Multiple Omics Uncovers Host–Gut Microbial Mutualism During Prebiotic Fructooligosaccharide Supplementation

DNA RESEARCH 21, 469–480, (2014) Advance Access publication on 19 May 2014 doi:10.1093/dnares/dsu013 Multiple Omics Uncovers Host– Gut Microbial Mutualism During Prebiotic Fructooligosaccharide Supplementation TAMOTSU Kato1,2, SHINJI Fukuda1,3, AKEMI Fujiwara1,2, WATARU Suda4, MASAHIRA Hattori4, JUN Kikuchi5,6, and HIROSHI Ohno1,5, * Laboratory for Intestinal Ecosystem, RIKEN Center for Integrative Medical Sciences (IMS), 1-7-22 Suehiro-cho, Tsurumi-ku, Yokohama, Kanagawa 230-0045, Japan1; Graduate School of Nanobioscience, Yokohama City University, Kanagawa 230-0045, Japan2; Institute for Advanced Biosciences, Keio University, Yamagata 997-0052, Japan3; Center for Omics and Bioinformatics, Department of Computational Biology, Graduate School of Frontier Sciences, The University of Tokyo, Kashiwanoha 5-1-5, Kashiwa, Chiba 277-8561, Japan4; Graduate School of Medical Life Science, Yokohama City University, Kanagawa 230-0045, Japan5 and Environmental Metabolic Analysis Research Team, RIKEN Center for Sustainable Resource Science, Kanagawa 230-0045, Japan6 *To whom correspondence should be addressed. Tel. þ81 45-503-7031. Fax. þ81 45-503-7068. E-mail: Edited by Dr Osamu Ohara (Received 19 November 2013; accepted 31 March 2014) Abstract Fructooligosaccharide (FOS), a prebiotic well known for its health-promoting properties, can improve the human gut ecosystem most likely through changes in its microbial composition. However, the detailed mechanism(s) of action of FOS in the modulation of the gut ecosystem remain(s) obscure. Traditional methods of profiling microbes and metabolites could barely show any significant features due to the existence of large interindividual differences, but our novel microbe – metabolite correlation approach, combined with faecal immunoglobulin A (IgA) measurements, has revealed that the induction of mucosal IgA by FOS supplementation correlated with the presence of specific bacteria. Furthermore, the metabolic dynamics of butyrate, L-phenylalanine, L-lysine and tyramine were positively correlated with that of these bacteria and IgA production, whereas p-cresol was negatively correlated. Taken together, our focused intraindividual analysis with omics approaches is a powerful strategy for uncovering the gut molecular network and could provide a new vista for understanding the human gut ecosystem. Key words: commensal microbiota; correlation analysis; gut ecosystem; metabolite; prebiotics 1. Introduction Our gastrointestinal tract provides residence to the intestinal microbiota, which includes both beneficial and potentially pathogenic microorganisms.1,2 It has been postulated that an imbalance in the composition of the microbiota is a risk factor in several human disorders, including inflammatory bowel disease, metabolic syndrome, allergy and cancer.3 – 5 Furthermore, recent reports have shown that even minor changes in the gut microbiome can have an impact on the host phenotype.6,7 Thus, the ability to shape the intestinal microbiota should have clinical importance. The mucosal surface of the intestine is continuously exposed to an enormous variety of antigens, such as food antigens and microorganisms. Immunoglobulin A (IgA) plays important roles in the mucosal immune system, and it has been shown that the production of IgA is limited in germ-free mice compared with conventional mice.8 In addition, microbial colonization is required for secretory IgA (SIgA) production in the intestine.9,10 In studies of gnotobiotic mice, it was shown that # The Author 2014. Published by Oxford University Press on behalf of Kazusa DNA Research Institute. This is an Open Access article distributed under the terms of the Creative Commons Attribution Non-Commercial License (http://creativecommons.org/ licenses/by-nc/4.0/), which permits non-commercial re-use, distribution, and reproduction in any medium, provided the original work is properly cited. For commercial re-use, please contact 470 Multiple Omics and Host – Gut Microbial Mutualism colonization by microbes, particularly segmented filamentous bacteria, clostridia and Bacteroides species, stimulates production of IgA.11,12 However, it is still unclear what molecule(s) produced by/derived from commensal microbes induce(s) mucosal IgA production. Prebiotics are defined as food ingredients that are nondigestible and non-absorbable in the upper gastrointestinal tract and which improve the condition of the host through selective stimulation of the growth of probiotic bacteria.13 Fructooligosaccharide (FOS) is a well-known prebiotic that has anti-tumor,14 infection-protective15 and allergy-preventive effects16 in the host through host–microbial crosstalk in the gut. The impact of FOS intake on the intestinal IgA response has been extensively studied in mouse models. The concentration of IgA in the small and large intestines is significantly increased with FOS intake.17 Furthermore, the number of B220þ IgAþ cells in Peyer’s patches is significantly increased, and the level of secretory component and SIgA in the ileal gut lumen is elevated. It has also been shown that FOS intake enhances production of cytokines, such as interleukin (IL)-5, IL-6 and interferon-g, in Peyer’s patches; these cytokines can induce IgA production through their effects on CD4þ helper T cells, which further increases the amount of IgA in the mucosa.18 In humans, ulcerative colitis patients supplemented with Bifidobacterium longum and oligofructose-enriched inulin showed improvement in the clinical features of chronic inflammation,19 and daily intake of oligofructose and inulin significantly decreased Crohn’s disease activity.20 Supplementation with FOS has also been shown to support the growth of Bifidobacterium species, accompanied by an increase in T lymphocytes.21 Some studies have also reported a tendency for prebiotics-treated individuals to have higher faecal SIgA levels.22,23 Although commensal microbiota have been implicated in the FOS-induced production of IgA, evaluation of the gut microbial ecosystem is not an easy task, mainly due to its highly complex composition and the large individual difference among human subjects.22 We have developed a meta-analysis platform based on a multi-dimensional profiling technique to evaluate gut environmental changes, including host – microbial crosstalk.24 In order to understand the molecular mechanisms for the induction of IgA production in human subjects by FOS supplementation through gut microbes and/or their metabolite(s), we applied the multivariate microbe – metabolite correlation analysis combined with faecal IgA secretion of the host to evaluate the inter- and intraindividual changes in the gut ecosystem occurring with FOS supplementation. Here, we show a significant correlation of faecal IgA content with microbial composition and metabolites, and further implicate the likely involvement of particular metabolites in FOS-induced IgA secretion. 2. [Vol. 21, Materials an (...truncated)