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      The use of biomarkers associated with leaky gut as a diagnostic tool for early intervention in autism spectrum disorder: a systematic review


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          Innovative research highlighted the probable connection between autism spectrum disorder (ASD) and gut microbiota as many autistic individuals have gastrointestinal problems as co-morbidities. This review emphasizes the role of altered gut microbiota observed frequently in autistic patients, and the mechanisms through which such alterations may trigger leaky gut.

          Main body

          Different bacterial metabolite levels in the blood and urine of autistic children, such as short-chain fatty acids, lipopolysaccharides, beta-cresol, and bacterial toxins, were reviewed. Moreover, the importance of selected proteins, among which are calprotectin, zonulin, and lysozyme, were discussed as biomarkers for the early detection of leaky gut as an etiological mechanism of ASD through the less integrative gut–blood–brain barriers. Disrupted gut–blood–brain barriers can explain the leakage of bacterial metabolites in these patients.


          Although the cause-to-effect relationship between ASD and altered gut microbiota is not yet well understood, this review shows that with the consumption of specific diets, definite probiotics may represent a noninvasive tool to reestablish healthy gut microbiota and stimulate gut health. The diagnostic and therapeutic value of intestinal proteins and bacterial-derived compounds as new possible biomarkers, as well as potential therapeutic targets, are discussed.

          Supplementary Information

          The online version contains supplementary material available at 10.1186/s13099-021-00448-y.

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          Most cited references123

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          IDF Diabetes Atlas: Global estimates of diabetes prevalence for 2017 and projections for 2045

          Since the year 2000, IDF has been measuring the prevalence of diabetes nationally, regionally and globally.
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            Indigenous bacteria from the gut microbiota regulate host serotonin biosynthesis.

            The gastrointestinal (GI) tract contains much of the body's serotonin (5-hydroxytryptamine, 5-HT), but mechanisms controlling the metabolism of gut-derived 5-HT remain unclear. Here, we demonstrate that the microbiota plays a critical role in regulating host 5-HT. Indigenous spore-forming bacteria (Sp) from the mouse and human microbiota promote 5-HT biosynthesis from colonic enterochromaffin cells (ECs), which supply 5-HT to the mucosa, lumen, and circulating platelets. Importantly, microbiota-dependent effects on gut 5-HT significantly impact host physiology, modulating GI motility and platelet function. We identify select fecal metabolites that are increased by Sp and that elevate 5-HT in chromaffin cell cultures, suggesting direct metabolic signaling of gut microbes to ECs. Furthermore, elevating luminal concentrations of particular microbial metabolites increases colonic and blood 5-HT in germ-free mice. Altogether, these findings demonstrate that Sp are important modulators of host 5-HT and further highlight a key role for host-microbiota interactions in regulating fundamental 5-HT-related biological processes.
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              Gut microbiota in health and disease.

              Gut microbiota is an assortment of microorganisms inhabiting the length and width of the mammalian gastrointestinal tract. The composition of this microbial community is host specific, evolving throughout an individual's lifetime and susceptible to both exogenous and endogenous modifications. Recent renewed interest in the structure and function of this "organ" has illuminated its central position in health and disease. The microbiota is intimately involved in numerous aspects of normal host physiology, from nutritional status to behavior and stress response. Additionally, they can be a central or a contributing cause of many diseases, affecting both near and far organ systems. The overall balance in the composition of the gut microbial community, as well as the presence or absence of key species capable of effecting specific responses, is important in ensuring homeostasis or lack thereof at the intestinal mucosa and beyond. The mechanisms through which microbiota exerts its beneficial or detrimental influences remain largely undefined, but include elaboration of signaling molecules and recognition of bacterial epitopes by both intestinal epithelial and mucosal immune cells. The advances in modeling and analysis of gut microbiota will further our knowledge of their role in health and disease, allowing customization of existing and future therapeutic and prophylactic modalities.

                Author and article information

                Gut Pathog
                Gut Pathog
                Gut Pathogens
                BioMed Central (London )
                13 September 2021
                13 September 2021
                : 13
                : 54
                [1 ]GRID grid.56302.32, ISNI 0000 0004 1773 5396, Department of Physiology, Faculty of Medicine, , King Saud University, ; Riyadh, Saudi Arabia
                [2 ]Autism Research and Treatment Center, Riyadh, Saudi Arabia
                [3 ]GRID grid.419725.c, ISNI 0000 0001 2151 8157, Therapuetic Chemistry Department, , National Research Centre, ; Dokki, Cairo, Egypt
                [4 ]GRID grid.56302.32, ISNI 0000 0004 1773 5396, Biochemistry Department, College of Sciences, , King Saud University, ; Riyadh, Saudi Arabia
                [5 ]GRID grid.56302.32, ISNI 0000 0004 1773 5396, Botany and Microbiology Department, College of Science, Female Campus, , King Saud University, ; Riyadh, Saudi Arabia
                [6 ]GRID grid.56302.32, ISNI 0000 0004 1773 5396, Department of Community Health, College of Applied Medical Sciences, , King Saud University, ; Riyadh, Saudi Arabia
                [7 ]GRID grid.56302.32, ISNI 0000 0004 1773 5396, Central Laboratory, Female Centre for Scientific and Medical Studies, , King Saud University, ; P.O box 22452, Zip code 11495 Riyadh, Saudi Arabia
                Author information
                © The Author(s) 2021

                Open AccessThis article is licensed under a Creative Commons Attribution 4.0 International License, which permits use, sharing, adaptation, distribution and reproduction in any medium or format, as long as you give appropriate credit to the original author(s) and the source, provide a link to the Creative Commons licence, and indicate if changes were made. The images or other third party material in this article are included in the article's Creative Commons licence, unless indicated otherwise in a credit line to the material. If material is not included in the article's Creative Commons licence and your intended use is not permitted by statutory regulation or exceeds the permitted use, you will need to obtain permission directly from the copyright holder. To view a copy of this licence, visit http://creativecommons.org/licenses/by/4.0/. The Creative Commons Public Domain Dedication waiver ( http://creativecommons.org/publicdomain/zero/1.0/) applies to the data made available in this article, unless otherwise stated in a credit line to the data.

                : 6 December 2020
                : 4 August 2021
                Funded by: FundRef http://dx.doi.org/10.13039/501100005725, National Plan for Science, Technology and Innovation;
                Custom metadata
                © The Author(s) 2021

                Gastroenterology & Hepatology
                autism,leaky gut,gut microbiota,short-chain fatty acids,diet,probiotics,zonulin


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