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Gut microbial products direct growth, differentiation, and development in animal hosts. However, we lack system-wide understanding of cell-specific responses to the microbiome. We profiled cell transcriptomes from the intestine, and associated tissue, of zebrafish larvae raised in the presence or absence of a microbiome. We uncovered extensive cellular heterogeneity in the conventional zebrafish intestinal epithelium, including previously undescribed cell types with known mammalian homologs. By comparing conventional to germ-free profiles, we mapped microbial impacts on transcriptional activity in each cell population. We revealed intricate degrees of cellular specificity in host responses to the microbiome that included regulatory effects on patterning and on metabolic and immune activity. For example, we showed that the absence of microbes hindered pro-angiogenic signals in the developing vasculature, causing impaired intestinal vascularization. Our work provides a high-resolution atlas of intestinal cellular composition in the developing fish gut and details the effects of the microbiome on each cell type., Competing Interests: Declaration of interests The authors declare no competing interests., (Copyright © 2022 The Authors. Published by Elsevier Inc. All rights reserved.)

The development of inflammatory bowel disease (IBD) is driven by the interaction among host genetics, microbiota, and the immune system of the entire digestive tract. Atg16L1T300A polymorphism is a genetic factor that confers increased risk for the pathogenesis of Crohn's disease. However, the exact contributions of Atg16L1T300A to intestinal mucosal homeostasis are not well understood. Here we show that Atg16L1T300A polymorphism impacts commensal bacterial flora in the intestine under a steady state. Analysis of intestinal bacteria from Atg16L1 T300A/T300A mice showed that they harbored an altered microbiota in both the terminal ileum and colon compared to cohoused WT mice. Interestingly, Atg16L1 T300A/T300A mice harbored a significant increase in the abundance of Tyzzerella , Mucispirillum , Ruminococcaceae , and Cyanobacteria which were known associated with IBD. Moreover, Akkermansia , a bacterium that is mucin-associated, was reduced greatly in Atg16L1 T300A/T300A mice. Further analysis indicated that goblet cells of Atg16L1 T300A/T300A mice had diminished mucin secretion that resulted from defective autophagy. Finally, Atg16L1 T300A/T300A mice developed more severe inflammation in the DSS colitis model than in WT mice. These results indicate that the altered microbiota in Atg16L1 T300A/T300A mice might be an important factor that contributed to the risk of Atg16L1T300A carriers to Crohn's disease and supports a multi-hit disease model involving specific gene-microbe interactions., Competing Interests: The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest., (Copyright © 2022 Liu, Gao, Jia, Lu, Zhu and Zhang.)

Background: Lung cancer is the leading cause of cancer-related deaths worldwide (Ferlay et al., Int J Cancer 136:E359-386, 2015). In addition, lung cancer is associated with the highest mortality among all cancer types (Wu et al., Exp Ther Med 16:3004-3010, 2018). Previous studies report that microbiota play an important role in lung cancer. Notably, changes in lung and gut microbiota, are associated with progression of lung cancer. Several studies report that lung and gut microbiome promote lung cancer initiation and development by modulating metabolic pathways, inhibiting the function of immune cells, and producing pro-inflammatory factors. In addition, some factors such as microbiota dysbiosis, affect production of bacteriotoxins, genotoxicity and virulence effect, therefore, they play a key role in cancer progression. These findings imply that lung and gut microbiome are potential markers and targets for lung cancer. However, the role of microbiota in development and progression of lung cancer has not been fully explored., Purpose: The aim of this study was to systemically review recent research findings on relationship of lung and gut microbiota with lung cancer. In addition, we explored gut-lung axis and potential mechanisms of lung and gut microbiota in modulating lung cancer progression., Conclusion: Pulmonary and intestinal flora influence the occurrence, development, treatment and prognosis of lung cancer, and will provide novel strategies for prevention, diagnosis, and treatment of lung cancer.

Objective: Chronic alcohol consumption is an important cause of liver-related deaths. Specific intestinal microbiota profiles are associated with susceptibility or resistance to alcoholic liver disease in both mice and humans. We aimed to identify the mechanisms by which targeting intestinal microbiota can improve alcohol-induced liver lesions., Design: We used human associated mice, a mouse model of alcoholic liver disease transplanted with the intestinal microbiota of alcoholic patients and used the prebiotic, pectin, to modulate the intestinal microbiota. Based on metabolomic analyses, we focused on microbiota tryptophan metabolites, which are ligands of the aryl hydrocarbon receptor (AhR). Involvement of the AhR pathway was assessed using both a pharmacological approach and AhR-deficient mice., Results: Pectin treatment modified the microbiome and metabolome in human microbiota-associated alcohol-fed mice, leading to a specific faecal signature. High production of bacterial tryptophan metabolites was associated with an improvement of liver injury. The AhR agonist Ficz (6-formylindolo (3,2-b) carbazole) reduced liver lesions, similarly to prebiotic treatment. Conversely, inactivation of the ahr gene in alcohol-fed AhR knock-out mice abrogated the beneficial effects of the prebiotic. Importantly, patients with severe alcoholic hepatitis have low levels of bacterial tryptophan derivatives that are AhR agonists., Conclusions: Improvement of alcoholic liver disease by targeting the intestinal microbiota involves the AhR pathway, which should be considered as a new therapeutic target., Competing Interests: Competing interests: Disclosures: DC received travel funds from Biocodex and Gilead, lecture fees from Gilead, and royalties from John Libbey Eurotext. GK is a cofounder of everImmune. HS received unrestricted study grants from Danone, Biocodex, and Enterome and board membership, consultancy or lecture fees from Carenity, Abbvie, Astellas, Danone, Ferring, Mayoly Spindler, MSD, Novartis, Roche, Tillots, Enterome, Maat, BiomX, Biose, Novartis, and Takeda and is a cofounder of Exeliom Biosciences. GP received travel funds from Janssen and Gilead, consulting fees from Bayer, Biocodex, Roche, Gilead, Pierre Fabre, and Servier, and royalties from Elsevier-Masson, Solar, Flammation/Versilio, and John Libbey Eurotext. A-MC received travel funds and consulting fees from Biocodex and royalties from Elsevier-Masson, Solar, Flammation/Versilio and John Libbey Eurotext. All other authors declare no conflicts of interest., (© Author(s) (or their employer(s)) 2021. No commercial re-use. See rights and permissions. Published by BMJ.)

Blood glucose and insulin homeostasis is disrupted during the progression of type 2 diabetes. Insulin levels and action are regulated by both peripheral and central responses that involve the intestine and microbiome. The intestine and its microbiota process nutrients and generate molecules that influence blood glucose and insulin. Peripheral insulin regulation is regulated by gut-segment-dependent nutrient sensing and microbial factors such as short-chain fatty acids and bile acids that engage G-protein-coupled receptors. Innate immune sensing of gut-derived bacterial cell wall components and lipopolysaccharides also alter insulin homeostasis. These bacterial metabolites and postbiotics influence insulin secretion and insulin clearance in part by altering endocrine responses such as glucagon-like peptide-1. Gut-derived bacterial factors can promote inflammation and insulin resistance, but other postbiotics can be insulin sensitizers. In parallel, activation of small intestinal sirtuin 1 increases insulin sensitivity by reversing high fat-induced hypothalamic insulin resistance through a gut-brain neuronal axis, whereas high fat-feeding alters small intestinal microbiome and increases taurochenodeoxycholic acid in the plasma and the dorsal vagal complex to induce insulin resistance. In summary, emerging evidence indicates that intestinal molecular signaling involving nutrient sensing and the host-microbe symbiosis alters insulin homeostasis and action. Gut-derived host endocrine and paracrine factors as well as microbial metabolites act on the liver, pancreas, and the brain, and in parallel on the gut-brain neuronal axis. Understanding common nodes of peripheral and central insulin homeostasis and action may reveal new ways to target the intestinal host-microbe relationship in obesity, metabolic disease, and type 2 diabetes.

Aims: The present study aimed to reveal microbial relationship between shrimp intestine and ambient in higher place shrimp ponds from the aspects of composition and function., Methods and Results: Metagenome and 16S rRNA gene sequencing were used to compare microbial compositions and functions of water, effluent and shrimp intestine in higher place Litopenaeus vannamei ponds. Although the three groups had similar dominant phyla, such as Proteobacteria, Bacteroidetes and Tenericutes, their bacterial compositions at the genus level were obviously different. Compared to effluent and intestine, the relative abundance of Vibrio as common opportunistic pathogen for shrimp was significantly higher in water. However, cluster analysis showed that intestinal microbial composition was more similar to that of effluent than water. Metagenomic data showed that the predominant microbial functions in the three groups were mostly related to energy production and biosynthesis, while carbohydrate metabolism was relatively enriched in intestinal microbiota. More importantly, Proteobacteria played a critical role in carbon metabolism and biosynthesis of amino acids in the three habitats, and Vibrio had the most functions related to bacterial virulence and infection., Conclusions: Shrimp intestinal microbiota had a close correlation with the ambient microbiota in both structure and function. As the most dominant phylum, Proteobacteria was very important for microbiota communication and nutrient cycling in higher place shrimp ponds. Moreover, due to the pathogenicity, it was necessary to monitor the abundant changes of Vibrio in water to decrease the risk of shrimp disease outbreaks., Significance and Impact of the Study: These above results may be helpful to comprehensively understand the characteristics and functions of microbiota in higher place shrimp ponds, thereby providing basic information for developing the management strategies of entire microbiota to sustain shrimp health., (© 2020 The Society for Applied Microbiology.)

Very low-carbohydrate, high-fat ketogenic diets (KDs) induce a pronounced shift in metabolic fuel utilization that elevates circulating ketone bodies; however, the consequences of these compounds for host-microbiome interactions remain unknown. Here, we show that KDs alter the human and mouse gut microbiota in a manner distinct from high-fat diets (HFDs). Metagenomic and metabolomic analyses of stool samples from an 8-week inpatient study revealed marked shifts in gut microbial community structure and function during the KD. Gradient diet experiments in mice confirmed the unique impact of KDs relative to HFDs with a reproducible depletion of bifidobacteria. In vitro and in vivo experiments showed that ketone bodies selectively inhibited bifidobacterial growth. Finally, mono-colonizations and human microbiome transplantations into germ-free mice revealed that the KD-associated gut microbiota reduces the levels of intestinal pro-inflammatory Th17 cells. Together, these results highlight the importance of trans-kingdom chemical dialogs for mediating the host response to dietary interventions., Competing Interests: Declaration of Interests J.C.N. and E.V. are co-founders with equity interest of BHB Therapeutics, which is developing products related to ketone bodies. P.J.T. is on the scientific advisory boards for Kaleido, Pendulum, Seres, and SNIPRbiome; there is no direct overlap between the current study and these consulting duties., (Copyright © 2020 Elsevier Inc. All rights reserved.)

Colorectal cancer is the third largest cancer in worldwide and has been proven to be closely related to the intestinal microbiota. Many reports and clinical studies have shown that intestinal microbial behavior may lead to pathological changes in the host intestines. The changes can be divided into epigenetic changes and carcinogenic changes at the gene level, which ultimately promote the production and development of colorectal cancer. This article reviews the pathways of microbial signaling in the intestinal epithelial barrier, the role of microbiota in inflammatory colorectal tumors, and typical microbial carcinogenesis. Finally, by gaining a deeper understanding of the intestinal microbiota, we hope to achieve the goal of treating colorectal cancer using current microbiota technologies, such as fecal microbiological transplantation., (© 2018 UICC.)

Numerous bacterial pathogens infect the mammalian host by initially associating with epithelial cells that line the intestinal lumen. Recent work has revealed that commensal bacteria that reside in the intestine promote defense against pathogenic infection, however whether the microbiota direct host pathways that alter pathogen adherence is not well-understood. Here, by comparing germ-free mice, we identify that the microbiota decrease bacterial pathogen adherence and dampen epithelial expression of the cell surface glycoprotein C-type lectin 2e (Clec2e). Functional studies revealed that overexpression of this lectin promotes adherence of intestinal bacterial pathogens to mammalian cells. Interestingly, microbiota-sensitive downregulation of Clec2e corresponds with decreased histone acetylation of the Clec2e gene in intestinal epithelial cells. Histone deacetylation and transcriptional regulation of Clec2e depends on expression and recruitment of the histone deacetylase HDAC3. Thus, commensal bacteria epigenetically instruct epithelial cells to decrease expression of a C-type lectin that promotes pathogen adherence, revealing a novel mechanism for how the microbiota promote innate defense against infection.

Despite considerable attention, the mechanisms by which the microbiota affect brain function and host behaviour via the gut-brain axis remain undefined. Identifying microbe-specific pathways that influence neuronal function and bi-directional communication between the gut microbiota and the host central nervous system is challenging due to the extreme microbial diversity in the gut of conventionally-reared mice. Herein, we describe the use of the altered Schaedler flora (ASF) mouse model as an alternative to conventionally-reared and germ-free animals. Colonized with only 8 bacterial species, use of ASF mice greatly simplifies the examination of microbiota-host interactions. We assessed the extent to which behaviour differed between mice with a limited consortium of bacteria compared with a complex, conventional microbiota. The elevated plus maze and open-field assays were utilized to assess murine behaviour. Histological analysis of ileum and colon was performed to evaluate intestinal morphology, and 16 s rRNA gene taxonomic profiling was performed to determine host-stress induced changes in fecal microbial communities. Behavioural and serum corticosterone differences were observed between ASF and conventionally-reared mice, while no differences were found between the intestinal morphology of these two groups. The stress of the behavioural tests induced significant changes in the ASF fecal microbial community but not in that of the conventionally-reared mice. In contrast to the conventionally-reared mice, the results indicated that the ASF mice displayed a marked anxiogenic-like behaviour. These data indicate that ASF mice represent a unique model to elucidate mechanisms governing microbiota-gut-brain communication affecting behaviour., (Copyright © 2018 Elsevier B.V. All rights reserved.)

The 15th European Cystic Fibrosis Society (ECFS) Basic Science pre-conference Symposium focused on the topic of the microbiome, asking the question "The lung and gut microbiome: what has to be considered for cystic fibrosis (CF)?" This review gives an overview of the main points raised during the symposium, which dealt with the technical considerations, pathophysiology and clinical implications of the microbiome in CF., (Copyright © 2018 European Cystic Fibrosis Society. Published by Elsevier B.V. All rights reserved.)

The RNA-SIP technology allows for linking the structure and function of complex microbial communities, that is, the identification of microbial key players involved in distinct degradation and assimilation processes under in situ conditions. Being dependent on RNA, this technique is particularly suited for environments with high numbers of very active, that is, significantly RNA-expressing microorganisms, such as intestinal tract samples. We use RNA-SIP for the identification of bacteria involved in the degradation and assimilation of prebiotic carbohydrates in order to better understand the functionality of these medically and economically important nutrients in human and animal intestinal environments.

Microorganisms play crucial roles in nutrient cycling, water quality maintenance, and farmed animal health. Increasing evidences have revealed a close association between unstable microbial environments and disease occurrences in aquaculture. Thereupon, we used high-throughput sequencing technology to comprehensively compare the bacterial communities of water, sediment, and intestine in mariculture ponds at the middle and late stages of Litopenaeus vannamei farming and analyzed whether changes of their microbiota assemblages were associated with environmental factors and shrimp physiological health. Results showed that bacterial community structures were significantly distinct among water, sediment, and intestine; meanwhile, the relative abundances of intestinal dominant taxa were significantly changed between different rearing stages. Compared with intestine and water, shrimp intestine and sediment had a similar profile of the dominant bacterial genera by cluster analysis, and the observed species, diversity indexes, and shared OTUs of bacterial communities in intestine and sediment were simultaneously increased after shrimp were farmed for 90 days. These results reflected a closer relationship between microbiotas in sediment and intestine, which was further proved by nonmetric multidimensional scaling analysis. However, bacterial communities in water, sediment, and intestine responded differently to environmental variables by redundancy and correlation analysis. More importantly, shrimp physiological parameters were closely associated with bacterial variations in the gut and/or ambient, especially the gut microbiota owning significantly high levels of predicted functional pathways involved in disease emergence. These findings may greatly add to our understanding of the microbiota characteristics of the shrimp pond ecosystem and the complex interactions among shrimp, ambient microflora, and environmental variables.

The incidence of inflammatory bowel disease (IBD) is increasing worldwide, most notably in young children. The development of disease is a combination of several factors, including genetics, environment, the microbiota, and immune system. Recently, next-generation sequencing has allowed for the identification of novel genetic causes for intestinal disease, including pediatric inflammatory bowel disease (IBD). These IBD genes can generally be grouped into genes causing either primary immunodeficiency or intestinal epithelial defects (the focus of this review). Most of these genes have been functionally validated with in vitro and/or animal models, and have been demonstrated to cause intestinal disease. Intestinal epithelial IBD genes are of particular interest since they are the least amenable to current therapies; therefore, further research is warranted to develop potential therapies. A number of cellular pathways are impacted with intestinal epithelial IBD genes, including intestinal epithelial cell adhesion and generation of reactive oxygen species. Here, we describe the currently known IBD risk alleles and monogenic causal intestinal epithelial genes, their putative roles in preserving intestinal epithelial cell homeostasis, and their implications for IBD pathophysiology.

Physiologic microbe-host interactions in the intestine require the maintenance of the microbiota in a luminal compartment through a complex interplay between epithelial and immune cells. However, the roles of mucosal myeloid cells in this process remain incompletely understood. In this study, we identified that decreased myeloid cell phagocytic activity promotes colon tumorigenesis. We show that this is due to bacterial accumulation in the lamina propria and present evidence that the underlying mechanism is bacterial induction of prostaglandin production by myeloid cells. Moreover, we show that similar events in the normal colonic mucosa lead to reductions in Tuft cells, goblet cells, and the mucus barrier of the colonic epithelium. These alterations are again linked to the induction of prostaglandin production in response to bacterial penetration of the mucosa. Altogether, our work highlights immune cell-epithelial cell interactions triggered by the microbiota that control intestinal immunity, epithelial differentiation, and carcinogenesis., (Copyright © 2018 The Authors. Published by Elsevier Inc. All rights reserved.)

Fermented milk products like yogurt or soft cheese provide calcium, phosphorus, and protein. All these nutrients influence bone growth and bone loss. In addition, fermented milk products may contain prebiotics like inulin which may be added to yogurt, and provide probiotics which are capable of modifying intestinal calcium absorption and/or bone metabolism. On the other hand, yogurt consumption may ensure a more regular ingestion of milk products and higher compliance, because of various flavors and sweetness. Bone mass accrual, bone homeostasis, and attenuation of sex hormone deficiency-induced bone loss seem to benefit from calcium, protein, pre-, or probiotics ingestion, which may modify gut microbiota composition and metabolism. Fermented milk products might also represent a marker of lifestyle promoting healthy bone health.

Epidemiological data indicate a disproportional increase in the incidence of multiple sclerosis (MS) over the last decades, particularly in industrialized countries. Although this increase is also associated with altered diagnostic criteria and improved sensitivity of imaging procedures, current data suggest that particularly alterations in our way of life play an important role. In recent years the importance of the gut and intestinal microbiome for some neurological diseases and in particular for MS was recognized. Because nutritional habits have a substantial influence on the composition of the microbiome and our nutrition has changed considerably in the last decades, nutritional components can play an important role in the pathogenesis of MS. In this further education article we summarize the currently available evidence on the role of the gut and on the effects of dietary components on the microbiome in the pathogenesis of MS.

We developed a gnotobiotic (Gn) pig model colonised with defined commensal microbiota (DMF) to provide a simplified and controlled system to study the interactions between intestinal commensals, antibiotics (ciprofloxacin, CIP), probiotics (Escherichia coli Nissle 1917, EcN) and virulent human rotavirus (VirHRV). The DMF included seven gut commensal species of porcine origin that mimic the predominant species in the infant gut. Gn piglets were divided into four groups: DMF control (non-treated), DMF+CIP (CIP treated), DMF+CIP+EcN (CIP/EcN treated), DMF+EcN (EcN treated) and inoculated orally with 10 5 cfu of each DMF strain. The pig gut was successfully colonised by all DMF species and established a simplified bacterial community by post-bacteria colonisation day (PBCD) 14/post-VirHRV challenge day (PCD) 0. Overall, Bifidobacterium adolescentis was commonly observed in faeces in all groups and time points. At PCD0, after six days of CIP treatment (DMF+CIP), we observed significantly decreased aerobic and anaerobic bacteria counts especially in jejunum (P<0.001), where no DMF species were detected in jejunum by T-RFLP. Following HRV challenge, 100% of pigs in DMF+CIP group developed diarrhoea with higher diarrhoea scores and duration as compared to all other groups. However, only 33% of pigs treated with EcN plus CIP developed diarrhoea. EcN treatment also enhanced the bacterial diversity and all seven DMF species were detected with a higher proportion of Bifidobacterium longum in jejunum in the DMF+CIP+EcN group on PBCD14/PCD0. Our results suggest that EcN increased the proportion of B. longum especially in jejunum and mitigated adverse impacts of antibiotic use during acute-infectious diarrhoea. The DMF model with a simplified gut commensal community can further our knowledge of how commensals and probiotics promote intestinal homeostasis and contribute to host health.

The establishment of the infant gut microbiota is a highly dynamic process dependent on extrinsic and intrinsic factors. We characterized the faecal microbiota of 4 breastfed infants and 4 formula-fed infants at 17 consecutive time points during the first 12 weeks of life. Microbiota composition was analysed by a combination of 16S rRNA gene sequencing and quantitative PCR (qPCR). In this dataset, individuality was a major driver of microbiota composition (P = 0.002) and was more pronounced in breastfed infants. A developmental signature could be distinguished, characterized by sequential colonisation of i) intrauterine/vaginal birth associated taxa, ii) skin derived taxa and other typical early colonisers such as Streptococcus and Enterobacteriaceae, iii) domination of Bifidobacteriaceae, and iv) the appearance of adultlike taxa, particularly species associated with Blautia, Eggerthella, and the potential pathobiont Clostridium difficile. Low abundance of potential pathogens was detected by 16S profiling and confirmed by qPCR. Incidence and dominance of skin and breast milk associated microbes were increased in the gut microbiome of breastfed infants compared to formula-fed infants. The approaches in this study indicate that microbiota development of breastfed and formula-fed infants proceeds according to similar developmental stages with microbiota signatures that include stage-specific species.

To investigate the effects of Kluyveromyces marxianus on immune responses, intestinal structure and microbiota in broilers, 840 1-d-old broiler chicks were randomly divided into seven groups (eight replicates) and were fed basal diets without or with 0.25, 0.50, 1.0, 1.5, 2.0, and 2.5 g/kg of K. marxianus (2.0×1010 CFU/g). Serum and intestine samples were collected at 21 d of age. The results showed that increasing K. marxianus addition linearly reduced feed conversion ratio but linearly elevated relative thymus weight, as well as quadratically increased serum lysozyme and IgG levels, with the medium dose (1.0 g/kg) being the most effective. The ratio of villus height to crypt depth of jejunum and ileum, ileal villus height and sucrase activity, as well as the mRNA expression of ileal mucin-2, claudin-1 and sodium glucose cotransporter 1 linearly responded to the increasing K. marxianus addition. Supplemental K. marxianus at low (0.5 g/kg), medium (1.5 g/kg) and high (2.5 g/kg) dose all decreased the abundance of phylum Cyanobacteria, increased the abundance of phylum Firmicutes and genus Lactobacillus in ileum. The high dose of K. marxianus addition also reduced the abundance of order Rickettsiales and Pseudomonadales along with species Acinetobacter junii. Ileal bacterial communities between K. marxianus-treated and untreated groups formed distinctly different clusters. In summary, K. marxianus supplementation benefits feed efficiency and immune function, as well as intestinal structure in broilers, which might be attributed to the improved ileal microbial structure. Supplemental K. marxianus at high dose (2.5 g/kg) was more effective for feed efficiency and intestinal health of broilers, while the innate immunity was optimized at a medium dose (1.0 g/kg).

Understanding how intestinal enteropathogens cause acute and chronic alterations has direct animal and human health perspectives. Significant advances have been made on this field by studies focusing on the dynamic crosstalk between the intestinal protozoan parasite model Giardia duodenalis and the host intestinal mucosa. The concept of intestinal barrier function is of the highest importance in the context of many gastrointestinal diseases such as infectious enteritis, inflammatory bowel disease, and post-infectious gastrointestinal disorders. This crucial function relies on 3 biotic and abiotic components, first the commensal microbiota organized as a biofilm, then an overlaying mucus layer, and finally the tightly structured intestinal epithelium. Herein we review multiple strategies used by Giardia parasite to circumvent these 3 components. We will summarize what is known and discuss preliminary observations suggesting how such enteropathogen directly and/ or indirectly impairs commensal microbiota biofilm architecture, disrupts mucus layer and damages host epithelium physiology and survival.

Inflammatory bowel diseases (IBDs) are diseases characterized by various degrees of inflammation involving the gastrointestinal tract. Ulcerative colitis and Crohn's disease are characterized by a dysregulated immune response leading to structural gut alterations in genetically predisposed individuals. Diverticular disease is characterized by abnormal immune response to normal gut microbiota. IBDs are linked to a lack of physiological tolerance of the mucosal immune system to resident gut microbiota and pathogens. The disruption of immune tolerance involves inflammatory pathways characterized by an unbalance between the anti-inflammatory regulatory T cells and the proinflammatory Th1/Th17 cells. The interaction among T cell subpopulations and their related cytokines, mediators of inflammation, gut microbiota, and the intestinal mucosa constitute the gut "immunological niche." Several evidences have shown that xenobiotics, such as rifaximin, can positively modulate the inflammatory pathways at the site of gut immunological niche, acting as anti-inflammatory agents. Xenobiotics may interfere with components of the immunological niche, leading to activation of anti-inflammatory pathways and inhibition of several mediators of inflammation. In summary, xenobiotics may reduce disease-related gut mucosal alterations and clinical symptoms. Studying the complex interplay between gut immunological niche and xenobiotics will certainly open new horizons in the knowledge and therapy of intestinal pathologies.

The mucus layer and gut microbiota interplay contributes to host homeostasis. The mucus layer serves as a scaffold and a carbon source for gut microorganisms; conversely, gut microorganisms, including mucin degraders, influence mucin gene expression, glycosylation, and secretion. Conjointly they shield the epithelium from luminal pathogens, antigens, and toxins. Importantly, the mucus layer and gut microbiota are established in parallel during early postnatal life. During this period, the development of gut microbiota and mucus layer is coupled with that of the immune system. Developmental changes of different mucin types can impact the age-dependent patterns of intestinal infection in terms of incidence and severity. Altered mucus layer, dysbiotic microbiota, and abnormal mucus-gut microbiota interaction have the potential for inducing systemic effects, and accompany several intestinal diseases such as inflammatory bowel disease, colorectal cancer, and radiation-induced mucositis. Early life provides a pivotal window of opportunity to favorably modulate the mucus-microbiota interaction. The support of a health-compatible mucin-microbiota maturation in early life is paramount for long-term health and serves as an important opportunity for clinical intervention.

Objectives: Dysbiosis of the intestinal microbiota is associated with Crohn's disease (CD). Functional evidence for a causal role of bacteria in the development of chronic small intestinal inflammation is lacking. Similar to human pathology, TNF(deltaARE) mice develop a tumour necrosis factor (TNF)-driven CD-like transmural inflammation with predominant ileal involvement., Design: Heterozygous TNF(deltaARE) mice and wildtype (WT) littermates were housed under conventional (CONV), specific pathogen-free (SPF) and germ-free (GF) conditions. Microbial communities were analysed by high-throughput 16S ribosomal RNA gene sequencing. Metaproteomes were measured using LC-MS. Temporal and spatial resolution of disease development was followed after antibiotic treatment and transfer of microbial communities into GF mice. Granulocyte infiltration and Paneth cell function was assessed by immunofluorescence and gene expression analysis., Results: GF-TNF(deltaARE) mice were free of inflammation in the gut and antibiotic treatment of CONV-TNF(deltaARE) mice attenuated ileitis but not colitis, demonstrating that disease severity and location are microbiota-dependent. SPF-TNF(deltaARE) mice developed distinct ileitis-phenotypes associated with gradual loss of antimicrobial defence. 16S analysis and metaproteomics revealed specific compositional and functional alterations of bacterial communities in inflamed mice. Transplantation of disease-associated but not healthy microbiota transmitted CD-like ileitis to GF-TNF(deltaARE) recipients and triggered loss of lysozyme and cryptdin-2 expression. Monoassociation of GF-TNF(deltaARE) mice with the human CD-related Escherichia coli LF82 did not induce ileitis., Conclusions: We provide clear experimental evidence for the causal role of gut bacterial dysbiosis in the development of chronic ileal inflammation with subsequent failure of Paneth cell function., (Published by the BMJ Publishing Group Limited. For permission to use (where not already granted under a licence) please go to http://www.bmj.com/company/products-services/rights-and-licensing/)

Despite over 100-year history of research on schizophrenia, its etiology is still not fully understood, which might be due to the significant heterogeneity in terms of both its course, as well as the etiopathogenesis. One of the best-proven mediating mechanisms in the development of schizophrenia is the immuno-inflammatory response, the sources of which are believed to be the dysfunctions of brain-gut axis and pathological processes occurring in the intestines. This paper is a review of the literature on this subject which presents factors both involved in the functioning of brain-gut axis and important for the development of schizophrenia, i.e. 1. intestinal microbiome (intestinal microbiota), 2. permeable intestine (leaky gut syndrome), 3. hypersensitivity to food antigens, including gluten and casein of cow's milk. Research results seem to be very promising and indicate the possibility of improved clinical outcomes in some patients with schizophrenia by modifying diet, use of probiotics, and the implementation of antibiotic therapy of specific treatment groups. However, further research is needed on links between the intestinal microbiome and intestinal function as factors mediating the activation of the immune system and the development and further course of schizophrenia.

Background and Aim: Because neutrophil gelatinase-associated lipocalin (NGAL) is known to provide significant bacteriostatic effects during infectious conditions, we tested the hypothesis that this protein is up-regulated and secreted into the intraluminal cavity of the gut under critically ill conditions and is thus responsible for the regulation of bacterial overgrowth., Methods: With our institutional approval, male C57BL/6J mouse (6-7 weeks) were enrolled and applied for lipopolysaccharide or peritonitis model compared with naïve control. We assessed NGAL protein concentrations in intestinal lumen and up-regulation of NGAL expression in intestinal tissues in in vivo as well as ex vivo settings. Simultaneously, we examined the effects of NGAL protein administration on the growth of Escherichia coli (E. coli) in in vivo and in vitro experimental settings. The localization of NGAL in intestinal tissues and lumen was also assessed by immunohistological approach using NGAL antibody., Results: Both lipopolysaccharide and peritonitis insults evoked the marked up-regulation of NGAL mRNA and protein levels in gut tissues such as crypt cells. In addition, the administration of NGAL protein significantly inhibited the outgrowth of enteric E. coli under both in vitro and in vivo conditions, accompanied by histological evidence., Conclusion: Neutrophil gelatinase-associated lipocalin protein accompanied by apparent bacteriostatic action accumulated in the intestinal wall and streamed into the mucosal layer during critically ill state, thereby possibly shaping microbiota homeostasis in the gut., (© 2015 Journal of Gastroenterology and Hepatology Foundation and Wiley Publishing Asia Pty Ltd.)

The bacterial populations in the human intestine impact host physiological functions through their metabolic activity. In addition to performing essential catabolic and biotransformation functions, the gut microbiota produces bioactive small molecules that mediate interactions with the host and contribute to the neurohumoral axes connecting the intestine with other parts of the body. This review discusses recent progress in characterizing the metabolic products of the gut microbiota and their biological functions, focusing on studies that investigate the responsible bacterial pathways and cognate host receptors. Several key areas are highlighted for future development: context-based analysis targeting pathways; integration of analytical approaches; metabolic modeling; and synthetic systems for in vivo manipulation of microbiota functions. Prospectively, these developments could further our mechanistic understanding of host-microbiota interactions., (Copyright © 2015 Elsevier Ltd. All rights reserved.)

Background: The complexity and diversity of the human intestinal microbiome has only recently been characterized. The multiple metabolic and immunologic effects of the bacterial flora have demonstrated the symbiosis between the microbiome and its host. This symbiosis is disturbed in a multitude of diseases, especially in critically ill patients., Objectives: A review of the changes in the intestinal microbiome of critically ill patients and the use of probiotics., Material and Methods: Nonsystematic literature search in PubMed on the topics: (1) changes in the intestinal microbiome in critically ill patients, (2) interventions using probiotics in critically ill patients, and (3) use of fecal transplantation in Clostridium difficile colitis., Results: Trauma, sepsis, systemic inflammatory response syndrome, and other conditions lead to shifts in the composition of the intestinal microbiome, which are correlated with clinical outcome. The most obvious change is a profound loss of obligate anaerobe bacteria, leading also to metabolic changes. Probiotics have been used in several studies and show efficacy in the reduction of infectious complication but not in overall mortality. C. difficile colitis as the model disease for a disturbed microbiome can be treated effectively by transfer of donor feces, which also restores the diversity of the microbiome., Conclusion: Taking into account the successful intervention of fecal transplantation on the intestinal microbiome, new products developed using the current knowledge of the intestinal microbiome could be more effective.

The present study was carried out to investigate the effect of dietary supplementation of different levels of mannan-oligosaccharides (MOS) on performance, egg quality, immune responses, and gut microflora in laying hens exposed to Escherichia coli (E. coli) challenge. A total of 180 Hy-Line W-36 laying hens, 55 wk of age, were randomly distributed among 5 dietary treatments with 6 replicates of 6 hens each. Experimental diets consisted of 5 graded levels of MOS (0, 0.05, 0.1, 0.15, and 0.2% of diet). The study lasted 77 d including 7 d for adaptation and 70 d as the main experimental period subdivided into two 35-d periods. The results showed increases (P<0.05) in egg production percentage and egg mass, and a decrease (P<0.05) in feed conversion ratio (FCR) in birds fed the diets containing 0.1 and 0.15% MOS compared with control birds during the first 35-d period. In addition, there were significant differences between dietary treatments for egg mass and FCR during the second 35-d, with the best (P<0.05) values observed for hens fed on 0.1% MOS-supplemented diet. Feed intake and egg weight, however, were not influenced by dietary treatments throughout the experimental period. Compared to control birds, supplemental MOS resulted in 9.8% (P<0.01) and 8.1% (P<0.05) increases in hen-day egg production and egg mass, respectively, during the entire experimental period. Dietary supplementation with 0.1 to 0.2% MOS decreased (P<0.01) serum triglycerides concentration compared with control birds. In addition, serum concentration of low-density lipoproteins was reduced (P<0.001) by all supplemental MOS levels. In contrast to Newcastle antibody titer, primary antibody response against sheep red blood cell was significantly (P<0.05) affected by supplemental MOS. Supplementation of MOS into the diet caused increases in digestibility coefficients of DM (P<0.05) and CP (P<0.01). In addition, there was a significant (P<0.01) difference between dietary treatments for ileal ether extract digestibility, with the highest digestibility values assigned to the hens supplemented with 0.05% MOS. Although dietary MOS supplementation had no effect on ileal E. coli and total bacteria enumerations, it resulted in a decrease (P<0.01) in Salmonella count and increased Lactobacillus. The present findings indicate that MOS supplementation of laying hens under bacterial challenge could improve productive performance probably through modification of intestinal bacterial populations and improving nutrient digestibility., (© 2015 Poultry Science Association Inc.)

Antimicrobial peptides (AMPs) expressed by epithelial and immune cells are largely described for the defense against invading microorganisms. Recently, their immunomodulatory functions have been highlighted in various contexts. However how AMPs expressed by non-immune cells might influence autoimmune responses in peripheral tissues, such as the pancreas, is unknown. Here, we found that insulin-secreting β-cells produced the cathelicidin related antimicrobial peptide (CRAMP) and that this production was defective in non-obese diabetic (NOD) mice. CRAMP administrated to prediabetic NOD mice induced regulatory immune cells in the pancreatic islets, dampening the incidence of autoimmune diabetes. Additional investigation revealed that the production of CRAMP by β-cells was controlled by short-chain fatty acids produced by the gut microbiota. Accordingly, gut microbiota manipulations in NOD mice modulated CRAMP production and inflammation in the pancreatic islets, revealing that the gut microbiota directly shape the pancreatic immune environment and autoimmune diabetes development., (Copyright © 2015 Elsevier Inc. All rights reserved.)

Microbially derived metabolites in the intestine regulate host immunity and impact disease pathophysiology in various organs. Sun et al. (2015) suggest a direct effect of microbial metabolites on pancreatic endocrine cells in regulating type 1 diabetes pathophysiology., (Copyright © 2015 Elsevier Inc. All rights reserved.)

The human gut microbiome is known to be associated with various human disorders, but a major challenge is to go beyond association studies and elucidate causalities. Mathematical modeling of the human gut microbiome at a genome scale is a useful tool to decipher microbe-microbe, diet-microbe and microbe-host interactions. Here, we describe the CASINO (Community And Systems-level INteractive Optimization) toolbox, a comprehensive computational platform for analysis of microbial communities through metabolic modeling. We first validated the toolbox by simulating and testing the performance of single bacteria and whole communities in vitro. Focusing on metabolic interactions between the diet, gut microbiota, and host metabolism, we demonstrated the predictive power of the toolbox in a diet-intervention study of 45 obese and overweight individuals and validated our predictions by fecal and blood metabolomics data. Thus, modeling could quantitatively describe altered fecal and serum amino acid levels in response to diet intervention., (Copyright © 2015 Elsevier Inc. All rights reserved.)

All vertebrates contain a diverse collection of commensal, symbiotic and pathogenic microorganisms, such as bacteria, viruses and fungi, on their various body surfaces, and the ecological community of these microorganisms is referred to as the microbiota. Mucosal sites, such as the intestine, harbour the majority of microorganisms, and the human intestine contains the largest community of commensal and symbiotic bacteria. This intestinal community of bacteria is diverse, and there is a significant variability among individuals with respect to the composition of the intestinal microbiome. Both genetic and environmental factors can influence the diversity and composition of the intestinal bacteria with the predominant environmental factor being diet. So far, studies have shown that diet-dependent differences in the composition of intestinal bacteria can be classified into three groups, called enterotypes. Other environmental factors that can influence the composition include antibiotics, probiotics, smoking and drugs. Studies of monozygotic and dizygotic twins have proven that genetics plays a role. Recently, MHC II genes have been associated with specific microbial compositions in human infants and transgenic mice that express different HLA alleles. There is a growing list of genes/molecules that are involved with the sensing and monitoring of the intestinal lumen by the intestinal immune system that, when genetically altered, will significantly alter the composition of the intestinal microflora. The focus of this review will be on the genetic factors that influence the composition of the intestinal microflora., (© 2015 John Wiley & Sons Ltd.)

Recent studies suggest that gastrointestinal tract microbiota modulate cancer development in distant non-intestinal tissues. Here we tested mechanistic hypotheses using a targeted pathogenic gut microbial infection animal model with a predilection to breast cancer. FVB-Tg(C3-1-TAg)cJeg/JegJ female mice were infected by gastric gavage with Helicobacter hepaticus at three-months-of-age putting them at increased risk for mammary tumor development. Tumorigenesis was multifocal and characterized by extensive infiltrates of myeloperoxidase-positive neutrophils otherwise implicated in cancer progression in humans and animal models. To test whether neutrophils were important in etiopathogenesis in this bacteria-triggered model system, we next systemically depleted mice of neutrophils using thrice weekly intraperitoneal injections with anti-Ly-6G antibody. We found that antibody depletion entirely inhibited tumor development in this H. hepaticus-infected model. These data demonstrate that host neutrophil-associated immune responses to intestinal tract microbes significantly impact cancer progression in distal tissues such as mammary glands, and identify gut microbes as novel targets for extra-intestinal cancer therapy.

Gut microbiota remains a very interesting, yet largely unexplored ecosystem inside the human organism. The importance of this ecosystem for the physiology and the pathophysiology of the organism is being slowly unraveled. Recent studies reveal a connection between intestinal microbiota and atherosclerosis development. It seems that alterations in the function and composition of this bacterial population lead through complex mechanisms to a high risk for atherosclerosis. Although these mechanisms remain largely unknown, published studies show that microbiota can lead to atherosclerosis either by augmenting known risk factors or via other, more "direct" mechanisms. This review article summarizes the available literature regarding this matter., (Copyright © 2015 Elsevier Inc. All rights reserved.)

The mammalian gut microbiota harbors a diverse ecosystem where hundreds of bacterial species interact with each other and their host. Given that bacteria use signals to communicate and regulate group behaviors (quorum sensing), we asked whether such communication between different commensal species can influence the interactions occurring in this environment. We engineered the enteric bacterium, Escherichia coli, to manipulate the levels of the interspecies quorum sensing signal, autoinducer-2 (AI-2), in the mouse intestine and investigated the effect upon antibiotic-induced gut microbiota dysbiosis. E. coli that increased intestinal AI-2 levels altered the composition of the antibiotic-treated gut microbiota, favoring the expansion of the Firmicutes phylum. This significantly increased the Firmicutes/Bacteroidetes ratio, to oppose the strong effect of the antibiotic, which had almost cleared the Firmicutes. This demonstrates that AI-2 levels influence the abundance of the major phyla of the gut microbiota, the balance of which is known to influence human health.

The Reproducibility Project: Cancer Biology seeks to address growing concerns about reproducibility in scientific research by conducting replications of 50 papers in the field of cancer biology published between 2010 and 2012. This Registered report describes the proposed replication plan of key experiments from ‘Intestinal Inflammation Targets Cancer-Inducing Activity of the Microbiota’ by Arthur et al. (2012), published in Science in 2012. Arthur and colleagues identified a genotoxic island in Escherichia coli NC101 that appeared to be responsible for causing neoplastic lesions in inflammation-induced IL10-/- mice treated with azoxymethane. The experiments that will be replicated are those reported in Figure 4 (Arthur et al., 2012). Arthur and colleagues inoculated IL10-/- mice with a mutated strain of E. coli NC101 lacking the genotoxic island, and showed that those mice suffered from fewer neoplastic lesions than mice inoculated with the wild type form of E. coli NC101 (Figure 4). The Reproducibility Project: Cancer Biology is a collaboration between the Center for Open Science and Science Exchange, and the results of the replications will be published by eLife.

Objective: This study aimed at establishing bacterial flagellin-recognizing toll-like receptor 5 (TLR5) as a novel link between gut microbiota composition, adipose tissue inflammation, and obesity., Methods: An adipose tissue microarray database was used to compare women having the highest (n = 4, H-TLR) and lowest (n = 4, L-TLR) expression levels of TLR5-signaling pathway genes. Gut microbiota composition was profiled using flow cytometry and FISH. Standard laboratory techniques were used to determine anthropometric and clinical variables. In vivo results were verified using cultured human adipocytes., Results: The H-TLR group had higher flagellated Clostridium cluster XIV abundance and Firmicutes-to-Bacteroides ratio. H-TLR subjects had obese phenotype characterized by greater waist circumference, fat %, and blood pressure (P < 0.05 for all). They also had higher leptin and lower adiponectin levels (P < 0.05 for both). Six hundred and sixty-eight metabolism- and inflammation-related adipose tissue genes were differentially expressed between the groups. In vitro studies confirmed that flagellin activated TLR5 inflammatory pathways, decreased insulin signaling, and increased glycerol secretion., Conclusions: The in vivo findings suggest that flagellated Clostridium cluster XIV bacteria contribute to the development of obesity through distorted adipose tissue metabolism and inflammation. The in vitro studies in adipocytes show that the underlying mechanisms of the human findings may be due to flagellin-activated TLR5 signaling., (© 2015 The Obesity Society.)