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EDITORIAL
The microbiome in health and disease: a new role of microbes
in molecular medicine
Ingo B. Autenrieth1,2,3
Published online: 17 December 2016
# The Author(s) 2016. This article is published with open access at Springerlink.com
For more than a hundred years, medicine was profoundly
influenced by the groundbreaking work of Robert Koch
[1] and others demonstrating microbes as causative agents
of disease (era Koch 1.0, Table 1). Subsequently, novel
treatment and prevention strategies including antimicrobi-
al agents, vaccines, and immunotherapies and the imple-
mentation of antiseptic and hygiene measures were devel-
oped and proved highly effective in combating infectious
diseases. As the field of molecular genetics proceeded,
molecular equivalents to the Koch-Henle postulates
claimed by Falkow [2] have defined the genetic and mo-
lecular principles of microbial pathogenesis (era Koch
2.0, Table 1). At the same time, diagnostic microbiology
became highly sophisticated in developing methods to
isolate pathogens from microbiota-contaminated samples.
The microbiota itself, however, remained largely unex-
plored and elusive. Despite the well-established notion
that humans are colonized by a microbiota with important
functional roles such as vitamin synthesis, digestion, and
colonization resistance against enteric pathogens [3], the
global role of the microbiota in health and disease was
until recently largely neglected due to the lack of appro-
priate analytical methods.
Although molecular methods like polymerase chain re-
action, Sanger sequencing, and fluorescence in situ hy-
bridization techniques brought a deeper insight into the
composition of the intestinal microbiota, it turned out that
many members of the microbiota cannot be cultivated with
current laboratory methods [4]. Experimental approaches
tackling the role of microbes in disease, however, largely
depend on the ability to cultivate (according to Koch’s
postulates) and to genetically manipulate microbes (ac-
cording to Falkow’s molecular equivalents) in order to test
them in experimental systems. The rising field of mucosal
immunology together with the development of germ-free
and gnotobiotic mouse models, however, attracted atten-
tion and provided the tools necessary to address the role of
commensal microbes as putative disease-associated oppor-
tunistic pathogens or Bpathobionts^. Pathobionts are resi-
dent microbes innocuous to the host under normal condi-
tions but with pathogenic potential in susceptible hosts
(e.g., genetic risk factors). However, the absence of appro-
priate experimental methods to determine and to analyze
the noncultivable microbes from the microbiota had ham-
pered further elucidation of their role in etiology and path-
ogenesis of diseases.
A breakthrough was achieved by the implementation of the
next generation sequencing and new bioinformatic algorithms
for metagenomic data analysis [5–7] and provided the foun-
dation for more sophisticated exploration of the microbiota.
Consequently, an enormous number of publications reported
on the composition and changes of the microbiota, designated
as microbiomes of specific body sites, and raised questions
and new hypotheses of their roles in health and disease. In
fact, nowadays microbes are not only considered as causative
pathogens of infectious diseases but also as causative or con-
tributing agents of noninfectious, particularly chronic diseases
like allergies, chronic inflammatory bowel diseases, colon
* Ingo B. Autenrieth
Ingo.Autenrieth@med.uni-tuebingen.de
1 Institute of Medical and Hygiene, University Hospital Tübingen,
Elfriede Aulhorn Str. 6, 72076 Tübingen, Germany
2 Interfaculty Institute of Microbiology and Infection Medicine,
Tübingen, Germany
3 German Center for Infection Research (DZIF), partner site Tübingen,
Tübingen, Germany
J Mol Med (2017) 95:1–3
DOI 10.1007/s00109-016-1499-8
cancer, diabetes, and neurodegenerative diseases [8]. Recent
achievements to a better understanding of the metabolic func-
tion of the microbiome and its role in shaping the immune
system shed new light on the mechanisms governing the bal-
ance between tolerance, immune effector mechanisms, and
inflammatory reactions [9, 10]. Nonetheless, technical limita-
tions of analytic and pre-analytic procedures, experimental
setups, and study designs of many studies had hampered the
ability to distinguish if composition and changes of the
microbiomes are a cause or consequence of disease. In turn,
metagenomic shotgun sequencing, humanized gnotobiotic an-
imal models, population-based or long-term patient cohort
epidemiologic studies provide suitable tools to test hypotheses
and to design proof of concept studies to explore the causative
role of single members or communities of the microbiota in
aetiopathogenesis of noninfectious diseases.
Despite these achievements, comprehensive analytic pipe-
lines including targeted and nontargetedmetabolomic analysis
of body fluid compartments and the linkage to metagenomic
sequencing data and disease phenotypes are required for diag-
nostics directing therapeutic interventions via manipulations
of the microbiome. To this end, new postulates (era Koch 3.0)
based on metagenomics and new analytic tools are necessary
(Table 1) to explore and to prove the impact of singlemicrobes
or of the concerted action of microbial communities and their
metabolites on chronic, noninfectious diseases in the context
of an individual host genome with an individual lifestyle and
environment.
In the present issue of the Journal of Molecular
Medicine, several important aspects of current research
around the microbiome and its role in human health and
disease are discussed: Johnson and colleagues elaborate
on the specific components of the microbiota, the
Bacteroidetes, by discussing the genetic variability of this
phylum, the sometimes opposing effects on metabolic dis-
eases such as obesity or type II diabetes and the problem
of health-interpretable microbiome data [11]. Yiu and col-
leagues extend this by reporting recent findings and ideas
how host metabolism, body weight, and diseases like obe-
sity may be affected by interactions with the immune sys-
tem, metabolism, and the microbiota [12]. Referring to
chronic inflammatory bowel disease, Frick and Wehkamp
discuss current strategies to shape mucosal immunity and
the microbiome by innovative therapeutic interventions
[13], while Lee et al. discuss new molecular aspects of
the gut-brain axis exemplified by how the microbiota af-
fects the cytoplasmic ligand-induced aryl hydrocarbon re-
ceptor, AhR, and how this in turn may affect host physi-
ology and diseases including neurodevelopmental and
neurodegenerative diseases [14]. Finally, Willmann and
Peter address how the rapidly increasing antimicrobial re-
sistance of bacterial pathogens can be tackled by exploring
the resistome of the microbiome with the next generation
sequencing methods and bioinformatic algorithms and
how clinical diagnostics and infection control may profit
from molecular microbiota analysis [15].
Future textbooks in human physiology will likely in-
clude comprehensive chapters on microbiomes in human
health, and future textbooks in clinical medicine will
possibly deal with microbes not only in the chapter of
classical infectious diseases (caused by typical patho-
gens) but also in noninfectious diseases (caused or driven
by pathobionts). Additionally, they may include how
modification of the microbiota by e.g., novel antimicro-
bial agents, smart and individualized probiotics, prebi-
otics, small molecules, and lifestyle intervention, or by
microbiota transfer may offer new opportunities for the
preservation of health and cure of disease. In any case,
these are exciting times for microbiology within molecular
medicine that herald a new dimension in the concepts of pre-
cision medicine.
Table 1 Progress since the Koch era
Koch 1.0: Microbes are causative agents of disease (1884)
•The microorganism must be found in abundance in all organisms
suffering from the disease but should not be found in healthy
organisms.
•The microorganism must be isolated from a diseased organism and
grown in pure culture.
•The cultured microorganism should cause disease when introduced into
a healthy organism.
•The microorganism must be reisolated from the inoculated, diseased
experimental host and identified as being identical to the original
specific causative agent.
Koch 2.0: Genetic and molecular principles of microbial
pathogenesis (Falkow 1988)
•The phenotype or property under investigation should be associated with
pathogenic members of a genus or pathogenic strains of a species.
•Specific inactivation of the gene(s) associated with the suspected
virulence trait should lead to a measurable loss in pathogenicity or
virulence.
•Reversion or allelic replacement of the mutated gene should lead to
restoration of pathogenicity.
Koch 3.0: Metagenomic equivalents of Koch postulates applied to
noninfectious pathobiont-associated diseases
•A single strain, species, genus or phylum, or various combinations
thereof, or genomically encoded functions, are significantly correlated
with the disease phenotype of a host.
•Microbiota transfer into an appropriate gnotobiotic defined animal
model causes at least some aspects of the disease phenotype or a
corresponding change of the metabolome or immune response.
•The qualitative or quantitative metagenome alteration should be reported
in the newly diseased host.
•Depletion of the identified taxa or functions, by intervention via e.g.,
antibiotics, expansion of beneficial microbes by probiotics, prebiotics,
microbiota transfer, or diet reduces progression or ameliorates the
disease.
•Transmissibility is not essentially required as diseases are often the
results of a shift of the abundance of endogenous members/functional
capacities of the microbiota.
2 J Mol Med (2017) 95:1–3
Acknowledgments I would like to thank Ruth Ley, Samuel Wagner,
Julia Frick and Silke Peter, and CeMeT GmbH, all Tübingen, for the
discussions on the topic of this editorial and critically reading the
manuscript.
Compliance with ethical standards
Funding German Research Foundation (DFG) Priority Program 1656;
German Center for Infection Research, DZIF.
Open Access This article is distributed under the terms of the Creative
Commons At t r ibut ion 4 .0 In te rna t ional License (h t tp : / /
creativecommons.org/licenses/by/4.0/), which permits unrestricted use,
distribution, and reproduction in any medium, provided you give appro-
priate credit to the original author(s) and the source, provide a link to the
Creative Commons license, and indicate if changes were made.
References
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4. Turnbaugh PJ, Ley RE, Hamady M, Fraser-Liggett CM, Knight R,
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J Mol Med (2017) 95:1–3 3


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