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      Healthy infants harbor intestinal bacteria that protect against food allergy

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          Abstract

          There has been a striking generational increase in life-threatening food allergies in Westernized societies 1, 2 One hypothesis to explain this rising prevalence is that 21 st century lifestyle practices, including misuse of antibiotics, dietary changes, and higher rates of Caesarean birth and formula feeding have altered intestinal bacterial communities; early life alterations may be particularly detrimental. 3, 4 To better understand how commensal bacteria regulate food allergy in humans we colonized germ free (GF) mice with feces from healthy or cow’s milk allergic (CMA) infants 5 . We show here that GF mice colonized with bacteria from healthy, but not CMA, infants were protected against anaphylactic responses to a cow’s milk allergen. Differences in bacterial composition separated the healthy and CMA populations in both the human donors and the colonized mice. Healthy and CMA colonized mice also exhibited unique transciptome signatures in the ileal epithelium. Correlation of ileal bacteria with genes upregulated in the ileum of healthy or CMA colonized mice identified a Clostridial species, Anaerostipes caccae, that protected against an allergic response to food. Our findings demonstrate that intestinal bacteria are critical for regulating allergic responses to dietary antigens and suggest that interventions that modulate bacterial communities may be therapeutically relevant for food allergy.

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          Most cited references31

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          Controlling the False Discovery Rate: A Practical and Powerful Approach to Multiple Testing

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            The microbiome and innate immunity.

            The intestinal microbiome is a signalling hub that integrates environmental inputs, such as diet, with genetic and immune signals to affect the host's metabolism, immunity and response to infection. The haematopoietic and non-haematopoietic cells of the innate immune system are located strategically at the host-microbiome interface. These cells have the ability to sense microorganisms or their metabolic products and to translate the signals into host physiological responses and the regulation of microbial ecology. Aberrations in the communication between the innate immune system and the gut microbiota might contribute to complex diseases.
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              The microbiome and butyrate regulate energy metabolism and autophagy in the mammalian colon.

              The microbiome is being characterized by large-scale sequencing efforts, yet it is not known whether it regulates host metabolism in a general versus tissue-specific manner or which bacterial metabolites are important. Here, we demonstrate that microbiota have a strong effect on energy homeostasis in the colon compared to other tissues. This tissue specificity is due to colonocytes utilizing bacterially produced butyrate as their primary energy source. Colonocytes from germfree mice are in an energy-deprived state and exhibit decreased expression of enzymes that catalyze key steps in intermediary metabolism including the TCA cycle. Consequently, there is a marked decrease in NADH/NAD(+), oxidative phosphorylation, and ATP levels, which results in AMPK activation, p27(kip1) phosphorylation, and autophagy. When butyrate is added to germfree colonocytes, it rescues their deficit in mitochondrial respiration and prevents them from undergoing autophagy. The mechanism is due to butyrate acting as an energy source rather than as an HDAC inhibitor. Copyright © 2011 Elsevier Inc. All rights reserved.
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                Author and article information

                Journal
                9502015
                8791
                Nat Med
                Nat. Med.
                Nature medicine
                1078-8956
                1546-170X
                6 December 2018
                14 January 2019
                March 2019
                14 July 2019
                : 25
                : 3
                : 448-453
                Affiliations
                [1 ]Department of Pathology and Committee on Immunology, The University of Chicago, Chicago, IL 60637, USA
                [2 ]Center for Research Informatics, The University of Chicago, Chicago, IL 60637, USA
                [3 ]Department of Pediatrics, The University of Chicago, Chicago, IL 60637, USA
                [4 ]Department of Translational Medical Science, Section of Pediatrics, University of Naples, Federico II, Naples, Italy
                [5 ]Department of Medicine, The University of Chicago, Chicago, IL 60637, USA and Biosciences Division, Argonne National Laboratory, Argonne, IL 60439, USA
                [6 ]European Laboratory for the Investigation of Food-Induced Diseases, University of Naples, Federico II, Naples, Italy
                [7 ]CEINGE Advanced Biotechnologies, University of Naples, Federico II, Naples, Italy
                Author notes

                Author contributions

                T.F., C.H.P, R.B. R.B.C. and C.R.N. designed the study. C.H.P. and T.F performed mouse experiments with help from P.B.F., R.A, E.C., E.C. and S.C.H. R.B., P.B.F and J.A. performed bioinformatics analysis. T.F., C.H.P., R.B., P.B.F. and C.R.N. analyzed results. R.B.C., R.N. and L.A. cared for patients and provided donor fecal samples. D.A.A. provided protocols and assisted with the colonization of GF mice with human feces and A. caccae. T.F., C.H.P., R.B., R.B.C. and C.R.N. wrote the manuscript. All authors read and commented on manuscript.

                Author Information

                C.R.N. is President and co-founder of ClostraBio, Inc. The other authors declare that they have no competing financial interests. Correspondence and requests for materials should be addressed to C.R.N. ( cnagler@ 123456bsd.uchicago.edu ).

                [* ]To whom correspondence should be addressed; cnagler@ 123456bsd.uchicago.edu
                Article
                NIHMS1515997
                10.1038/s41591-018-0324-z
                6408964
                30643289
                c6e0505f-e0ec-40cf-91cc-8bde6cf5e7cc

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