Sci. Bull. (2016) 61(15):1151–1153
com
DOI 10.1007/s11434-016-1142-7
News & Views
Metabolomics in gut microbiota: applications and challenges
Shijuan Yan • Jianfeng Huang • Zhongjian Chen •
Zongyong Jiang • Xue Li • Zhuang Chen
Published online: 6 July 2016
Ó Science China Press and Springer-Verlag Berlin Heidelberg 2016
On May 13, 2016, the American government launched a
121-million USD investment for the National Microbiome
Initiative (NMI), which aims to provide an in-depth
understanding of microbiomes in order to develop new
applications in the areas of human health, food security,
and environmental restoration [1]. NMI also calls for pro-
jects to develop platform technologies, reference libraries,
and databases for microbiome research in all habitats,
including in the human gut. As an important platform
technology, metabolomics is able to characterize and
quantify small-molecular weight compounds in complex
biological samples using technologies such as mass spec-
trometry (MS) and nuclear magnetic resonance (NMR)
spectroscopy [2]. Metabolomics has been applied exten-
sively in gut microbiota to understand how gut microbiota
affect the metabolic status of the host through gut micro-
biota metabolism and host-microbiota co-metabolisms. It is
plausible that metabolomics, together with the high-
throughput DNA and RNA sequencing techniques, may
help to establish connections between gut microbiota and
altered metabolites at the systems level, and may help to
identify and validate the role of gut microbial metabolites
on their hosts [3, 4]. Over the past decade, seven common
types of gut microbial metabolites have been identified and
characterized via untargeted metabolic profiling or targeted
Shijuan Yan and Jianfeng Huang contributed equally to this work.
S. Yan
J. Huang
Z. Chen
Z. Jiang
Z. Chen (&)
Agro-biological Gene Research Center, Guangdong Academy of
Agricultural Sciences, Guangzhou 510640, China
e-mail: chenzhuang@agrogene.ac.cn
J. Huang
X. Li
Institute of Pharmaceutical Research, South China Normal
University, Guangzhou 510631, China
www.scibull.
www.springer.com/scp
metabolic analysis. Some of these metabolites such as
trimethylamine N-oxide (TMAO) and indoles have been
shown to play specific roles on the host (Fig. 1) [5, 6].
As symbiotic gut microbiota may interact with hosts to
impose positive or negative effects on disease risks, it is
not surprising that metabolomics studies may identify
metabolites that can potentially be used as biomarkers of
diseases. However, the fact that different biomarker com-
pounds with varying quantities have been reported in
studies using different metabolomics platforms [7, 8] has
prompted researchers from different laboratories to ensure
the metabolomics data are generated and maintained in a
unified manner (by, for example, standardizing sample
preparation protocols, instrument settings, and analysis
workflows). It is also important to build metabolomics
databases for clinics and laboratories to which the meta-
bolic fingerprinting data of fecal, urinary, serum, and tissue
samples can be deposited and accessed by the research
community.
Further, metabolomics studies may be used to decipher
the contribution of gut microbiota in drug metabolism. In
particular, some bacteria are known to secrete distinct sets
of enzymes, and some of these enzymes may transform
drugs into compounds with altered toxicity and/or
bioavailability to the host. CD 6168, a major metabolite
produced from anti-hepatitis C drug deleobuvir, was
detected in plasma of rats with a concentration approxi-
mately nine folds higher than that in pseudo-germ free rats
in which almost all administrated deleobuvir was excreted
in feces [9]. It has been showed recently via untargeted
metabolic profiling that the antioxidant drug tempol, which
is able to reduce body weight, acts through modulating the
gut microbial SCFA metabolic pathway and thereby affects
the glycogenolysis, glycolysis, and lipolysis pathways of
the host [10]. The altered levels of gut microbiota-related
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1152 Sci. Bull. (2016) 61(15):1151–1153

O H
N
Bile acids OH O-
R
H R
Indoles
H H
HO H Regulate gastrointestinal barrier function, immune
system and activities of digestive enzymes; modulate
Activate GPCRs to promote glucose homeostasis; incretin secretion; influence lipid membranes and
involve in lipid metabolism, liver disease, colon attenuate pathogenic bacteria toxicity.
cancer, intestinal mucosal and cardiovascular
functions. O

R OH
SCFAs
Methylamines N Activate GPR43,GPR41,GPR109A, and OLFR78;
R regulate energy homoeostasis, autism spectrum,
intestinal cancer, and blood pressure.
Relate to trimethylamininuria,
atherosclerosis, colorectal cancer, and impaired
R
glucose tolerance; alleviate glaucoma and
stimulate tubulin assembly; modulate Polyamines
p38/c-jun N-terminal kinase (JNK) H 2N NH2
activation and heat shock protein
expressing; enhances platelet Involve in cell-growing procedure, intestinal
hyperreactivity and thrombosis risk. epithelial integrity and aging; promote tumor
growing and reduce antitumorimmunity;
promisingly act as cancer- therapeutic target.
R
OH
H O
Polyphenolics N
OH
O
Vitamins
Regulate gut bacteria community; reduce DNA Involve in fat, carbohydrate and amino acid metabolism,
damage and diminish inflammatory factors DNA and RNA synthesis; function to nervous system
expressing; exert antioxidant activity and reduce abnormalities and modulate bone mass; link to intracranial
colon cancer risk. haemorrhage, bone fracture and colorectal cancer.

Fig. 1 (Color online) Putative functions of gut microbiota-related metabolites. Functions refer to possible roles of products derived from foods
and host secretions by gut microbiota, as well as the co-metabolites combined with the host. ‘R-’ represents an unspecified substituent group,
which is possibly distributed at any position of the parent nucleus. The species and variety of the substituent groups are diverse

metabolites that result from antibiotics treatment, including
bile acids, glucose, free fatty acids, dipeptides, and sugar
alcohols, may generate a metabolic environment favoring
the susceptibility of Clostridium difficile infection [11].
The metabolic perturbation of drugs in the host and drug–
drug interactions mediated by gut microbiota were revealed
through metabolomics approaches; which will guide doc-
tors’ prescriptions in a personalized manner and facilitate
the design of new drugs with low toxicity [9–12].
Metabolomics analyses may also be used to study how
diet modulates gut microbial communities and influences
host health [13–15]. Understanding the biosynthetic path-
ways of gut microbial metabolites from otherwise indi-
gestible dietary nutrients under different physiological
states of the host may enable doctors to recommend proper
diets to decrease risks and to improve health. Metabo-
lomics studies have shown that the levels of gut micro-
biota-related metabolites such as TMAO, indoxylsulfate,
phenylacetylglutamine, and hippurate that are known for
their functions in metabolic disorders were down-regulated
in the urine of children supplemented with non-digestible
carbohydrates [13]. Parallel metagenomics analyses of gut
microbiota showed that 67 pathways, including fat and
protein metabolism, carbohydrate catabolism, and
lipopolysaccharide biosynthesis of gut microbiota, were
altered by dietary interventions, suggesting that foods
strongly influence the metabolic activity of gut microbiota
[13]. Another metabonomics study of fecal samples from
rats fed with high-fat diet (HFD) revealed dynamic changes
of fecal metabonomic profiles for TMA, SCFAs, amino
acids, 4-hydroxyphenylacetate, and other compounds,
suggesting that HFD may contribute to metabolic disorders
of the host [15]. Notably, the accumulated levels of gut
microbial metabolites in the intestinal tract does not always
correspond with that in the host blood or other tissues.
Specifically, indole-3-acetate and indole-3-lactate, two
functional gut microbial metabolites, exhibited increased
accumulation levels in the blood of rats fed with high levels
of fermentable dietary fiber but elevated levels were not
detected in fecal samples [14].
No doubt, studies in gut microbial metabolomics have
great potential to facilitate the analysis of metabolic pat-
terns of gut microbiota and microbiota-host interactions.
Some limitations currently prevent researchers in gut

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Sci. Bull. (2016) 61(15):1151–1153
microbial metabolomics from determining how these
metabolic changes are produced and regulated and which
specific gut bacteria are responsible for these differences.
To this end, metagenomic and metatranscriptomic analyses
offer complementary tools for capturing an informative
view of gut microbiota. Recently, Sridharan et al. [16]
established a microbiota metabolic network model based
on genome annotation information in which 26 metage-
nomics-predicted metabolites were detected using MS-
based metabolomics. We strongly believe that the effective
integration of metabolomics with other ‘‘omics’’ data such
as metagenomics, metatranscriptomics, and metapro-
teomics will enable a deeper understanding of complex
biosynthetic pathways of gut microbiota. Insights gained
with such integrative studies may also facilitate the
development of non-invasive diagnostic tools for patho-
logical disorders, help optimize personalized medicine, and
improve the efficacy of individual-specific food
supplements.
Many challenges still remained to be tackled in gut
microbial metabolomics in the future. First, gut metabolites
are heterogeneous, owing to their mixture with undigested
food and host secretions. Second, many compounds are
easily oxidized and degraded when exposed to extracting
agents and oxygen, which may affect the metabolic pro-
files. Third, current databases available for metabolite
identification in both MS- and NMR-based technologies
are still not comprehensive and therefore hinder global
assessments in high-throughput metabolomics studies. The
last but certainly not the least challenge is translating the
knowledge gained from gut microbial metabolomic studies
to the clinic.
Acknowledgments We thank Prof. Chun-Ming Liu and Dr. John
Hugh Snyder for help in revising the manuscript, and Dr. Qunjie
Zhang for designing Fig. 1. This work was supported by the Presi-
dential Foundation of the Guangdong Academy of Agricultural Sci-
ences, China (201420), the Science and Technology Program of
Guangdong Province, China (2016B070701013), and the National
Natural Youth Science Foundation of China (31500045).
Conflict of interest The authors declare that they have no conflict of
interest.
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