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      Alterations in children’s sub-dominant gut microbiota by HIV infection and anti-retroviral therapy

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          Abstract

          Objective

          We investigated the impact of human immunodeficiency virus (HIV) infection and anti-retroviral therapy (ART) on the gut microbiota of children.

          Design

          This cross-sectional study investigated the gut microbiota of children with and without HIV.

          Methods

          We collected fecal samples from 59 children with HIV (29 treated with ART [ART(+)] and 30 without ART [HIV(+)]) and 20 children without HIV [HIV(–)] in Vietnam. We performed quantitative RT-PCR to detect 14 representative intestinal bacteria targeting 16S/23S rRNA molecules. We also collected the blood samples for immunological analyses.

          Results

          In spearman’s correlation analyses, no significant correlation between the number of dominant bacteria and age was found among children in the HIV(−) group. However, the number of sub-dominant bacteria, including Streptococcus, Enterococcus, and Enterobacteriaceae, positively correlated with age in the HIV(−) group, but not in the HIV(+) group. In the HIV(+) group, Clostridium coccoides group positively associated with the CD4 + cell count and its subsets. In the ART(+) group, Staphylococcus and C. perfringens positively correlated with CD4 + cells and their subsets and negatively with activated CD8 + cells. C. coccoides group and Bacteroides fragilis group were associated with regulatory T-cell counts. In multiple linear regression analyses, ART duration was independently associated with the number of C. perfringens, and Th17 cell count with the number of Staphylococcus in the ART(+) group.

          Conclusions

          HIV infection and ART may influence sub-dominant gut bacteria, directly or indirectly, in association with immune status in children with HIV.

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          Most cited references57

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          A human gut microbial gene catalogue established by metagenomic sequencing.

          To understand the impact of gut microbes on human health and well-being it is crucial to assess their genetic potential. Here we describe the Illumina-based metagenomic sequencing, assembly and characterization of 3.3 million non-redundant microbial genes, derived from 576.7 gigabases of sequence, from faecal samples of 124 European individuals. The gene set, approximately 150 times larger than the human gene complement, contains an overwhelming majority of the prevalent (more frequent) microbial genes of the cohort and probably includes a large proportion of the prevalent human intestinal microbial genes. The genes are largely shared among individuals of the cohort. Over 99% of the genes are bacterial, indicating that the entire cohort harbours between 1,000 and 1,150 prevalent bacterial species and each individual at least 160 such species, which are also largely shared. We define and describe the minimal gut metagenome and the minimal gut bacterial genome in terms of functions present in all individuals and most bacteria, respectively.
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            Human gut microbiome viewed across age and geography

            Gut microbial communities represent one source of human genetic and metabolic diversity. To examine how gut microbiomes differ between human populations when viewed from the perspective of component microbial lineages, encoded metabolic functions, stage of postnatal development, and environmental exposures, we characterized bacterial species present in fecal samples obtained from 531 individuals representing healthy Amerindians from the Amazonas of Venezuela, residents of rural Malawian communities, and inhabitants of USA metropolitan areas, as well as the gene content of 110 of their microbiomes. This cohort encompassed infants, children, teenagers and adults, parents and offspring, and included mono- and dizygotic twins. Shared features of the functional maturation of the gut microbiome were identified during the first three years of life in all three populations, including age-associated changes in the representation of genes involved in vitamin biosynthesis and metabolism. Pronounced differences in bacterial species assemblages and functional gene repertoires were noted between individuals residing in the USA compared to the other two countries. These distinctive features are evident in early infancy as well as adulthood. In addition, the similarity of fecal microbiomes among family members extends across cultures. These findings underscore the need to consider the microbiome when evaluating human development, nutritional needs, physiological variations, and the impact of Westernization.
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              Commensal microbe-derived butyrate induces the differentiation of colonic regulatory T cells.

              Gut commensal microbes shape the mucosal immune system by regulating the differentiation and expansion of several types of T cell. Clostridia, a dominant class of commensal microbe, can induce colonic regulatory T (Treg) cells, which have a central role in the suppression of inflammatory and allergic responses. However, the molecular mechanisms by which commensal microbes induce colonic Treg cells have been unclear. Here we show that a large bowel microbial fermentation product, butyrate, induces the differentiation of colonic Treg cells in mice. A comparative NMR-based metabolome analysis suggests that the luminal concentrations of short-chain fatty acids positively correlates with the number of Treg cells in the colon. Among short-chain fatty acids, butyrate induced the differentiation of Treg cells in vitro and in vivo, and ameliorated the development of colitis induced by adoptive transfer of CD4(+) CD45RB(hi) T cells in Rag1(-/-) mice. Treatment of naive T cells under the Treg-cell-polarizing conditions with butyrate enhanced histone H3 acetylation in the promoter and conserved non-coding sequence regions of the Foxp3 locus, suggesting a possible mechanism for how microbial-derived butyrate regulates the differentiation of Treg cells. Our findings provide new insight into the mechanisms by which host-microbe interactions establish immunological homeostasis in the gut.
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                Author and article information

                Contributors
                Role: Data curationRole: Formal analysisRole: InvestigationRole: SoftwareRole: ValidationRole: VisualizationRole: Writing – original draft
                Role: ConceptualizationRole: Data curationRole: Formal analysisRole: InvestigationRole: MethodologyRole: ResourcesRole: SoftwareRole: VisualizationRole: Writing – original draft
                Role: Data curationRole: InvestigationRole: MethodologyRole: SoftwareRole: ValidationRole: VisualizationRole: Writing – review & editing
                Role: Data curationRole: Formal analysisRole: InvestigationRole: MethodologyRole: SoftwareRole: ValidationRole: Writing – review & editing
                Role: Data curationRole: ResourcesRole: Writing – review & editing
                Role: Data curationRole: InvestigationRole: MethodologyRole: ResourcesRole: Writing – review & editing
                Role: Data curationRole: InvestigationRole: ResourcesRole: Writing – review & editing
                Role: MethodologyRole: ValidationRole: Writing – review & editing
                Role: Data curationRole: Project administrationRole: ResourcesRole: Writing – review & editing
                Role: ResourcesRole: SoftwareRole: ValidationRole: Writing – review & editing
                Role: Project administrationRole: ResourcesRole: Writing – review & editing
                Role: ConceptualizationRole: Funding acquisitionRole: Project administrationRole: SupervisionRole: ValidationRole: Writing – review & editing
                Role: Editor
                Journal
                PLoS One
                PLoS One
                plos
                PLoS ONE
                Public Library of Science (San Francisco, CA USA )
                1932-6203
                11 October 2021
                2021
                : 16
                : 10
                : e0258226
                Affiliations
                [1 ] Department of Viral infection and International Health, Graduate school of Medical Science, Kanazawa University, Kanazawa, Japan
                [2 ] Yakult Central Institute, Tokyo, Japan
                [3 ] Vietnam National Children’s Hospital, Hanoi, Viet Nam
                Tulane National Primate Research Center, UNITED STATES
                Author notes

                Competing Interests: The authors have declared that no competing interests exist.

                Author information
                https://orcid.org/0000-0002-5242-6332
                https://orcid.org/0000-0003-4478-1964
                Article
                PONE-D-21-16737
                10.1371/journal.pone.0258226
                8504761
                34634074
                bbf69d9b-91cd-4b1c-ae08-beee43d87010
                © 2021 Nguyen et al

                This is an open access article distributed under the terms of the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited.

                History
                : 20 May 2021
                : 21 September 2021
                Page count
                Figures: 3, Tables: 3, Pages: 15
                Funding
                Funded by: Ministry of Education, Culture, Sports, Science and Technology (JP)
                Award ID: The Program of Founding Research Centers for Emerging and Reemerging Infectious Disease; grant number 23406013
                Award Recipient :
                Funded by: Kanazawa University (JP)
                Award ID: President Strategic Research Fund
                Award Recipient :
                This study was supported, in part, by the Ministry of Education, Culture, Sports, Science, and Technology (MEXT) in Japan (the Program of Founding Research Centers for Emerging and Reemerging Infectious Disease; grant number 23406013, https://www.mext.go.jp/en/publication/whitepaper/title03/detail03/sdetail03/sdetail03/1372928.htm) and the Kanazawa University President Strategic Research Fund ( https://www.kanazawa-u.ac.jp/research_bulletin/contact.html). The funders had no role in study design, data collection and analysis, decision to publish, or preparation of the manuscript.
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