scholarly journals Aryl hydrocarbon receptor ligand production by the gut microbiota is decreased in celiac disease leading to intestinal inflammation

2020 ◽  
Vol 12 (566) ◽  
pp. eaba0624 ◽  
Author(s):  
Bruno Lamas ◽  
Leticia Hernandez-Galan ◽  
Heather J. Galipeau ◽  
Marco Constante ◽  
Alexandra Clarizio ◽  
...  

Metabolism of tryptophan by the gut microbiota into derivatives that activate the aryl hydrocarbon receptor (AhR) contributes to intestinal homeostasis. Many chronic inflammatory conditions, including celiac disease involving a loss of tolerance to dietary gluten, are influenced by cues from the gut microbiota. We investigated whether AhR ligand production by the gut microbiota could influence gluten immunopathology in nonobese diabetic (NOD) mice expressing DQ8, a celiac disease susceptibility gene. NOD/DQ8 mice, exposed or not exposed to gluten, were subjected to three interventions directed at enhancing AhR pathway activation. These included a high-tryptophan diet, gavage with Lactobacillus reuteri that produces AhR ligands or treatment with an AhR agonist. We investigated intestinal permeability, gut microbiota composition determined by 16S rRNA gene sequencing, AhR pathway activation in intestinal contents, and small intestinal pathology and inflammatory markers. In NOD/DQ8 mice, a high-tryptophan diet modulated gut microbiota composition and enhanced AhR ligand production. AhR pathway activation by an enriched tryptophan diet, treatment with the AhR ligand producer L. reuteri, or pharmacological stimulation using 6-formylindolo (3,2-b) carbazole (Ficz) decreased immunopathology in NOD/DQ8 mice exposed to gluten. We then determined AhR ligand production by the fecal microbiota and AhR activation in patients with active celiac disease compared to nonceliac control individuals. Patients with active celiac disease demonstrated reduced AhR ligand production and lower intestinal AhR pathway activation. These results highlight gut microbiota-dependent modulation of the AhR pathway in celiac disease and suggest a new therapeutic strategy for treating this disorder.

Author(s):  
Qian Huang ◽  
Yi Yang ◽  
Vladimir Tolstikov ◽  
Michael A. Kiebish ◽  
Jonas F Ludvigsson ◽  
...  

ABSTRACTObjectiveCeliac disease (CD) is an immune-mediated disease characterized by small intestinal inflammation. CD is associated with HLA-DQ2 and HLA-DQ8 haplotypes, however, genetics alone cannot explain the increasing incidence rates. The main goal of this study was to determine the role of the gut microbiota in CD pathogenesis in the first five years of life.DesignWe conducted a longitudinal study focusing on three developmental phases of the gut microbiota (ages 1, 2.5 and 5 years). The fecal samples were obtained from 16 children who developed CD and 16 matched controls. We used 16S sequencing combined with functional analysis, flow cytometry, immunoglobulin A (IgA) sequencing (IgA-seq), and plasma metabolomics to determine a microbial link to CD pathogenesis.ResultsWe identified a distinct gut microbiota composition in CD progressors (CDP, children who developed CD during or after their gut microbiota were sampled) in each developmental phase. Pathogenesis and inflammation-related microbial pathways were enriched in CDP. Moreover, they had significantly more IgA coated bacteria and the IgA targets were significantly different compared to controls. Proinflammatory and pathogenesis-related metabolic pathways were enriched in CDP. Further, we identified inflammatory metabolites, particularly microbiota-derived taurodeoxycholic acid (TDCA) as increased in CDP.ConclusionOur study defines an inflammatory gut microbiota for the CDP including its composition, function, IgA response and related plasma metabolites. The inflammatory nature of CD gut microbiota during development is potentially related to the onset of the disease. Targeting inflammatory bacteria in this critical window could affect the pathogenesis and prognosis of CD.Significance of this studyWhat is already known on this subject?Celiac Disease (CD) is a gluten induced immune-mediated disease in genetically predisposed individuals.CD incidence is increasing worldwide which genetics alone cannot explain. Previous studies have shown that the gut microbiota of CD patients differ from that of healthy populations. However, the role of the microbiome in CD pathogenesis and its role in chronic inflammation is yet be established.What are the new findings?In a prospective longitudinal study in children using samples representing all three phases of gut microbiota development (ages 1, 2.5 and 5), we identified significant differences in the composition and function of gut microbiota at each phase. Pathogenesis and inflammation-related functions are enriched in the gut microbiome of CD progressors.We applied IgA-sequencing to identify inflammatory bacteria in both healthy subjects and CD progressors. Flow Cytometry analysis identified more IgA coated bacteria at ages 1 and 5 in CD progressors, indicating an early inflammatory response. CD bacterial IgA targets also differed significantly from healthy controls.We analyzed plasma metabolites obtained at age 5. The CD plasma metabolome was significantly different from healthy controls. Particularly, proinflammatory plasma metabolites, including microbiota-derived taurodeoxycholic acid (TDCA) and isobutyryl-L-carnitine, were increased two-fold in CD progressors.How might it impact clinical practice in the foreseeable future?Our results establish a link between gut microbiota composition and chronic inflammation in CD during child development. The highly IgA-coated bacteria identified in IgA sequencing and inflammatory bacteria potentially contribute to CD pathogenesis. Targeting these bacteria in the early stages of CD development could be a preventative tool.TDCA is a microbiota-derived proinflammatory metabolite increased two-fold in CD progressors. Increased TDCA levels may be used as a predictive/diagnostic tool in genetically predisposed subjects. Moreover, targeting TDCA-producing bacteria (e.g., Clostridium XIVa species) could potentially help to control the intestinal inflammation in CD.Developing anti-inflammatory probiotics/prebiotics might be viable therapeutics for altering microbiota composition in children genetically predisposed for CD. These microbes/compounds may also complement a gluten-free diet in patients that continue to experience persistent CD symptoms.


2020 ◽  
Author(s):  
Katarina Butorac ◽  
Martina Banic ◽  
Jasna Novak ◽  
Andreja Leboš Pavunc ◽  
Ksenija Uroic ◽  
...  

Abstract Background: The influence of an S-layer-carrying strain Lactobacillus brevis SF9B and a plantaricin-producing strain Lactobacillus plantarum SF9C on the gut microbiota composition was evaluated in the rats. Considering the probiotic potential of Lb. brevis SF9B, this study aimed to examine the antibacterial activity of Lb. plantarum SF9C and potential for their in vivo colonisation, which could be the basis for the investigation of their synergistic functionality. Results: A plantaricin-encoding cluster was identified in Lb. plantarum SF9C, a strain which efficiently inhibited the growth of Listeria monocytogenes ATCC®19111™ and Staphylococcus aureus 3048. Contrary to the plantaricin-producing SF9C strain, the S-layer-carrying SF9B strain excluded Escherichia coli 3014 and Salmonella enterica serovar Typhimurium FP1 from adhesion to Caco-2 cells. Finally, DGGE analysis of the V2-V3 region of the 16S rRNA gene confirmed the transit of two selected lactobacilli through the gastrointestinal tract (GIT). Microbiome profiling via the Illumina MiSeq platform revealed the prevalence of Lactobacillus spp. in the gut microbiota of rats suggesting their colonisation potential in GIT.Conclusion: The combined application of Lb. plantarum SF9C and Lb. brevis SF9B could influence the intestinal microbiota composition, which is reflected through the increased abundance of Lactobacillus genus, but also through altered abundances of other bacterial genera, either in the model of healthy or aberrant microbiota of rats. The obtained results contributed to the functional aspects of SF9C and SF9B strains which could be incorporated in the probiotic-containing functional foods and therefore have a beneficial influence on the gut microbiota composition.


mBio ◽  
2015 ◽  
Vol 6 (5) ◽  
Author(s):  
Sandi Wong ◽  
W. Zac Stephens ◽  
Adam R. Burns ◽  
Keaton Stagaman ◽  
Lawrence A. David ◽  
...  

ABSTRACT Gut microbiota influence the development and physiology of their animal hosts, and these effects are determined in part by the composition of these microbial communities. Gut microbiota composition can be affected by introduction of microbes from the environment, changes in the gut habitat during development, and acute dietary alterations. However, little is known about the relationship between gut and environmental microbiotas or about how host development and dietary differences during development impact the assembly of gut microbiota. We sought to explore these relationships using zebrafish, an ideal model because they are constantly immersed in a defined environment and can be fed the same diet for their entire lives. We conducted a cross-sectional study in zebrafish raised on a high-fat, control, or low-fat diet and used bacterial 16S rRNA gene sequencing to survey microbial communities in the gut and external environment at different developmental ages. Gut and environmental microbiota compositions rapidly diverged following the initiation of feeding and became increasingly different as zebrafish grew under conditions of a constant diet. Different dietary fat levels were associated with distinct gut microbiota compositions at different ages. In addition to alterations in individual bacterial taxa, we identified putative assemblages of bacterial lineages that covaried in abundance as a function of age, diet, and location. These results reveal dynamic relationships between dietary fat levels and the microbial communities residing in the intestine and the surrounding environment during ontogenesis. IMPORTANCE The ability of gut microbiota to influence host health is determined in part by their composition. However, little is known about the relationship between gut and environmental microbiotas or about how ontogenetic differences in dietary fat impact gut microbiota composition. We addressed these gaps in knowledge using zebrafish, an ideal model organism because their environment can be thoroughly sampled and they can be fed the same diet for their entire lives. We found that microbial communities in the gut changed as zebrafish aged under conditions of a constant diet and became increasingly different from microbial communities in their surrounding environment. Further, we observed that the amount of fat in the diet had distinct age-specific effects on gut community assembly. These results reveal the complex relationships between microbial communities residing in the intestine and those in the surrounding environment and show that these relationships are shaped by dietary fat throughout the life of animal hosts.


2019 ◽  
Vol 9 (1) ◽  
Author(s):  
Jason R. Catanzaro ◽  
Juliet D. Strauss ◽  
Agata Bielecka ◽  
Anthony F. Porto ◽  
Francis M. Lobo ◽  
...  

Abstract Immunoglobulin A is the dominant antibody isotype found in mucosal secretions and enforces host-microbiota symbiosis in mice, yet selective IgA-deficiency (sIgAd) in humans is often described as asymptomatic. Here, we determined the effects of IgA deficiency on human gut microbiota composition and evaluated the possibility that mucosal secretion of IgM can compensate for a lack of secretory IgA. We used 16S rRNA gene sequencing and bacterial cell sorting to evaluate gut microbiota composition and taxa-specific antibody coating of the gut microbiota in 15 sIgAd subjects and matched controls. Despite the secretion of compensatory IgM into the gut lumen, sIgAd subjects displayed an altered gut microbiota composition as compared to healthy controls. These alterations were characterized by a trend towards decreased overall microbial diversity as well as significant shifts in the relative abundances of specific microbial taxa. While secretory IgA in healthy controls targeted a defined subset of the microbiota via high-level coating, compensatory IgM in sIgAd subjects showed less specificity than IgA and bound a broader subset of the microbiota. We conclude that IgA plays a critical and non-redundant role in controlling gut microbiota composition in humans and that secretory IgA has evolved to maintain a diverse and stable gut microbial community.


2020 ◽  
Vol 10 (1) ◽  
Author(s):  
Martin Iain Bahl ◽  
Anabelle Legarth Honoré ◽  
Sanne Tygesen Skønager ◽  
Oliver Legarth Honoré ◽  
Tove Clausen ◽  
...  

AbstractOn many mink farms, antibiotics are used extensively during the lactation period to reduce the prevalence and severity of pre-weaning diarrhoea (PWD) in mink kits (also referred to as greasy kit syndrome). Concerns have been raised, that routine treatment of PWD with antibiotics could affect the natural successional development of the gut microbiota, which may have long lasting consequences. Here we investigated the effects of early life antibiotic treatment administered for 1 week (postnatal days 13–20). Two routes of antibiotic administration were compared to a non-treated control group (CTR, n = 24). Routes of administration included indirect treatment, through the milk from dams receiving antibiotics by intramuscular administration (ABX_D, n = 24) and direct treatment by intramuscular administration to the kits (ABX_K, n = 24). A tendency for slightly increased weight at termination (Day 205) was observed in the ABX_K group. The gut microbiota composition was profiled by 16S rRNA gene sequencing at eight time points between Day 7 and Day 205. A clear successional development of the gut microbiota composition was observed and both treatment regimens caused detectable changes in the gut microbiota until at least eight days after treatment ceased. At termination, a significant positive correlation was identified between microbial diversity and animal weight.


2019 ◽  
Vol 3 (Supplement_1) ◽  
Author(s):  
Mei Wang ◽  
Brooke Smith ◽  
Brock Adams ◽  
Miller Tran ◽  
Ryan Dilger ◽  
...  

Abstract Objectives Enterotoxigenic Escherichia coli (ETEC) are an important cause of diarrhea in human infants and young farm animals. Osteopontin (OPN), a glycoprotein present in high concentration in human milk, has immunomodulatory functions, which could indirectly impact the microbiota. Furthermore, a previous study has shown fecal microbiota composition differs between wild-type and OPN knockout mice. Herein, the effects of OPN-enriched algae on the gut microbiota composition and volatile fatty acid (VFA) concentrations of ETEC-infected piglets were assessed. Methods Naturally-farrowed piglets were sow-reared for 21 days and then randomized to two weaning diets: WT (formula + 1% wild-type algae) or OPN (formula + 1% OPN-enriched algae). On postnatal day (PND) 31, all piglets were infected orally with a live culture of ETEC (1010 colony-forming unit/3 mL dose) daily for three consecutive days. On PND 41, ascending colon (AC) contents were collected. Gut microbiota was assessed by sequencing V3-V4 regions of 16S rRNA gene and VFAs were determined by gas chromatography. Alpha-diversity and VFAs were analyzed using PROC MIXED procedure of SAS. Beta-diversity was evaluated by permutational multivariate analysis of variance (PERMANOVA) and differential abundance analysis on the bacterial genera was performed using DESeq2 package of R. Results Shannon indices were lower in the AC contents of OPN piglets compared to WT piglets. The overall colonic microbiota of OPN piglets differed from that of WT piglets (PERMANOVA P = 0.015). At genus level, OPN-enriched algae increased the abundance of Streptococcus, decreased the abundances of Sutterella, Candidatus Soleaferrea, dga-11 gut group, Rikenellaceae RC9 gut group, Ruminococcaceae UCG-010, unculturedRuminococcaceae, Prevotella 2 and 7 compared to piglets consuming wild-type algae (P < 0. 05). OPN piglets also had higher (P < 0.05) concentrations of acetate, propionate, butyrate and valerate compared to WT. Conclusions In ETEC infected piglets, 1% OPN-enriched algae decreased alpha-diversity and modulated the microbiota composition and VFA profiles compared to 1% WT algae. Other studies have shown that OPN inhibits biofilm formation in vitro, but future research is needed to assess in vivo microbiome-modulation mechanisms. Funding Sources Triton Algae Innovations.


2020 ◽  
Vol 12 (1) ◽  
Author(s):  
Michael R. Goldberg ◽  
Hadar Mor ◽  
Dafna Magid Neriya ◽  
Faiga Magzal ◽  
Efrat Muller ◽  
...  

Abstract Background Multiple studies suggest a key role for gut microbiota in IgE-mediated food allergy (FA) development, but to date, none has studied it in the persistent state. Methods To characterize the gut microbiota composition and short-chain fatty acid (SCFAs) profiles associated with major food allergy groups, we recruited 233 patients with FA including milk (N = 66), sesame (N = 38), peanut (N = 71), and tree nuts (N = 58), and non-allergic controls (N = 58). DNA was isolated from fecal samples, and 16S rRNA gene sequences were analyzed. SCFAs in stool were analyzed from patients with a single allergy (N = 84) and controls (N = 31). Results The gut microbiota composition of allergic patients was significantly different compared to age-matched controls both in α-diversity and β-diversity. Distinct microbial signatures were noted for FA to different foods. Prevotella copri (P. copri) was the most overrepresented species in non-allergic controls. SCFAs levels were significantly higher in the non-allergic compared to the FA groups, whereas P. copri significantly correlated with all three SCFAs. We used these microbial differences to distinguish between FA patients and non-allergic healthy controls with an area under the curve of 0.90, and for the classification of FA patients according to their FA types using a supervised learning algorithm. Bacteroides and P. copri were identified as taxa potentially contributing to KEGG acetate-related pathways enriched in non-allergic compared to FA. In addition, overall pathway dissimilarities were found among different FAs. Conclusions Our results demonstrate a link between IgE-mediated FA and the composition and metabolic activity of the gut microbiota.


Cells ◽  
2019 ◽  
Vol 8 (6) ◽  
pp. 517 ◽  
Author(s):  
Claudia Burrello ◽  
Maria Rita Giuffrè ◽  
Angeli Dominique Macandog ◽  
Angelica Diaz-Basabe ◽  
Fulvia Milena Cribiù ◽  
...  

Different gastrointestinal disorders, including inflammatory bowel diseases (IBD), have been linked to alterations of the gut microbiota composition, namely dysbiosis. Fecal microbiota transplantation (FMT) is considered an encouraging therapeutic approach for ulcerative colitis patients, mostly as a consequence of normobiosis restoration. We recently showed that therapeutic effects of FMT during acute experimental colitis are linked to functional modulation of the mucosal immune system and of the gut microbiota composition. Here we analysed the effects of therapeutic FMT administration during chronic experimental colitis, a condition more similar to that of IBD patients, on immune-mediated mucosal inflammatory pathways. Mucus and feces from normobiotic donors were orally administered to mice with established chronic Dextran Sodium Sulphate (DSS)-induced colitis. Immunophenotypes and functions of infiltrating colonic immune cells were evaluated by cytofluorimetric analysis. Compositional differences in the intestinal microbiome were analyzed by 16S rRNA sequencing. Therapeutic FMT in mice undergoing chronic intestinal inflammation was capable to decrease colonic inflammation by modulating the expression of pro-inflammatory genes, antimicrobial peptides, and mucins. Innate and adaptive mucosal immune cells manifested a reduced pro-inflammatory profile in FMT-treated mice. Finally, restoration of a normobiotic core ecology contributed to the resolution of inflammation. Thus, FMT is capable of controlling chronic intestinal experimental colitis by inducing a concerted activation of anti-inflammatory immune pathways, mechanistically supporting the positive results of FMT treatment reported in ulcerative colitis patients.


Genes ◽  
2019 ◽  
Vol 10 (10) ◽  
pp. 748 ◽  
Author(s):  
Jin-Young Lee ◽  
Mohamed Mannaa ◽  
Yunkyung Kim ◽  
Jehun Kim ◽  
Geun-Tae Kim ◽  
...  

The aim of this study was to investigate differences between the gut microbiota composition in patients with rheumatoid arthritis (RA) and those with osteoarthritis (OA). Stool samples from nine RA patients and nine OA patients were collected, and DNA was extracted. The gut microbiome was assessed using 16S rRNA gene amplicon sequencing. The structures and differences in the gut microbiome between RA and OA were analyzed. The analysis of diversity revealed no differences in the complexity of samples. The RA group had a lower Bacteroidetes: Firmicutes ratio than did the OA group. Lactobacilli and Prevotella, particularly Prevotella copri, were more abundant in the RA than in the OA group, although these differences were not statistically significant. The relative abundance of Bacteroides and Bifidobacterium was lower in the RA group. At the species level, the abundance of certain bacterial species was significantly lower in the RA group, such as Fusicatenibacter saccharivorans, Dialister invisus, Clostridium leptum, Ruthenibacterium lactatiformans, Anaerotruncus colihominis, Bacteroides faecichinchillae, Harryflintia acetispora, Bacteroides acidifaciens, and Christensenella minuta. The microbial properties of the gut differed between RA and OA patients, and the RA dysbiosis revealed results similar to those of other autoimmune diseases, suggesting that a specific gut microbiota pattern is related to autoimmunity.


2020 ◽  
Author(s):  
Dandan Jiang ◽  
Xin He ◽  
Marc Valitutto ◽  
Li Chen ◽  
Qin Xu ◽  
...  

Abstract Background:The Chinese monal (Lophophorus lhuysii) is an endangered bird species, with a wild population restricted to the mountains of southwest China, and only one known captive population in the world. We investigated the fecal microbiota and metabolome of wild and captive Chinese monals to explore differences and similarities in nutritional status and digestive characteristics. An integrated approach combining 16S ribosomal RNA (16S rRNA) gene sequencing and ultra-high performance liquid chromatography (UHPLC) based metabolomics were used to examine the fecal microbiota composition and the metabolomic profile of Chinese monals. Results: The results showed that the alpha diversity of gut microbes in the wild group were significantly higher than that in the captive group and the core bacterial taxa in the two groups showed remarkable differences at phylum, class, order, and family levels. Metabolomic profiling also revealed differences, mainly related to galactose, starch and sucrose metabolism, fatty acid, bile acid biosynthesis and bile secretion. Furthermore, strong correlations of metabolite types and bacterial genus were detected. Conclusions: There were remarkable differences in the gut microbiota composition and metabolomic profile between wild and captive Chinese monals. This study has established a baseline for a normal gut microbiota and metabolomic profile for wild Chinese monals, thus allowing us to evaluate if differences seen in captive organisms have an impact on their overall health and reproduction.


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