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Lee et al. Journal of Biomedical Science (2017) 24:36 DOI 10.1186/s12929-017-0342-z REVIEW Open Access Metaproteomic analysis of human gut microbiota: where are we heading? Pey Yee Lee, Siok-Fong Chin*, Hui-min Neoh and Rahman Jamal Abstract The human gut is home to complex microbial populations that change dynamically in response to various internal and external stimuli. The gut microbiota provides numerous functional benefits that are crucial for human health but in the setting of a disturbed equilibrium, the microbial community can cause deleterious outcomes such as diseases and cancers. Characterization of the functional activities of human gut microbiota is fundamental to understand their roles in human health and disease. Metaproteomics, which refers to the study of the entire protein collection of the microbial community in a given sample is an emerging area of research that provides informative details concerning functional aspects of the microbiota. In this mini review, we present a summary of the progress of metaproteomic analysis for studying the functional role of gut microbiota. This is followed by an overview of the experimental approaches focusing on fecal specimen for metaproteomics and is concluded by a discussion on the challenges and future directions of metaproteomic research. Keywords: Metaproteomics, Human, Gut Microbiota, Multi-omics, Technologies Background that aims to provide a reference catalog of gut microbiome The human gastrointestinal (GI) tract is colonized by a in association with obesity and inflammatory bowel highly diverse population of microbial community collect- disease (IBD) [6]. Over the years, much effort has been ively known as the gut microbiota that play vital roles in devoted to determine microbiome composition in various maintaining human health [1]. Although relatively stable, diseased patients using metagenomic analysis to identify alterations in the microbial consortium may occur due to potential links between gut microbiota and diseases [7]. factors such as aging, genetic mutations, inflammation To date, the growing number of metagenomic studies and dietary change [2, 3]. Accumulating evidence indicates have provided valuable insights into the structure and di- that imbalances in the microbial community or dysbiosis versity of the gut microbial community and their genetic have potential adverse effects on human health, whereby composition. However, it is important to note that there such alterations are implicated in the development of are several limitations in these studies. Firstly, these stud- numerous diseases, including metabolic disorders, inflam- ies only uncovered gene sequences that were present but matory diseases and cancers [4]. do not provide any clues regarding their actual gene or Given the importance of gut microbiota in human protein expression levels. Besides, metagenomic analysis health and disease development, it has been the subject of does not discriminate between microbiota that are active, extensive investigations in recent years. The completion of dormant or dead, as all microbial cells will be sequenced. a large-scale initiative known as the Human Microbiome Consequently, the precise functions of the gut microbiota Project in 2012 has marked an important milestone in the are still largely unknown. Hence, other complementary characterization of human microbiome in healthy individ- approaches are needed to elucidate the functional capacity uals, which led to the establishment of a reference micro- of human gut microbiota. bial genome database [5]. MetaHIT (Metagenomics of the Over the past decade, metaproteomics which is de- Human Intestinal Tract) is another collaborative effort fined as the large-scale profiling of the whole protein complement expressed by a complex microbial ecosys- * Correspondence: [email protected] tem [8], has been applied to analyze human gut micro- UKM Medical Molecular Biology Institute (UMBI), Universiti Kebangsaan biota. In comparison to metagenomics, metaproteomics Malaysia, 56000Cheras, Kuala Lumpur, Malaysia © The Author(s). 2017 Open Access This article is distributed under the terms of the Creative Commons Attribution 4.0 International License (http://creativecommons.org/licenses/by/4.0/), which permits unrestricted use, distribution, and reproduction in any medium, provided you give appropriate credit to the original author(s) and the source, provide a link to the Creative Commons license, and indicate if changes were made. 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. Lee et al. Journal of Biomedical Science (2017) 24:36 Page 2 of 8 is capable to reveal functional traits relevant to the within specific intestinal niches. This approach would be underlying physiological states, thereby providing de- useful to investigate spatial distribution and activities at tailed insights into the connection between microbial the mucosa-lumen interface, but might not be practically diversity, functions and the impact on host biology. In feasible as being invasive and costly. this mini review, we summarize the recent progress of Apart from cataloguing gut microbial metaproteome in metaproteomic study in the context of human gut healthy individuals, comparative analyses to characterize microbiota. Further, we discuss experimental approaches differential protein profiles under altered physiological for metaproteomics and conclude by providing an out- conditions have been performed. Antibiotics are known to look on the challenges and future research direction for cause disturbance in the microbiota composition and metaproteomics. functions, which in turn will have potential consequences on health and disease [17]. A comprehensive multi-omics Metaproteomics of human gut microbiota study revealed drastic changes in the protein profiles of In a pioneering metaproteomic study of human gut the gut-associated microbiota following β-lactam therapy microbiota, an initial input into the establishment and [18], which reflect functional adaptation of gut microbiota functional role of gut microbiota during early growth in response to the drug. Clearly, more studies are needed was obtained from the analysis of fecal microbiota from to understand how different antibiotics can shape the gut two infants [9]. Undoubtedly, the study is limited in the microbiota and the resulting effect on the host. depth of analysis due to the absence of a suitable data- There is increasing evidence linking gut microbiota to base. Despite the relatively simple fecal protein profile, diseases such as Inflammatory Bowel Disease (IBD), only Bifidobacterial transaldolases protein was success- including Crohn's Disease (CD) and ulcerative colitis fully identified by de novo sequencing back then. A few (UC), but the exact role of the microbiota is still unclear years along the road, with the likes of more powerful [19]. Erickson et al. studied alterations of gut microbiota analytical tools and metagenome data availability, Young in CD patients and found differentially expressed pro- et al. recently provided a more detailed fecal metapro- teins that could be linked to the disease [20]. In another teome profile of a preterm infant, shedding light on the metaproteomic study that focused on mucosal-luminal functional clues and host-microbiota interactions during interface in IBD, changes in the bacterial phylotypes early development [10]. were reported to be associated with host immune As for the more complex human adult, an initial com- response and inflammation [21]. These findings provide prehensive fecal metaproteome analysis was performed an insight into host-microbiota interactions that may be on a healthy monozygotic twin pair [11] and subse- correlated to the disease etiology. The disease-associated quently followed by a high-throughput temporal analysis features were further corroborated by the discovery of of intestinal metaproteomes between three female adults distinct protein modules associated with IBD in the mu- [12]. Both studies identified a common core proteome cosal metaproteome of IBD patients, which were verified that was mainly mapped to metabolic pathways and in an independent cohort [22]. detected a distinctive but relatively stable metaproteome Besides, altered intestinal microbiota has been impli- for each individual. Notably, both studies also demon- cated in the development of obesity but the mechanistic strated discrepancies between protein levels predicted link remains obscure [23]. Striking enrichment of gut from the metagenomes and phylogenetic data with their microbiota proteins involved in cell motility and vitamin actual abundances, hence further emphasize the essenti- B12 synthesis was reported in an obese adolescent sub- ality of metaproteomics in understanding the protein ject, whereas the lean adolescent showed more active expression dynamics. vitamin B6 synthesis [24]. Nevertheless, the results are As noted from prior study, the composition of mucosa- rather preliminary as only one subject from each group associated microbiota varies from those residing inside the was analyzed. In a recent fecal metaproteome study lumen [13]. This finding was further corroborated in an involving a larger group of individuals, Kolmeder et al. animal study where dissimilar metaproteome profiles of reported that the phylum Bacteroidetes was biologically mucus, gut content and feces were reported [14]. More-

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