading pathogen, regulation of diverse host physiologic functions including metamorphosis, development and homeostasis of immunity and the nervous system. We elaborate on how intestine microbial asymmetry ( dysbiosis ) may lead to dysfunction of server machineries, thereby contributing to pathogenesis and/or progress toward a wide spectrum of diseases. Some of the most luminary diseases namely Clostridium difficile infection ( infectious disease ), inflammatory intestine disease ( intestinal immune-mediated disease ), celiac disease ( multisystemic autoimmune disorderliness ), fleshiness ( metabolic disease ), colorectal cancer, and autism spectrum disorder ( neuropsychiatric disorder ) have been discussed and delineated along with holocene findings. Novel therapies derived from microbiome studies such as faecal microbiota transplant, probiotic and prebiotics to target associate diseases have been reviewed to introduce the idea of how certain disease symptoms can be ameliorated through dysbiosis correction, frankincense revealing a new scientific approach toward disease treatment. Toward the end of this review, several research gaps and limitations have been described along with hint future studies to overcome the current inquiry lacuna. Despite the ongoing debate on whether gut microbiome plays a role in the above-mentioned diseases, we have in this review, gathered evidence showing a potentially far more complex liaison beyond the unidirectional cause-and-effect relationship between them .

Introduction

The human microbiome comprises of corporate genomes of microbiota inhabiting us, namely protozoa, archaea, eukaryotes, viruses and predominantly bacteria that live symbiotically on and within diverse sites of the human body. Examples of occupied habitats include our oral cavity, genital organs, respiratory tract, skin and gastrointestinal system ( Lloyd-Price et al., 2016 ). The human microbiota is estimated to be ∼1013–1014 microbial cells, with around 1:1 microbial cells to human cells proportion ( Sender et al., 2016 ). These numbers are derived from the sum bacterial cells in colon ( 3.8 × 1013 bacteria ), the organ that harbors the densest number of microbes ( Sender et al., 2016 ). The diverse gastrointestinal microbiota is predominantly composed of bacteria from three major phylum, namely Firmicutes, Bacteroidetes, and Actinobacteria ( Tap et al., 2009 ). This diverse and complex microbiome serves as a functional expansion of master of ceremonies genomes, and is estimated to harbor 50- to 100-fold more genes, compared to the master of ceremonies. These supernumerary genes have added respective types of enzymatic proteins which were non-encoded by the host, and play a critical character in facilitating host metabolism, therefore contributing to the regulation of host physiology ( Hooper and Gordon, 2001 ). Until late decades, the properties of the human microbiome and the host–microbiota interactions have been largely unknown due to engineering limitations particularly in examining non-cultivable microbes of pastime, and lack of population-scale data depicting the microbiota compositions and functions. however, advances in sequencing technologies and subsequent large-scale sequence-based microbiome projects such as the Human Microbiome Project ( HMP ) consortium funded by The United States National Institutes of Health ( NIH ), a well as the MetaHIT ( Metagenomics of the Human Intestinal Tract ) consortium funded by the european Commission, have served as catalysts in nourishing research on the human microbiome. These large-scale endeavors both share alike missions in characterizing the human microbiome and their roles in health and disease states, with MetaHIT entirely focusing on intestine microbiome. several analyses have been incorporated in these meta-omics projects including 16S ribosomal RNA ( rRNA ) sequencing to taxonomically characterize the microbiota communities ; Whole Genome Shotgun ( WGS ) metagenomic sequence of body-site particular whole community DNA, followed by reference genome mapping, metagenomic assembly, gene catalogue and metabolic reconstruction, to facilitate maximal capture of organismal and functional data of human microbiota ( The Human Microbiome Project Consortium, 2012 ) .
due to the implicit in complexity and heterogeneity of the homo microbiome, experiments are required to counteract the limitation of empiric methods in examining the causing or correlation coefficient links between microbiota disequilibrium ( dysbiosis ) and human diseases. Robust experimental mold enables taxonomic handling of variables to investigate hypotheses deduced from “ omics ” studies. For this, the application of ‘ humanized ’ gnotobiotic animal model that harbors defined solicitation of sequence microbial communities, has gained momentum in holocene years in microbiome research ( Faith et al., 2010 ). This allows proof-of-mechanism learn to examine the potential impacts of diet ( Turnbaugh et al., 2009b ), antibiotic, environmental toxicants ( Stedtfeld et al., 2017 ) and host genotypical variation ( Ley et al., 2005 ) on the microbiota and disease demonstration, due to changes in microbiota typography, transcriptomes, proteomes or metabolomes post-induced variations can be extracted and characterized to understand the operation of the microbiota. Besides, ‘ humanized ’ gnotobiotic mouse can be used in preliminary test of the therapeutic efficacy in treating dysbiosis-associated diseases, as they allow monitor of the pharmacokinetic–pharmacodynamic changes in microbial communities, thus facilitating optimization of treatment and dose government ( Mahe et al., 1987 ; Silva et al., 1999 ) .
undoubtedly, these efforts shed fall on the clinical meaning of the human microbiome which is pretty much a ‘ black box. ’ Although the human microbiome research is still at its preliminary degree, the findings are deemed challenging so far promising in terms of filling the cognition gap in microbiome-host relationships, and their character in disease pathogenesis, equally well as therapeutic value, which requires more in-depth investigations to uncover this excite however mysterious airfield of inquiry. Below, we review recent investigations specifically related to the bacterial microbiome in the GIT – the largest microbial reservoir of the homo body. Gut microbiota and the microbial-synthesized metabolites are discussed along with their roles in homo health and convention officiate. far, we review several studies related to the intestine microbiome dysbiosis and its association with specific human diseases. We introduce novel microbiome-based therapy employed in specific disease conditions to ‘ restore ’ health and ameliorating dysbiosis-associated diseases. finally, we discuss future directions and research areas that require far clarification in order to better understand the homo microbiome and its relationship with the host.

The Gut Microbiome and Its Multifarious Functions

The symbiotic relationship between the gut microbiota and the horde is regulated and stabilized by a complex network of interactions that encompass metabolic, immune, and neuroendocrine crosstalk between them. This crosstalk is potentially mediated by microbial-synthesized metabolites which exhibit pleiotropic effects, including acting as signaling molecules in regulating host neuro-immune-inflammatory axes that could physiologically link gut with other organ systems. The prevailing functions of gut microbiota and the associated samara metabolites in governing server health are depicted in the surveil subsections, with some early microbial metabolites being described in table 1 .

table 1

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TABLE 1. Metabolites contributed by gut microbiota and their respective functions .

Metabolism

Human faecal sample psychoanalysis using 16S ribosomal RNA and metagenomic sequence techniques reveal significant enrichment in metamorphosis of polysaccharides, amino acids, xenobiotics and micronutrients conferred by gut microbiota, suggest that these autochthonal microbes facilitate host department of energy reap and metabolic efficiency ( Gill et al., 2006 ). These findings were further validated by germ-free ( GF ) mouse experiments where it was found that germ-free shiner had 40 % lower epididymal fatten and an extra 10–30 % food pulmonary tuberculosis was needed to maintain the same consistency mass as mouse with normal microbiota ( Backhed et al., 2004 ). Gut microbiota is significant in fermenting unabsorbed starch and soluble dietary fiber. The ferment conclusion products exist in the mannequin of a SCFAs. SCFA ( such as butyrate, propionate, acetate rayon and pentanoate ) act as one of the energy substrates for the host ( Salminen et al., 1998 ) thereby contributing an extra 10 % casual dietary energy for use by the horde for early metabolic processes ( Payne et al., 2012 ). Microbial-synthesized SCFAs contribute 70 % of ATP production in colon, with butyrate as the choose fuel for colonocytes ( Firmansyah et al., 1989 ; Donohoe et al., 2011 ). Butyrate-producing microbes rescued the deficit mitochondrial respiration, ATP synthesis and autophagy in colonocytes of germ-free shiner ( Donohoe et al., 2011 ), proving the importance of butyrate in colonic cellular respiration and energy production. Furthermore, SCFAs which are the ligands for G protein-coupled receptor 41 ( GPR41 ) expressed by a subset of the intestine epithelial enteroendocrine cells, had been shown to regulate energy homeostasis by stimulating GPR41-mediated leptin production in sneak adipocytes, in which this multifunctional circulating hormone, leptin exhibits pleiotropic effects on a huge image of host physiologic functions such as department of energy metamorphosis, appetite, angstrom well as harmonic heart natural process and immune response, potentially giving rise to interactive host-microbe signal and gut-brain bloc immune-inflammatory crosstalk ( Xiong et al., 2004 ; Samuel et al., 2008 ) .
Besides SCFA, gut microbiota-synthesized micronutrients such as vitamins exhibit beneficial value for both microbial and server metabolisms. Vitamin-K-producing gut bacteria namely Bacteroides fragilis, Eubacterium lentum, Enterobacter agglomerans, Serratia marcescens, and Enterococcus faecium ( Fernandez and Collins, 1987 ; Cooke et al., 2006 ) anaerobically synthesize vitamin K2 ( menaquinone ) which is essential in decreasing vascular calcification, elevating HDL and lowering cholesterol levels, contributing to lower risk of cardiovascular disorders such as atherosclerosis and coronary center disease ( Kawashima et al., 1997 ; Geleijnse et al., 2004 ). Gut microbiota besides serves as an authoritative reservoir of vitamins B for the horde ( Salminen et al., 1998 ; Degnan et al., 2014 ). Among them, vitamins B5 and B12, which are entirely synthesized by intestinal microbiota, act as coenzyme for extensive range of host biochemical processes including production of acetylcholine and hydrocortisone which are required for convention serve of the skittish arrangement. insufficiency of vitamins B5 and B12 have been linked to several disorders such as gastrointestinal discomfort, insomnia, neuropsychological and hematologic disorders ( Andres et al., 2004 ; Gominak, 2016 ). however, the possible yoke between loss of vitamin-producing gut microbiota and disease attack has not so far been elucidated .
Gut microbiota besides plays an important role in the co-metabolism of bile acids with the host. These cholesterol derivatives are synthesized in the liver, followed by junction with taurine or glycine prior to storage in the resentment bladder and subsequent secretion into duodenum to aid digestion, cholesterol and lipid metabolisms. In humans, 95 % of bile acids are reabsorbed at distal ileum ( Staels and Fonseca, 2009 ). The 5 % unabsorbed primary bile acids are then bioconverted or deconjugated to secondary bile acids ( predominantly DCA and LCA ) by bile salt hydrolases secreted by several colonic irrigation microbiota such as Clostridium perfringens and Clostridium scindens, followed by partially colonic resorption and transportation back to liver for coupling ( Gopal-Srivastava and Hylemon, 1988 ; Ajouz et al., 2014 ) and the unabsorbed junior-grade bile acids are excreted by the host ( Sorg and Sonenshein, 2008 ). Both primary and secondary bile acids are able to activate master of ceremonies nuclear FXR signal, which in turn regulates the bile acids production, glucose metamorphosis, and potentially liverwort autophagy ( Lee et al., 2014 ; Nie et al., 2015 ). junior-grade bile acids serve as a potent activator of TGR5 ( a penis of the Rhodopsin-like subfamily of GPCRs ) which is widely expressed on different tissues including in gall bladder, liver, spleen, intestine, and the immune cells. such GPCR activation will stimulate second messenger c-AMP production, and the subsequent c-AMP-dependent downstream signal, inducing expressions of a battalion of genes, whereby its physiological importance remains to be fully elucidated, pointing toward impacts of secondary bile acid-TCR5 bloc ( Hylemon et al., 2009 ). secondary bile acids besides possess antimicrobial effects which alter microbial cell membrane integrity, causing spill of intracellular contents, frankincense inhibiting growth of bile acid-intolerant microbes ( Nie et al., 2015 ). such disinfectant properties may contribute in shaping the composition of the catgut microbiota and protecting the host from an align of infectious pathogens .

Immunity and the Nervous System

Gut barrier which is composed of mucus layer and epithelial level ( containing several junctional protein structures that regulate barrier integrity and paracellular permeability ), serves as the interface between the outside world and host internal environment. Disrupted catgut barrier function will increase gut permeability to commensal microbes, microbial derived products ( such as metabolites, virulence factors ) american samoa well as other sodium thiopental components, contributing to aberrant immune-inflammatory reaction such as excitement, allergy, and autoimmune disorder mediated by molecular mimicry and dysregulated T-cell reception ( Barnaba and Sinigaglia, 1997 ). such physical and immunological barrier ’ randomness function is cross-regulated by host-gut microbiota interactions. The regulation of gastrointestinal T-lymphocytes balance wheel [ regulative T cell/T assistant type 17 ( Treg/TH17 ) proportion ], which is all-important in maintaining intestinal homeostasis, discriminating between pathogens and commensal microbes via organizing “ immune tolerance-productive immune response ” status, is found to be involving the role of gut microbiota. several commensal microbes such as Bacteroides fragilis, Bifidobacterium infantis, and Firmicutes are capable in inducing expansion of Treg cells such as FOXP3 expressing Treg and anti-inflammatory IL-10-producing Treg lymphocytes, which are all-important in suppressing diseased inflammation induced by aberrant effector T cells, hence fortifying catgut barrier serve ( Paust et al., 2004 ; El Aidy et al., 2012 ; Lawley and Walker, 2013 ). suppression of incendiary reaction by Treg cells besides play a critical function in inducing host permissiveness in non-host cells, possibly enabling gut microbiota to construct their niches in host without being attacked by host exemption under normal circumstances. furthermore, several microbiota-derived metabolites such as SCFAs had been shown to confer protection to the gastrointestinal barrier integrity against the disruptive effects of proinflammatory cytokines resulted by aberrant immune-inflammatory bloc ( Peng et al., 2007 ; Chen et al., 2017 ), whereby the mechanism remains ill-defined. On the other hand, commensal SFB was shown to induce intestinal TH17 cells and production of proinflammatory IL-17 and IL-22, enhancing antimicrobial defensive structure and mucosal immunity in against of intestinal pathogen Citrobacter rodentium in gnotobiotic mouse model ( Ivanov et al., 2009 ). Besides, according to Atarashi et aluminum. ( 2008 ), ATP which can be contributed by gut microbiota, is able to activate specialization of lamina propria cells ( CD70 and CD11c ) into TH17. In short circuit, besotted regulation of Treg/TH17 libra by healthy host-gut microbiota interactions are critical to prevent aberrant immune-inflammatory reply .
engagement of intestine microbiota in host unsusceptibility growth and immune answer regulation at both local and systemic levels had been demonstrated, whereby transposition of the differentiation-suppressed states of myeloid and lymphoid progenitor cells in GF mouse was observed after colonization with convention microbiota, indicating gut microbiota facilitates growth of hematopoiesis ( congenital immunity ) and lymphocytopoiesis ( adaptive immunity ) ( Khosravi et al., 2014 ). Intriguingly, a holocene cogitation by Erny et aluminum. ( 2015 ) had revealed a novel officiate of host microbiota and their SCFAs in regulating maturation and functionality of microglia, the tissue macrophage of CNS. colonization of GF mouse with complex intestine microbiota had shown fond transposition in the initial green microglia phenotype in GF mouse. furthermore, mice model with convention microbiota but deficit SCFAs receptor had mimicked the defective feature of speech of microglia observed in GF shiner, therefore, indicating an important function of microbial-synthesized SCFAs in microglia homeostasis which is crucial in CNS health maintenance ( Nishioku et al., 2010 ) .
On the early hand, the emerging modulatory character of catgut microbiota in the ENS had been documented in versatile studies. The ENS is all-important for life and is capable in autonomously regulating the physiology and affair of the GIT, and bidirectionally communicate with the CNS via vagal pathways, forming the “ gut-brain axis. ” The major component of ENS is the EGC which resembles astrocyte in the CNS. EGCs form the enteric glial network that critically regulates a variety of GI functions including exocrine/endocrine secretions, catgut motion, blood flow, and immune-inflammatory reactions, via a complex repertoire of calcium-dependent signal ( Ochoa-Cortes et al., 2015 ). Dysfunctions in ENS and EGC have been implicated in respective gastrointestinal disorders ( such as IBD, IBS, postoperative intestinal obstruction ), motility disorder ( such as constipation ), neurodegenerative perturb ( such as PD ) and infection-induced intestine inflammation. Given the stopping point proximity of gut microbiota and the ENS that located throughout the GIT, it is not surprise that gut microbiota can affect and modulate the development and routine of ENS. In a study by Collins et aluminum. ( 2014 ), region-specific significant reduction of myenteric boldness fiber concentration was observed in jejunum and ileum, but not duodenum of early on postnatal GF mouse compared to the SPF shiner and ASF colonized mouse. In addition, notably decrease in catgut motion of GF mice compared with SPF and ASF counterparts was observed angstrom well, reflecting the importance of intestine microbiota in postnatal development of ENS in mid-to-distal belittled intestine, however, the reason underlies the region-specific myenteric ganglia reduction remains indecipherable. Another analyze by Kabouridis et aluminum. ( 2015 ) had demonstrated marked decrease in mean number and concentration of mucosal EGCs in 8-week old GF shiner compared to the conventionally-raised ( CONV-R ) counterparts, indicating the necessity of intestine microbiota in normal development of mucosal intestinal glial network. The same learn besides showed that gut microbiota-dependent EGC normal development does not restricted to critical early postnatal period as conventionalization of 4-week old GF mouse demonstrated renovation of enteric glial network .
Toll like receptors ( TLRs ) from the microorganism-sensing PRR syndicate serve a critical function in maintaining gut microbiota-host symbiotic relationship and intestinal homeostasis ( Rakoff-Nahoum et al., 2004 ). expression of TLR4 that recognizes the LPS of Gram-negative microbes, can be found on intestinal neurons and glial cells, possibly conferring ENS the ability to react square to the stimulation derived from intestine microbiota. The observation of decrease catgut motility and lesser nNOS ( neural NO synthase ) neurons had been demonstrated in GF and antibiotic-treated mouse, whereby such deficits are reproduced in TLR4-knockout mouse deoxyadenosine monophosphate well as TLR sign transducer MyD88-knockout mouse ( Anitha et al., 2012 ), suggesting TLRs signaling might be the mediator between intestinal microbiota and ENS growth. Furthermore, Soret et alabama. ( 2010 ) had reported a noteworthy natural elevation in ChAT but not nNOS-immunoreactive nerve cell, equally well as increased cholinergic-mediated colonic irrigation circular muscle contractile reaction, induced by intracecal perfusion of butyrate, hence indicating likely regulative effect of butyrate in ENS and gut motility .

Colonization Resistance

Another crucial function of human microbiota is colonization resistance where autochthonal microbiota confers auspices to host against colonization of infective invader and prevention against overgrowth of infective microbiota members ( pathobionts ). Although the molecular footing of colonization resistance remains to be elucidated, the contend mechanism of actions can be classified into ( 1 ) mastermind interaction between human microbiota and pathogens in competing for shared niches and nutrients, and ( 2 ) exploitation or enhancement of host defensive structure machinery by human microbiota to suppress pathogen ( refer to Table 2 ) .

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TABLE 2. Colonization resistance mechanisms employed by catgut microbiota .

dominant non-pathogenic intestine microbiota members play a central character in occupying the recess and suppressing the growth and colonization of pathogens. however, during gut microbiome disruption, decrease in dominant microbiota members reduces the colonization resistance capacitance, allowing opportunist infective strains to invade or colonize the empty niches, leading to occurrence of infection. C. difficile is a classic case of pathobiont which we have discussed below .

Gut Microbiome and Diseases

external factors ( such as antibiotic consumption, dietary component, psychological and physical stress ) and host factors can induce dysbiosis in gut microbiome. Dysbiosis is likely to impair the normal operation of gut microbiota in maintaining host health, and potentially induce selective-enumeration of certain microbiota member including pathobionts, leading to dysregulated production of microbial-derived products or metabolites which might be harmful to the host, causing divers crop of diseases on local, systemic or distant organ ( refer to Table 3 ), with some of the luminary diseases, along with their respective microbiome-based therapy being discussed as under .

table 3

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TABLE 3. Gut microbiome-associated human diseases and their respective dysbiotic features .

Clostridium difficile Infection (CDI)

Clostridium difficile is a gram-positive toxin- and spore-producing anaerobe. It is besides one of the Firmicutes members in normal gut microbiota. catalytic activity of C. difficile toxins A ( TcdA ) and B ( TcdB ) damages cytoskeleton and colonic epithelial barrier integrity, thereby inducing aberrant incendiary reception and cell end ( Genth et al., 2006 ; Pruitt et al., 2012 ). C. difficile infection ( CDI ) -associated symptoms include diarrhea, pseudo-membranous colitis, sepsis and death in dangerous cases ( Bartlett, 1982 ). In America, around 453,000 incidences of CDI with 453,000 mortality cases were observed in 2011 alone ( Lessa et al., 2015 ). Intriguingly, antibiotic government was found to be the major hazard factor for CDI ( Pear et al., 1994 ). Around 5–35 % antibiotic-treated individuals developed diarrhea as a common side effect. Association of C. difficile with antibiotic-associated diarrhea is the most frequent, which accounts for 10–20 % of total incidences, compared to other pathogens such as Staphylococcus aureus and Salmonella species ( Song et al., 2008 ). It was observed that greater incidence of diarrhea was correlated with uptake of antibiotics with broad-spectrum antibacterial effect ( Bartlett, 2002 ). besides, C. difficile acquisition of tolerant genes toward across-the-board spectrum clindamycin, erythromycin, chloramphenicol, and linezolid mediated by multiple horizontal gene transfer modes ( potentially via mobilizable transposon, bacteriophage transduction, conjugative plasmids ) within C. difficile strains and possibly among commensal microbes had been reported ( Johanesen et al., 2015 ). A cohort cogitation by Pépin et alabama. ( 2005 ) discovered that broad-spectrum fluoroquinolone appeared to be the most potent risk contributor to C. difficile -associated diarrhea compared to other antibiotics. Precise mechanism of this antibiotic-associated diarrhea remains unknown, however, its noteworthy correlation coefficient with CDI inspires research on the kinship between gut microbiome and its infective member – C. difficile in healthy non-disease state .
presently it is postulated that dominant gut microbiota species confer protection to the host by employing colonization resistance mechanisms against giantism of C. difficile in normal microbiome. One of the proposed mechanism is via the bio-conversion of primary bile acerb to secondary bile acids. Primary bile acids ( cholate derivatives ) serves as germinant for C. difficile spores, whereas secondary bile acids ( deoxycholate ) inhibits vegetal emergence of C. difficile ( Sorg and Sonenshein, 2008 ). antibiotic administration perturbs the gut microbial communities and reduces their diversity, specially secondary bile acids-synthesizing prevailing microbes such as C. scindens ( Antonopoulos et al., 2009 ). As a result, there is a significant reduction in microbial bioconversion of primary coil bile acids into disinfectant secondary bile acids, leading to reduced prohibition of C. difficile vegetative emergence, allowing C difficile outgrowth and colonization of the empty niches, leading to higher susceptibility of the server toward CDI ( Samuel et al., 1973 ; Theriot et al., 2014 ), as illustrated in Figure 1. The increased toxin secretion by greater sum of vegetative C. difficile exerts greater damage on intestinal barrier, stimulating severe inflammatory reply and causing disability in intestinal ion absorption that leads to diarrhea .

FIGURE 1

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FIGURE 1. Secondary bile acids synthesized by members of intestine microbiota ( such as C. scindens ) inhibit emergence of C. difficile, whilst broad spectrum antibiotic-induced dysbiosis favors C. difficile growth .

Improved sympathize on antibiotic-induced microbiome dysbiosis in pathogenesis of CDI and its recurrence has given upgrade to development of new promising curative approach path that involves restoration of intestine microbiota, such as FMT. This therapy has successfully restored catgut homeostasis via re-introduction of gut microbiota from healthy donor feces. Patients received FMT showed durable natural elevation of faecal microbial diverseness and a high recovery rate ( 90 % ) compared to vancomycin ( narrow-spectrum antibiotic ) therapy ( recovery rate = 60 % ) ( avant-garde Nood et al., 2013 ). Besides, elevation in intestine Bacteroidetes and Clostridium cluster IV and XIVa ( Firmicutes ), and reduction in Proteobacteria were observed post-FMT ( avant-garde Nood et al., 2013 ), indicating the importance of dominant microbes such as Bacteroidetes and non-pathogenic Clostridia penis in suppressing C. difficile process. like study by Konturek et aluminum. ( 2016 ) besides had demonstrated a high curative rate ( 94 % ) of CDI post FMT treatment, with no perennial CDI observed across 16 months follow-up. Besides, marked decrease of proinflammatory cytokines ( such as TNF-α, IL-1β, IL-6, IL-8, and IL-12 ), significant elevation in plasma flush of human disinfectant peptide LL-37, along with increase in beneficial bacteria ( such as Lactobacillaceae, Ruminococcaceae, Desulfovibrionaceae, Sutterellaceae, and Porphyromonadaceae ) were observed in successfully cover patients post FMT. Although the accurate beneficial strains and the underlying mechanism of FMT in conferring high cure rate of CDI have not yet been clarified, these studies undoubtedly demonstrate a strong association between intestine microbiome and development of CDI, and shed a light on the likely widespread manipulation of microbiota translation therapy in targeting CDI .

Inflammatory Bowel Disease (IBD)

Another exemplar of intestine microbiome-associated disease is IBD. IBD is a group of multifactorial, idiopathic, persistent and recurring gastrointestinal inflammations. Two coarse forms of IBD are CD and UC ( Lennard-Jones, 1989 ). In certificate of deposit, inflammation can occur anywhere along the wholly GIT, whereas UC is only restricted to the boastfully intestine. Both forms are associated with relapsing diarrhea, fever and abdominal annoyance. The occurrence of IBD is rising at alarming rate cosmopolitan, estimating 1.4 million and 2.2 million individuals in America and Europe, respectively ( Loftus, 2004 ). IBD broadly involves host factors combined with environmental factors ( Franceschi et al., 1987 ; Gent et al., 1994 ; Hugot et al., 2001 ). Although our understanding on the mechanism of pathogenesis for this disease is still lacking, crosstalk between gut microbiota and host factors show great potential in contributing to the disease development, as demonstrated in Figure 2. The inappropriate master of ceremonies immune answer against gastrointestinal microbiota in genetically predisposed person is speculated to be the chief perpetrator in causing severe excitement .

FIGURE 2

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FIGURE 2. Proposed complex interactional relationships among gut microbiome, host factors and environmental factors in IBD pathogenesis .

One of the possible etiologies for IBD is due to the hyper-responsiveness of T-lymphocyte toward non-pathogenic antigens presented on gut microbiota. several studies have observed the developments of antibodies against commensal microbial antigens and autoantigens such as anti- Saccharomyces cerevisiae, anti-OmpC, perinuclear anti-neutrophil cytoplasmic antibody and anti- Pseudomonas fluorescens -associated sequence 12 ( Duchmann et al., 1999 ; Landers et al., 2002 ). besides, it has been reported that each of these antibodies response patterns highly correlates with classifiable clinical characteristics, disease onset and asperity, suggesting passing of different microbiota species that would affect the gut barrier function and gut unsusceptibility, results in different degree of catgut excitement ( Vasiliauskas et al., 2000 ). In short, selective personnel casualty of tolerance toward catgut microbiota in IBD patient with aberrant immune reaction leads to dysbiosis and loss of microbiota that might be responsible in maintaining the gut mucus barrier integrity. Impaired barrier serve subsequently increases the photograph between gut microbiota and epithelial cells, causing foster foreplay of local anesthetic immunity, contributing to severe gut inflammation. All the studies mentioned above clearly suggest that dysbiosis in gastrointestinal microbiome might be a secondary coil consequence of gastrointestinal inflammation .
conversely, Nagao-Kitamoto et aluminum. ( 2016 ) suggested that intestine dysbiosis potentially contributes to IBD pathogenesis. In this study, elevated proinflammatory gene formulation was observed in GF shiner colonized by intestine microbiota isolated from IBD patients. Colitis-prone genetically predisposed GF mice colonized by IBD-associated-microbiota developed severe colitis compared to those that were colonized by goodly homo microbiota. together these findings strongly indicate bidirectional relationship between such disease and gut dysbiosis, in which dysbiosis potentially contributes to the attack of IBD and besides serves as a secondary consequence of intestine ignition. case of the dysbiotic features that are normally observed in IBD patients is the decrease in gut Firmicutes such as Faecalibacterium prausnitzii and Roseburia sp. ( Sokol et al., 2008 ; Willing et al., 2010 ; Machiels et al., 2014 ). These bacteria play an authoritative anti-inflammatory role in reducing proinflammatory cytokines ( IL-12, IFN-γ ) and increasing anti-inflammatory IL-10 ( Sokol et al., 2008 ). Besides, Firmicutes is crucial producer of butyrate, the primary energy substrates for colonocytes. therefore, decrease in Firmicutes could elicit or heighten local excitement by decreasing anti-inflammatory cytokine, an crucial regulator of mucosal immunity, and/or by SCFA-deficiency-induced damage in colonic irrigation barrier function ( Peng et al., 2007 ; Machiels et al., 2014 ). As such, it may be interesting to explore the curative manipulation of probiotic F. prausnitzii in managing IBD. Another dysbiotic feature observed in IBD patients is the elevation of virulent gut microbes such as Enterobacteriaceae species and Bacteroides fragilis with both having high endotoxic LPS in their out membranes ( Ruseler-van Embden and Both-Patoir, 1983 ; Darfeuille-Michaud et al., 1998 ). eminent endotoxic LPS expressed by microbiota has shown to induce gut inflammation and colitis development in mouse, possibly via suppression of regulative T-lymphocyte and/or activation of effector helper-T ( TH-1/TH-17 ) through server TLR4 signaling nerve pathway ( Gronbach et al., 2014 ). inversely, colonization of GF shiner with gloomy endotoxic microbiota prevented experimentally induced colitis ( Gronbach et al., 2014 ), indicating that an increase in catgut microbes with high endotoxic LPS and decrease in microbes with low endotoxic LPS in gut microbiome may lead to pathogenesis of IBD .
Another suggestion regarding the IBD-gut microbiome connect is the initial stultification in catgut mucus barrier serve ( either due to dysbiosis or other factors ), resulting in acme of mucus-eating ( mucolytic ) gut microbial species, which in twist aggravates the barrier function and stimulates austere incendiary answer. gastrointestinal mucus layer and disinfectant peptides ( such as human defensins ) secreted from epithelium work in concert as a barrier in preventing aim contact of sodium thiopental catgut microbiota with gastrointestinal epithelial cells and inhibit aberrant excitement ( Johansson et al., 2008 ; Salzman et al., 2010 ). Colon biopsy samples of patients with UC showed reduce mucus layer, defective epithelium and deep microbe- and leukocyte-infiltration in colon mucous membrane ( Swidsinski et al., 2007 ). furthermore, reduction in disinfectant peptides such as Paneth cells alpha-defensins in patients with ileal candle was reported ( Wehkamp et al., 2005 ). These findings propose that the afflicted horde disinfectant defense in mucus barrier reduces the initial suppression of certain commensal microbiota such as mucolytic bacteria. This is far supported by Png et alabama. ( 2010 ) where they observed a significant elevation of mucolytic Ruminococcus sp. in gut microbiome of IBDs patients. Decrease in microbial growth inhibition by homo defensins could enable emergence of mucolytic species, resulting in increased mucolytic species that feast on the mucus glycans, leading to deeper penetration of the inner mucous membrane level and microbial percolation, consequently, excitement ensues .
Since IBD involves heightened host inflammatory reception, stream therapeutic approaches broadly target the aberrant proinflammatory immune response at intestinal mucous membrane. Anti-inflammation therapies such as antibodies targeting proinflammatory cytokines ( anti-TNF-alpha, anti-IL12, anti-IL23 ) and employing α4β7-integrin antagonist to inhibit traffic of T-lymphocytes to gut tissue ( Feagan et al., 2013 ; Christensen et al., 2015 ). however, IBD tends to recur in long-run, and chronic discussion with immuno-suppressive agents will develop neurotoxic side effects ( Hyde et al., 1998 ; Croft et al., 2013 ). consequently, development of a safe and more effective novel treatment is in great indigence. Given the affiliation of IBD patients with decreased anti-inflammatory cytokines IL-10, presidency of genetically modified probiotic ( beneficial microorganism ) such as Lactococcus lactis to express IL-10 had demonstrated a significant remission of disease natural process in compact disk patients during trial ( Braat et al., 2006 ). In this study, 80 % four hundred patients demonstrated clinical improvements, with 50 % showing complete absolution, and no dangerous side effect was observed, frankincense, indicating a promise and safer alimony treatment scheme for chronic intestinal disease, as compared to sole administration of inflammatory cytokines. however, 40 % patients developed CD backsliding upon discontinuance of such therapy, indicating the need of long-run prescription drug of this medicine, which in turn will impact its economic viability. Besides, administration of prebiotics ( fermentable polysaccharides ) to stimulate growth and metabolic activity of beneficial protective intestine microbes such as butyrate-synthesizing bacteria might be an attractive concept to treat gastrointestinal inflammation in IBD ( Joossens et al., 2012 ; De Preter et al., 2013 ). plus result had been reported in a randomize controlled test by De Preter et alabama. ( 2013 ), whereby about 40–50 % of certificate of deposit patients with mild to reasonably active disease achieved remission stake treatment with prebiotic OF-IN. OF-IN consumption induced a significant decrease in mucolytic Ruminococcus gnavus and a marked elevation of beneficial Bifidobacterium longum, which the latter was powerfully correlated with the clinical improvement in CD disease activeness ( Joossens et al., 2012 ). This may due to the anti-oxidant and anti-inflammatory effects of B. longum in neutralizing reactive oxygen/nitrogen species ( ROS and RNS ) at site of excitement, reducing gastrointestinal discomfort and tissue injury. Despite these exciting novel approaches in treating or managing IBD, the elusive etiology of IBD in each patient renders individual-specific pas seul in remedy answer, posing a capital challenge in designing a curative discussion that is effective to all .

Celiac Disease

furthermore, tell has pointed to dysbiosis as the possible hazard divisor of autoimmune disorders, such as celiac disease. other examples of gut microbiome-associated autoimmune disorders such as Type 1 diabetes, SLE and RA are depicted in board 3. celiac disease is a multifactorial chronic immune-mediated disorderliness in small intestine characterized by permanent intolerance to dietary gluten ( such as gliadin peptides ) and prolamines in genetically predisposed individuals expressing human leukocyte antigen ( HLA ) -DQ2 and/or HLA-DQ8 ( Sanz et al., 2011 ). Celiac disease serves as one of the most prevailing lifelong disease in Europe, affecting 1 % of the general population of all ages ( Mustalahti et al., 2010 ), contributing to absolute deathrate rate of 10.4 per 1000 person-years in celiac disease ( Ludvigsson et al., 2009 ). In celiac patients, gluten triggers the energizing of adaptive immune reception in mucous membrane, inducing TH1 and TH17 mediated production of proinflammatory cytokines [ for case IL-21, interferon ( IFN ) -gamma, TNF-alpha ] ; vitamin a well as congenital immune reaction through stimulation of IL-15 synthesis, consequently leading to NKG2D-mediated enterocyte kill ( Stepniak and Koning, 2006 ). Gliadin-mediated zonulin ( a type of nasty articulation protein ) signaling activation besides had been reported, whereby it causes cytoskeleton rearrangement, reduced occludin – ZO-1 protein–protein interaction and increased catgut permeability, allowing traffic of sodium thiopental antigens to the submucosa ( Drago et al., 2006 ). The etiology of coeliac disease remains to be in full elucidated, with several factors including genetic predisposition, immunological factors ( mucosal IgA ), and environmental factors including gluten consumption, breast-feeding duration arsenic well as intestine infections ( for example rotavirus infection ), have been postulated to serve a concert campaign in contributing the gamble and time of celiac disease onset ( Akobeng et al., 2006 ; Mulder and Mulder-Bos, 2006 ; Stene et al., 2006 ). These factors besides play a critical function in shaping and altering gut microbiota musical composition, consequently potentially modulating catgut microbiota roles in catgut barrier function and immunity development .
Gut dysbiosis has been largely reported in celiac disease patients, in which the active voice phase of celiac disease is characterized by a noteworthy decrease in gram-positive bacteria, whereby this bacterial population is partially restored in patients that receive gluten-free diet, suggesting the initial reduction of the recover species might be the secondary consequences of the disease. Besides, inconsistent observation encompasses of increase, decrease and indifferent abundance changes in commensal Atopobium, Eubacterium rectale–Clostridium coccoides, Clostridium histolyticum, Clostridium lituseburense, Faecalibacterium prausnitzii, Escherichia coli, Lactobacillus-Enterococcus, and Staphylococcus in coeliac patients across different studies had been demonstrated ( Nadal et al., 2007 ; De Palma et al., 2010 ; Marasco et al., 2016 ), suspecting being of confounding factors ( such as disease badness, disease duration, diets, historic period and sex-related factors of the experiment discipline, and the experimental settings and sample types ) which remain elusive. Despite that, a significant decrease in sum gram-positive to gram-negative bacteria proportion was observed in all phases of coeliac disease patients as compared to that of healthy controls, with commemorate reduction in “ health-promoting ” Bifidobacteria, and elevation in virulent gram-negative Bacteroides–Prevotella groups being universally observed in multiple studies, reflecting possible pivotal function of Bifidobacteria and Bacteroides–prevotella in coeliac disease ( Nadal et al., 2007 ; De Palma et al., 2010 ; Marasco et al., 2016 ). together, it is suggested that dysbiosis potentially plays both secondary coil and chief roles in celiac disease pathogenesis. Although such dysbiotic sport and its mechanistic connection with celiac disease materialization remain elusive, it is suspected that giantism of these proinflammatory endotoxin-secreting gram-negative pathobionts may contribute to the gluten intolerance a well as the onset and/or progress of coeliac disease, through the enhancement of the proinflammatory responses such as increased IFN-gamma and TNF-alpha production, which will impair gut barrier integrity and convention operation. The resulting increased gut permeability could favor the infiltration of more sodium thiopental antigens ( gluten and microbial products ) to the submucosa, leading to amplification or prolongation of incendiary reactions. Intriguingly, despite the celebrated elevation in Bacteroides–Prevotella proportions, mucosal first line of defense mediated by secretory IgA was shown to be weaker in coeliac disease patients, in which the IgA-coated Bacteroides–Prevotella was significantly lower than that of goodly master ( De Palma et al., 2010 ). This find postulates the possible defect in mucosal barrier of coeliac disease patient which fails to stabilize gut microbiota, and loses its protective effect against invasion of noxious antigens and pathogens .
Another possible function of gut microbiota in contributing to celiac disease is their capability in synthesizing mTgs, which are the homologs of human-synthesized weave transglutaminases ( tTgs ). The mTg gene, which is potentially associated with microbial survivability, is encoded in the genome of many commensal bacteria, with huge majority belongs to Firmicutes phylum. Transglutaminase, which is besides the autoantigen in coeliac disease, is a protein cross-linker in which it transamidates or deamidates gliadin peptides to form stable neo-compounds in a process called PTMP ( Lerner et al., 2017a ). The Tg-linked proteins are found to be autoimmunogenic in coeliac disease patients, whereby trigger of anti-tTG autoantibodies serves as a remarkable serologic marker of coeliac disease. similar observation toward its microbial counterpart besides had been documented, in which specific anti-mTg and mTg-gliadin neo complex antibodies were found in the serum of coeliac disease patients but lacking in healthy controls ( Lerner and Matthias, 2015 ). Furthermore, mTgs which are extensively used as industrial food additives is capable in enhancing escape of the epithelial tight junction, which is the major part of gut epithelial barrier in regulating the equilibrium between immune permissiveness and immune answer to non-self antigens. Tight junction dysfunction and “ leaky intestine ” are normally observed in autoimmune diseases including celiac disease, as the resulting increase gut permeability promotes entry of sodium thiopental immunogenic antigens, eliciting both local anesthetic and systemic immune reactions, and the diseased autoimmune signaling cascade ( Lerner and Matthias, 2015 ). together, these findings speculate the endogenous mTgs synthesized by dysbiotic catgut microbiota ( specially dysregulation in Firmicutes / Bacteroidetes ratio ) potentially abrogate the close junction barrier integrity and drive autoimmunity through the intestinal sodium thiopental PTMP, in which the extra dietary source of mTgs may potentiate or exacerbate such deleterious effects .
Besides the aforesaid mTgs-mediated PTMP of dietary gluten by Firmicutes, PTMP-catalyzing ability had been reported in other commensal microbes, including those potentially deadly strains associated in the dysbiotic sport of celiac disease. Bacteroides fragilis of Bacteroidetes phylum was found to encode protein-modifier ubiquitin, suggesting potential aberrant ubiquitin specially in a dysbiotic configuration ( such as over-representation of Bacteroides in coeliac disease ) might cross-react and interfere human ubiquitin natural process, and its downriver bespeak, a well as induce inappropriate activation of host immune ( Patrick et al., 2011 ). gram-negative bacteria, specially those infective strains exhibit secretion systems to synthesize effector proteins with several enzymatic properties to manipulate host cellular bespeak, for case via modification of host phosphoproteome to facilitate microbial survival and niche institution in host ( Grishin et al., 2015 ). Linking the dysbiotic features, microbial-mediated PTMP activities with the aberrant immune-inflammatory response in celiac disease, it is hypothesized that dysbiosis-mediated dysregulated PTMP activities causing both functional and conformational transformations of dietary and horde proteins, generating novel aberrant epitopes which are potentially immunogenic and capable to interfere critical host cellular sign, hence, triggering manifestation of autoimmune disease such as coeliac disease ( Lerner et al., 2016 ) .
alteration in SCFAs compositions and the SCFA total abundance in coeliac children were besides been documented by Tjellström et alabama. ( 2005 ). significant increase in acetic, i-butyrate, i-valeric acerb and the full SCFAs horizontal surface were observed in celiac disease patients compared to that of healthy controls. Intriguingly, no significant difference of SCFAs writing and the full SCFAs was observed in the untreated coeliac patient and gluten-free diet treated coeliac patient, indicating the change intestine microbiota, particularly those SCFA-producing commensal microbes that responsible for such SCFAs composition profiles in coeliac patients, might be farseeing established in the familial predisposed master of ceremonies before the attack of the disease, rather than a bare secondary consequence of coeliac disease that can be corrected by eliminating gluten the “ trigger ” of celiac disease symptoms. however, the strange bacterial origin in contributing such SCFA patterns in coeliac patient renders a missing link between SCFA and the aforesaid key dysbiotic microbial communities .
Gluten-free diet has been largely employed to ameliorate the deleterious disease symptoms in coeliac patient. however, gluten-free diet exhibits curative limitation which it allows only a partial derivative recovery of gut microbiota in coeliac disease patients, both microbiologically ( for example decrease in certain potentially infective strains, incomplete restoration of beneficial Bifidobacteria ) and metabolically ( for example indifferent SCFA blueprint in treat and non-treated affected role ), possibly due to the familial factor of the patient, or the selective-enumeration of catgut microbiota mediated by the absence of dietary gluten, which the underlying cause remains ill-defined. rigorous adhesiveness to total gluten-free diet appears challenging to the patient a well due to the huge lotion of gluten in processed food, hence alternative measures using microbiome-based therapy such as probiotic might be a predict option to manage coeliac disease. respective in vivo, animal studies angstrom well as human studies had demonstrated diverse beneficial effects of probiotics Bifidobacterium and Lactobacillus strains in ameliorating epithelial-gliadin induced deleterious effects. For example, Bifidobacterium lactis exerts inhibitory effect on the increased gut permeability induced by gliadin, and it protects the healthy bosomy appearance of epithelial tight junctions from the unfavorable gliadin-induced “ straightening ” effect on tight articulation in human colon Caco-2 cells ( Lindfors et al., 2008 ). B. longum was shown to be capable in enhancing anti-inflammatory answer by stimulating markedly high Treg cell mediated product of IL-10, suppressing proinflammatory TH1 cytokine IFN-gamma induced by faecal microbiota of coeliac affected role in a cell culture-based cogitation ( Medina et al., 2008 ). B. longum and Lactobacillus casei besides have been reported to exert protective effect on animal model from gliadin-induced enteropathy, whereby B. longum can downregulate the production of proinflammatory TNF-alpha and reduce CD4+ T-cell mediated immune reactions ( Laparra et al., 2012 ) ; whilst L. casei can induce complete recovery of gliadin-induced villus blunt, recover the basal TNF-alpha tied, rescue homeostasis of GALT ( gut-associated lymphoid tissue ) ( D ’ arienzo et al., 2011 ). administration of probiotics Bifidobacterium in children with newly diagnosed celiac disease together with gluten-free diet had importantly reduced the potentially harmful Bacteroides fragilis abundance, decreased peripheral CD3+ T cells, and improved the disease symptoms ( Olivares et al., 2014 ). together, despite complete disease remission is not observed therefore far, these studies demonstrate great curative prize of probiotics Bifidobacterium and Lactobacillus in ameliorating gliadin-induced toxic effects and improving coeliac disease symptoms, indicating promising approaches in managing coeliac disease .

Obesity

In holocene years, the newly identified component – catgut microbiome which is largely involved in server metamorphosis regulation, has been integrated into crosstalk studies between genetic factors, demeanor and environmental factors as a possible contributor to fleshiness. Obesity is a ball-shaped health hazard affecting more than 600 million people worldwide in 2014 ( World Health Organization [ WHO ], 2016 ). It is associated with raised energy intake and decreased energy outgo, causing excessive fatten collection with raised body mass exponent ( BMI ≥ 30kg/m2 ), and is linked to metabolic syndrome, posing corpulent individuals to have a higher risk of developing obesity-associated disorders ( for example cardiovascular disease, type-II diabetes, and liver abnormalities ), low-grade excitement, and previous deathrate ( Donnelly et al., 2005 ; Cani et al., 2007 ) .
Metagenomics studies had discovered a significant increase in butyrate-producing Firmicutes and broadly a decrease in Bacteroidetes were observed in distal colonic irrigation microbiome of corpulent patients and genetically corpulent mouse, compared to their normal lean counterparts. These obesity-associated dysbiosis features were besides accompanied by elevation in starch-degrading glycoside hydrolase and SCFAs ( butyrate and acetate ), and increased energy reap capability as evidenced by markedly decrease faecal energy in corpulent mouse ( Ley et al., 2006 ; Turnbaugh et al., 2006 ), speculating significant natural elevation in host metabolism-related microbial communities would abnormally increase energy harvest, thus increasing the gamble of developing fleshiness. This meditation is supported by gnotobiotic sneak model, whereby noteworthy elevations in body fatten, fasting glucose and insulin levels, and development of insulin resistance that mimic physiological alterations in fleshiness patients, have been observed in GF mice post-colonization with a single saccharolytic intestine bacterial species ( Bacteroides thetaiotaomicron ) and with catgut microbiota from corpulent mice respectively ( Backhed et al., 2004 ; Turnbaugh et al., 2006 ). Elevations in monosaccharides delivered to liver and liver triglycerides level due to enhanced starch metamorphosis facilitated by gut microbiota indicate a impregnable association between intestine microbiota and host metabolism in glucose homeostasis and lipogenesis. These findings are consistent with previous studies where lipogenic substrates ( such as monosaccharides and SCFAs ) were able to trigger the expression of liverwort fatso acids-synthesizing enzymes like ACC-1 and FAS, promoting liverwort DNL ( Higuchi et al., 2008 ). The subsequent store of triacyl glycerides in adipocytes besides has been shown to be possibly mediated by gut microbiota via suppress of lipoprotein lipase-inhibitors ( Backhed et al., 2004 ; Solinas et al., 2006 ). together, this datum suggests that over-representation of saccharolytic gut microbiota facilitates augmentation in food digestion, leading to higher energy reap and increased fat deposition, therefore contributing to fleshiness development .
furthermore, several studies suggest that increase in endotoxic LPS of Gram-negative gut bacteria contributes to obesity-associated metabolic syndrome. For case, it was reported that elevated LPS led to obesity-associated insulin resistance and low-grade ignition as demonstrated by Cani et alabama. ( 2007 ). similarly, plasma LPS ( metabolic endotoxemia ) showed a tag increase in high-fat-fed mouse, along with decrease of Bifidobacteria, a likely down-regulator of intestinal endotoxin ( Griffiths et al., 2004 ). In investigation of the association between metabolic endotoxemia with obesity-associated metabolic disorders, continuous-LPS-infused mouse were shown to develop fasting glycaemia, insulinemia, liverwort insulin resistance, increased hepatic and whole-body adipose tissue gains, exchangeable to high-fat-fed mouse phenotypes ( Cani et al., 2007 ). In addition, absence of LPS-receptor resisted these adverse features regardless of LPS-infusion or high-fat diet treatments as shown in CD14 ( LPS-receptor ) knockout mouse, indicating that the LPS/CD14 system mediates insulin insensitivity, therefore inducing the onset of fleshiness and obesity-related metabolic disorders ( Cani et al., 2007 ) .
Since obesity-related metabolic disorderliness has been associated with gut microbiota dysbiosis, selective modulation of microbial composing via dietary interposition such as administration of prebiotics or probiotics might be a bright curative approach. Administration of bacterial-synthesized CLA or CLA-producing bacteria such as Lactobacillus rhamnosus has shown a meaning decrease in plasma cholesterol, triacyl glycerides and white adipose weave in animal models ( Koba et al., 2002 ; Lee H.Y. et al., 2006 ). Prebiotics such as inulin-type fructans that selectively nourish Roseburia and Clostridium bunch XIVa, and arabinoxylan that increases the abundance of Bifidobacterium, Roseburia, and Bacteroides, have demonstrated anti-adipogenic effect in high-fat-induced corpulent mouse ( Dewulf et al., 2011 ; Neyrinck et al., 2011 ). These findings demonstrate predict application of prebiotics and probiotics in fleshiness management, however, more supportive data from human models and clinical trials are required to justify these discussion strategies and their respective success rates .

Colorectal Cancer (CRC)

colorectal cancer ( CRC ) is the fourth leading campaign of cancer-related mortality cosmopolitan ( Arnold et al., 2017 ). similar to other cancer forms, CRC is a many-sided diseases associated with genetic and environmental factors. late findings have suggested that gut microbiota plays a role in the overlap of these factors, probably through shaping a tumor-promoting environment. colorectal carcinogenesis of the catgut has been demonstrated by Li et alabama. ( 2012 ) using sneak model of APC-related CRC. In this study, GF mice displayed a significantly lower colonic irrigation tumor incidence and decreased tumor load as compared to that of conventionally raised mouse, which the latter besides exhibited other distinctive phenotypes of CRC such as rectal bleed and anemia with a massive infiltration of incendiary cells arising from a dysfunctional intestinal epithelial barrier at older ages, thereby suggesting gut microbiome and host factor ( such as age and familial sensitivity ) exert a concert effort in contributing to CRC growth and progress. conversely, tumor emergence into gut lumen would damage the intestinal barrier, resulting in increase infiltration of gut microbiota and potentially harmful sodium thiopental substrates into deep tissue, leading to far stimulation of immune-inflammatory response and myeloid cell recruitment, which could in turn perturb the gut microbiome ( Li et al., 2012 ). together, intestine microbiome and CRC display a bidirectional self-feeding relationship .
16S rRNA sequencing discipline of faecal microbiota of CRC patients has revealed a significant enrichment of Bacteroides fragilis ( Wang et al., 2012 ; Wu et al., 2013 ). Despite the low detection limit of some metagenomics studies in providing strain-level information, it is suspected that possible efflorescence of enterotoxigenic strains of B. fragilis ( ETBF ) contributes to CRC through enhanced production of oncogenic B. fragilis enterotoxin ( BFT ). This meditation is consistent with the findings of Ulger Toprak et alabama. ( 2006 ) in which the bft gene construction was significantly higher in CRC patients than healthy controls. Wu et alabama. ( 2009 ) had demonstrated that colonization of tumor-prone mouse with ETBF strains can trigger TH17-dependent colon tumorigenesis, possibly facilitated by its major virulence component – BFT. BFT is cytopathic to intestinal epithelial cells and can cause colitis and colonic tumor, owing to its capability of catalyzing proteolytic degradation of tight-junction proteins ZO-1 and E-cadherin, leading to break of intestinal paracellular barriers ( Moncrief et al., 1998 ; Wu et al., 1998 ). furthermore, BFT-mediated loss of membrane-associated E-cadherin could in turn activate T-cell factor–dependent Wnt ( Wingless-Int ) /β-catenin nuclear signaling in intestinal epithelial cells, stimulating oncogene c-Myc expression that results in persistent cellular proliferation ( Wu et al., 2003 ). Furthermore, unite legal action of BFT and IL-17 on colonic epithelial cell can induce myeloid differentiation into pro-tumoral monocytic-myeloid-derived suppressor cells ( MO-MDSCs ), leading to selective upregulation of Arg1 and NO synthase 2 ( Nos2 ) thereby stimulating NO synthesis that could promote vascular endothelial growth factor ( VEGF ) -mediated tumor angiogenesis ( Cianchi et al., 2003 ), and suppression of anti-tumor immunity ( for example, suppress CD8+ T-cell proliferation ) ( Orberg et al., 2017 ) .
On the other hand, non-colitogenic Fusobacterium nucleatum which is markedly enriched in CRC patients, is able in inducing intestinal tumorigenesis in murine models, suggesting overrepresentation of the gut microbiota may be the driver for CRC that is non-associated with colitis or IBD ( Castellarin et al., 2012 ; Wang et al., 2012 ; Wu et al., 2013 ). Although the causality and underlying mechanisms remain to be elucidated, it has been demonstrated that FadA adhesin of F. nucleatum could promote bacterial attachment and invasion into E-cadherin expressing CRC cells, subsequently activating β-catenin-regulated transcriptions, as shown by upregulation of lymphoid foil factor/T cell gene, host NF-κB, oncogene c-Myc and cyclin D1, consequently promoting CRC cell proliferation and inflammation ( Rubinstein et al., 2013 ). Besides, F. nucleatum extinct membrane protein, Fap2 besides has been shown to mediate specific Fusobacterial fastening to Gal-GalNAc overexpressed in CRC, facilitating F. nucleatum invasion and colonization of CRC cells ( Abed et al., 2016 ). In addition, participation of TLR4/phosphorylated-p21-activated kinase 1/phosphorylated-β-catenin S675 shower was found to be employed by invasive F. nucleatum a well ( Wu et al., 2018 ). Briefly, both oncogenic ETBF and F. nucleatum along with their respective alone molecular signatures serve as electric potential biomarkers in identifying the gamble of developing ETBF- and F. nucleatum -related CRC, and predicting malignity progress. Antibiotics specifically targeting these pathobionts adenine good as the application of pharmacological inhibitors for infective signaling pathways may be a bright approach to be ventured in. Further longitudinal studies are consequently recommend to assess the feasibility of such applications .
microbial metabolites such as butyrate have been reported to inhibit proliferation and survival of tumor cells as evidenced by butyrate-induced upregulation of pro-apoptotic Bax, Fas, cell cycle checkpoint regulator p21 and p27, downregulation of anti-apoptotic Bcl-2, Bcl-xL, cyclin D1, and possible inhibition of LPS-induced activation of proinflammatory and pro-tumorigenic NF-κB signal, via intracellular action of butyrate as HDAC inhibitor that could epigenetically regulate gene expression, and/or its extracellular action as a ligand that targets G-protein conjugate sense organ GPR109A-expressing cancer cell ( Hassig et al., 1997 ; Thangaraju et al., 2009 ; Wei et al., 2016 ). Butyrate besides exhibits chemoprotective effects in which colonocytes pre-treated with butyrate attest higher resistor against hydrogen peroxide-induced oxidative tension and DNA damage, possibly via butyrate-mediated enhance formula of GST M2 in colonocytes, which is a detoxifying isoenzyme specific for substrates that arise from oxidative try, thereby reducing the impact of certain genotoxic CRC risk factors ( Abrahamse et al., 1999 ; Ebert et al., 2003 ). together with the observation of importantly reduced butyrate-producers Faecalibacterium and Roseburia in catgut microbiota of CRC patients ( Wang et al., 2012 ; Wu et al., 2013 ), it is speculated that the subsequent decrease in colonic butyrate could partially impair the anticancer immunosurveillance and potentiate tumorigenesis. Hence, the concept of increasing colonic butyrate either by supplement of butyrogenic dietary fermentable carbohydrates ( high fiber diet ) or butyrate-producing probiotics exhibits big intervention potential on the prevention and therapy of CRC, whereby far studies are required to evaluate the therapeutic success rate, american samoa good as to determine the effective concentration of butyrate in vivo, required to attain desirable clinical profit. In a study by Femia et aluminum. ( 2002 ), anti-tumorigenic natural process of prebiotic OF-IN on azoxymethane-induced colon cancer scab model was demonstrated, as evidenced by significant decrease of tumor loads ( adenoma and cancer ) compared to control rat. however, serum metabolome such as butyrate floor and the gut microbiota compositional change post-prebiotic treatment were not determined in this study. This makes it difficult to decipher which key microbiota and microbial products actually confer such anti-tumorigenic effect .
Accumulating data has besides demonstrated protective effect of probiotics using lactic acid-producing bacteria ( Lactobacillus and Bifidobacterium ) against experimentally induce colon cancer, as shown by repress tumor incidence and tumor loads. The underlying mechanisms are suggested to involve direct anti-proliferative effect on tumor cells, prevention of carcinogen-induced DNA damage, partially via inhibition of carcinogen and mutagen geological formation, reduction of pro-carcinogenic enzyme ( ornithine decarboxylase ) bodily process, and aggrandizement of detoxifying enzyme activeness, american samoa well as enhancement of anti-tumor exemption as evidenced by increased natural killer whale cells, MHC class II antigen presenting cells, and CD4–CD8+ T cells post-probiotic treatment ( Goldin et al., 1996 ; Pool-Zobel et al., 1996 ; Singh et al., 1997 ; Wollowski et al., 1999 ; Lee et al., 2004 ). furthermore, the gut microbiome is pivotal in influencing therapeutic efficacy of anti-cancer immunotherapy employing immune-checkpoint inhibitors. The anti-tumor impression of antibodies targeting CTLA-4, a major negative regulator of T-cell energizing, is compromised in both GF shiner and broad-spectrum antibiotics-treated mouse, confirmed in both melanoma and colon cancer models, along with the observations of significantly reduced CD4+ T-cell and tumor-infiltrating lymphocytes. such defects can be overcome by the administration of non-enterotoxin-producing strains of B. fragilis, immunization with immunostimulatory B. fragilis polysaccharide, or by adoptive transfer of B. fragilis -specific T-cells, in which the mechanism underlie the restoration of remedy response to CTLA-4 blockade is suggested to be via generalization of the IL-12-dependent TH1 immune response in tumor-draining lymph nodes, and stimulation of intratumoral dendritic cells ( DCs ) growth ( Vétizou et al., 2015 ). similarly, Sivan et alabama. ( 2015 ) reported that Bifidobacterium could facilitate PD-L1 blockade efficacy via augmenting DCs function, enhancing CD8+ T-cell flat coat and accumulation at the tumor microenvironment grade. The concept of combination treatment that encompasses anticancer immunotherapy and commensal microbes holds great promise for future CRC treatment .

Autism Spectrum Disorder (ASD)

In holocene years, increasing count of studies have explored a potential radio link between the gut microbiome and brain- or neuro-developmental disorders, such as ASD, with symptoms like temper disorder ( depressive disorder ), neurodegenerative Alzheimer ’ sulfur and PDs ( Table 3 ). ASD is a many-sided group of neurobiological disorders affecting 1 in 68, 8-year-old children in America ( Christensen et al., 2016 ) and 1 in 160 children globally ( World Health Organization [ WHO ], 2017 ). It is characterized by sociable and communication deficits, and repetitive, stereotyped behaviors ( Constantino et al., 2000 ; Kim and Lord, 2012 ). Despite the ill understand causative factor of ASD, several studies had observed a significant association between ASD, gastrointestinal dysfunction and dysbiosis in gut microbiota. Comorbidity analysis of ASD patients revealed high occurrence of gastrointestinal symptoms, with the austereness positively associated with that of ASD ( Wang L.W. et al., 2011 ). This accompaniment is speculated to be implicated by impaired tyrosine kinase MET signaling which is important in genius growth, gastrointestinal health and immune reaction regulation ( Ieraci et al., 2002 ; Okunishi et al., 2005 ). This hypothesis is supported by the observation of impair MET-signaling in ASD patients specially those that comorbid with familial gastrointestinal perturb ( Campbell et al., 2009 ; Jackson et al., 2009 ). besides, clinical data has shown that physical health problems like chronic abdominal annoyance caused by gastrointestinal disorders aggravate self-injury and fit in ASD patients ( Carr and Owen-Deschryver, 2007 ), thereby suggesting that treating the gastrointestinal dysfunction will possibly alleviate such ASD-associated symptoms .
During the investigation of microbiota typography in ASD patients, dysbiotic features such as increase Clostridium sp., Bacteroidetes, Lactobacillus, Desulfovibrio, and reduce Bifidobacteria were reported ( Song et al., 2004 ; Adams et al., 2011 ), suggesting a possible link between dysbiosis and ASD. In a sketch by Shultz et alabama. ( 2015 ), shiner treated with PPA via intra-cerebroventricular injection had shown to develop brain abnormalities and ASD-like symptoms. PPA is a type of SCFA, synthesized by enteric bacteria include the aforesaid Clostridium, Bacteroidetes, and Desulfovibrio species, but PPA level normally exist at humble levels in normal goodly individuals. This suggests that possible bloom in PPA-producing gut microbes leads to elevated neurotoxic PPA assiduity in blood, contributing to neuropsychiatric disorders. however, to date, dysbiosis-associated elevation in microbial-synthesized PPA in plasma of ASD patients has not been reported. future studies in examining plasma PPA level in ASD patients are required. surprisingly, treatment targeting gut microbiome has demonstrated beneficial effects in alleviating ASD-like symptoms in murine model. Desbonnet et aluminum. ( 2010 ) reported that probiotic Bifidobacterium infantis improved the behavioral abnormalities and stress-associated gastrointestinal dysfunction which were initially induced in mouse distress MS. reduction in Bifidobacterium is normally observed in ASD patients, positive result post-probiotic treatment indicates a potential protective role of Bifidobacterium in neuro-immune aspects, suggesting probiotic B. infantis as a potential ASD therapy. Despite the indecipherable fundamental mechanisms, antioxidant properties of Bifidobacterium are suggested to have a neutralize neurotoxic consequence, induced by excess NO in ASD ( Yui et al., 2016 ). far studies that mimic the human physiologic environment are very a lot required to assess the curative success and implicit in mechanism of probiotic B. infantis in managing ASD .

Perspectives and Future Direction

Emerging research on human microbiome and its function in human health and disease are presently making it to the limelight, by virtue of which, researchers of diverse clinical forte areas are attempting to fit this electric potential “ missing piece of puzzle ” into existing disease models, particularly those with unknown etiology. Tremendous data has demonstrated potent affiliation of the catgut microbiome with host metabolism, immune and neuroendocrine homeostasis, and the possible dysregulation or revision of gut microbiome. perturbation of such delicate chemical equilibrium will in turn contribute to disease demonstration. however, the causal or correlation coefficient link remains debatable due to lack of steer testify and mechanistic details. Our understanding on gut microbiome is calm at a very preliminary stage, whereby there are respective limitations and inquiry gaps that are worth far exploration to better justify the link. For example, large-scale longitudinal studies that account for subject-specific variations in characterizing the homo microbiome are strongly required. On the other bridge player, another important component of human microbiome – the human virome that is dominated by bacteriophage ( viruses that infect bacteria ), is relatively less established compared to that of commensal bacteriome research. only recently the presence of bacteriophage ( or bacteriophage ) in the homo microbiome has been highlighted. Their electric potential character in modulating immune homeostasis has been suggested via ( 1 ) indirect mechanisms such as through regulating bacterial microbiome composition ( phage-mediated lytic kill of host bacteria ) and officiate ( phage-mediated introduction of novel functional genes to lysogenic host such as production of endotoxin and antibiotic resistance ), and ( 2 ) calculate hindrance with homo immune-inflammatory responses such as downregulation of the proinflammatory NF-κB pathway, inhibition of excessive ROS deduction, induction of anti-inflammatory IL-10 production, and T4 bacteriophage adhesin gp12 – mediated neutralization to LPS-induced ignition, as evidenced by downregulation of inflammation markers IL-1α and IL-6, and diminished leukocyte infiltration ( Górski et al., 2016 ; Miernikiewicz et al., 2016 ). In addition, coincident increase in proinflammatory markers such as IL-1β, IL-1α, along with upregulation in anti-inflammatory IL-1 receptor antagonist and SOCS3 have been observed in P. aeruginosa and S. aureus phages treated cells, and the authors postulate that at least some phages have evolved anti-inflammatory properties to aid their survival and generation, while retaining some proinflammatory properties ( Van Belleghem et al., 2017 ). On the reverse to the largely reported anti-inflammatory properties of bacteriophage, significantly increased abundance of bacteriophages and changes in bacteriophage communities writing in four hundred patients compared to healthy controls have indicated a possible conducive character of bacteriophage in aberrant immune answer ( Lepage et al., 2008 ; Wagner et al., 2013 ). undeniably, integrating human virome studies into the existing human bacterial microbiome will provide a bigger and clearer mental picture on how such transkingdom interactions could impact human health, thus, facilitating disease etiology studies. however, overcoming the obstacles such as limitations in virome sequence techniques, uninformative database for word picture of fresh viral genomes and the difficulties in identifying origin of virus from patient sample distribution followed by deciphering the underlying mechanisms are urgently required .
Another noteworthy aspect is that the note association of homo microbiome with the host in healthy and disease states in fact reflects a army for the liberation of rwanda more complicated synergistic relationship, rather than a mere unidirectional “ induce and effect. ” Hence, experimental design should be revised and tailored consequently to comprehensively investigate at which point of the disease ( for exercise : disease onset, early on disease stage, disease progress, active or latent disease ) does the human microbiota play a character in, as this will reveal either the basal function, junior-grade character, or both roles undertaken by human microbiota in disease demonstration. Besides, varying observations such as dysbiotic features in specific diseases, and host response toward introduced stimuli across published literatures on this topic, suspecting the being of confounding factors, for example, subject-specific differences or distinctive experimental designs across studies become crucial. Subject-specific factors such as familial, old age, gender, life style, diet, contagion, disease and postnatal exposure to maternal and environmental microflora serve a crucial function in shaping the unique composition of homo microbiota in each individual. besides the commensal microbial writing will in turn affect the growth, festering and normal officiate of the server factors ( such as the neuro-immune network development and festering ), will contribute toward issues on varying disease susceptibility. interconnection of these factors make it much more challenging to design constructive and conclusive experiments to test the character of the microbiome in target disease and establishing the true homo microbiome-host relationship in multifactorial disease conditions. Whilst for the experimental blueprint, differences across studies, standardization of research protocols are required to enable effective comparison of findings across studies, reduce data variance and biases, and producing reasoned and robust findings for better explanation of human microbiome-disease relationships .
A better agreement of human microbiome and how the commensal microbes interact with the horde is undeniably useful to delineate the etiology and pathophysiological aspects of several human diseases, equally good as developing a more effective curative choice to counteract the restriction of presently existing treatments. application of FMT, probiotic and prebiotics derived from advances in gut microbiome studies to ‘ rectify ’ or ‘ restore ’ the change intestine microbiota in the dysbiosis-associated disease country back to the ‘ healthy ’ chemical equilibrium, holds great promise as the option curative option in respective diagnostic disease management. however, the beneficial remedy effect of microbiome-based therapy is largely dependent on the function of dysbiosis in contributing to the nature of the disease. Accurate recognition of winder microbiota members, intricate selection of microbial strains used in probiotics, or types of prebiotics administered to selectively enumerate the desirable commensal, have decidedly added supernumerary challenges to the across-the-board application of microbiome-based therapy to future clinical practices. In summation, majority of the probiotics are by and large regarded as safe but it does not warrant permanent safety. respective electric potential risks include possible transfer of antibiotic electric resistance gene or acerb genes among microbes. Although austere systemic side effects post-microbiome therapy are not observed to date, minor gastrointestinal discomforts such as abdominal annoyance, vomit, nausea are normally reported. This subsequently leads to withdrawal or non-compliance by patients during field trials. consequently, improvement on discussion regimen, road of administration, and effective communication with the patients are strongly encouraged. In short, Human Microbiome field of research is still relatively new but quickly growing, showing several preliminary but predict studies on the modulatory function of homo microbiome in homo health and disease. future applications of microbiome-based disease diagnosis, prognosis monitor, prophylaxis and treatments which exhibit capital potential in revolutionizing the current measures in disease management and treatment, are decidedly worth anticipating .

Author Contributions

ZK conducted the literature search and compiled the data. SL contributed academic aid and edited the manuscript .

Funding

This publication was supported by funding from the Tropical Medicine and Biology Platform .

Conflict of Interest Statement

The authors declare that the inquiry was conducted in the absence of any commercial or fiscal relationships that could be construed as a electric potential conflict of matter to .

Abbreviations

ACC-1, acetyl-CoA carboxylase ; APC, adenomatous polyposis coli ; Arg1, arginase 1 ; ASD, autism spectrum disorder ; ASF, altered Schaedler vegetation ; ATP, adenosine triphosphate ; BFT, Bacteroides fragilis enterotoxin ; BMI, body mass index ; c-AMP, cyclic adenosine monophosphate ; CD, Crohn ’ south disease ; CD14, bunch of differentiation 14 ; CDI, Clostridium difficile infection ; new world chat, choline acetyltransferase ; CLA, conjugated linoleic acid ; CNS, central anxious system ; CoA, coenzyme A ; CRC, colorectal cancer ; CTLA-4, cytotoxic T lymphocyte protein 4 ; DCA, deoxycholic acidic ; DNL, de novo lipogenesis ; EGC, intestinal glial cell ; ENS, intestinal skittish system ; ETBF, enterotoxigenic Bacteroides fragilis; FAS, fatty acid synthase ; Fiaf, fasting-induced adipose gene ; FMT, faecal microbiota transplant ; FOXP3, forkhead box P3 ; FXR, farnesoid X receptor ; GABA, γ-aminobutyric acidic ; GF, germ barren ; GIT, gastrointestinal tract ; GLP, glucagon-like peptide ; GPCR, G protein-coupled receptor ; GST, glutathione S -transferase ; HDAC, histone deacetylase ; HDL, high-density lipoprotein ; IBD, inflammatory intestine disease ; IBS, cranky intestine syndrome ; IFN-γ, interferon gamma ; IgA, immunoglobulin A ; IL, interleukin ; IPA, indole-3-propionic acid ; LCA, lithocholic acerb ; LPS, lipopolysaccharide ; MET, mesenchymal epithelial transition ; MHC, major histocompatibility building complex ; MS, maternal separation ; mTg, microbial transglutaminase ; NF-κB, nuclear factor-kappa B ; NKG2D, natural-killer group 2, member D ; NLR, nod-like sense organ ; NO, azotic oxide ; NOS, azotic oxide synthase ; OF-IN, oligofructose-enriched inulin ; OmpC, Escherichia coli extinct membrane protein ; PD, Parkinson ’ second disease ; PD-L1, programmed cellular telephone death protein 1 ligand 1 ; PPA, propionic acid ; PRR, pattern recognition sense organ ; PTMP, post-translational modification of proteins ; PXR, pregnane X sense organ ; RA, arthritic arthritis ; RNA, ribonucleic acid ; RNS, reactive nitrogen species ; ROS, reactive oxygen species ; SCFA, short-chain fatso acid ; SFB, segmented filamentous bacteria ; SLE, systemic lupus erythematosus ; SOCS3, suppressor of cytokine signaling 3 ; sp, species ; SPF, specific-pathogen free ; TcdA, Clostridium difficile toxin A ; TcdB, Clostridium difficile toxin B ; Tg, transglutaminase ; TH, helper T-cell ; TLR, toll-like receptor ; TMAO, trimethylamine N-oxide ; TNF, tumor necrosis component ; Treg, regulative T cellular telephone ; tTg, weave transglutaminase ; UC, ulcerative colitis ; WGS, unharmed genome sequence ; WHO, World Health Organization ; Wnt, Wingless Int ; ZO-1, zonula occludens-1 .

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