Volumen IVVolumen IV
José-Luis Gómez Pérez
Maria-José Trujillo Tiebas
José-Luis Gómez Pérez
Maria-José Trujillo Tiebas
Microbiota today: the legacy of René Dubos
This is a translation of the original Chapter text in Spanish:
Daschner A: Microbiota hoy: El legado de René Dubos in Daschner A,
Gómez-Pérez JL, Trujillo-Tiebas MJ (Editores): Medicina Evolucionista.
Aportaciones pluridisciplinares Volumen IV, pp. 51-64.
More information at www.medicinayevolucion.com
Book available at https://www.amazon.es/dp/1986667316/
Microbiota today: the legacy of René Dubos
René Dubos, was a microbiologist and humanist who between the 40’s
and 70’s of the last century performed a series of relevant experiments to
show that the intestinal flora (microbiota) is essential for the proper
development of living organisms, health and the prevention of infections.
When the microbial theory of disease was established in the 19th Century,
the concept of a specific cause for diseases was given, according to this
author, too much priority in medical research programs, leaving aside the
total environment and ecological perspective, whose understanding has
proved to be fundamental to the knowledge of disease susceptibility, not
only of infections. Even so, the proposed ideas seem to have been
forgotten until the new techniques of metagenomic sequencing have
reopened the interest for that ecological vision, co-evolution and
relationship between the host and multiple microorganisms. If in
Evolutionary Medicine one of the study fields is the adaptation ability of
organisms, R. Dubos can be considered one of the early (unrecognized)
thinkers in this field. Without underestimating new knowledge through new
tools, they are currently re-evoking ideas that already existed, but they
remained in the background for a long time when research with a
reductionist vision still predominates. If we are aware of the role of
recurrent ideas over time, we will approach the interpretation of scientific
advances with more openness.
René Dubos was a scientist and humanist of the last century who has
been forgotten today and we need to rescue some of his ideas in the era
of the microbiota study. Likewise, we could say that his model about the
interaction of organisms with the environment, ecological thinking and
deliberations about the multiple perspectives on the causes of the
disease, attribute him being a clear pioneer in the field of Evolutionary
Evolutionary Medicine, an evolving field in itself , moves in its content
and understanding, not only by new advanced scientific findings, as it is
the case of metagenomic sequencing methods that give us data of great
interest on the human microbiota and other organisms. We always insist
that scientific progress is not possible without a basic philosophical model,
a model on the relationship of different knowledge. The evolutionary
biologist Stephen Jay Gould wrote "If scientific progress were motivated
exclusively by the accumulation of information under the single, fruitful
aegis of the" scientific method ", then speculation based on a different
metaphysics would be vain and harmful, for it would chain facts to theory
and direct inquiry along incorrect lines. But facts never exist outside
theory, and imaginative theory may be even more essential in yielding
scientific 'progress' .
There is a widely spread, very superficial idea that our genes are
Paleolithic, that very little has changed since we were hunter-gatherers,
and that this would be the cause of today’s appearance of diseases, that
have not existed before. While the idea itself is probably not incorrect, its
interpretation and the relevance of this phenomenon in the broad
evolutionary context of the human being is incorrect. Something similar
happens with the idea that diseases appear when the human being leaves
the natural environment, It is again its interpretation that turns this idea
into incorrect if it is assessed superficially. There is an association of this
conception with that of the Noble Savage, as well as the necessary
degeneration of everything that man touches. We have previously insisted
that evolution, as well as the possible mechanisms of adaptation, does not
operate only on a basis of genetic modification . Marlene Zuk wrote a
book on Paleo-phantasy, and offers many examples of cultural adaptation,
but also of genetic evolution in only a few tens of thousands of years,
contradicting the idea that Paleolithic genes are the only ones responsible
for our vulnerability to diseases .
A basic idea of Dubos is that man, by manipulating the environment,
renders it "natural" . This is possible because the human being is
characterized in particular among living beings by his great capacity for
Much of Dubos's reasoning begins with the analysis of the Germ Theory of
Disease, followed by a prudent critique of it, not so much of the theory
itself, but of the exaggerated and weighted use that science has
subsequently made. We must bear in mind that many of his books of the
60’s and 70’s of the last century convey his ideas based on his
experimental studies published around the 1950’s, but initiated in the late
1920’s. 50 years have passed and I would like to show how his ideas are
still valid, or rather, how we should rescue again old ideas in a weighted
interpretation of new scientific findings. The repeated and fundamental
message of Dubos is that in order to understand the relationship of the
microbe with disease, it is necessary to situate it in different environments
or possible situations. This is related to a change in the microbiological
paradigm in a scientific environment with a predominant vision of the
microorganism as the specific cause of disease.
Returning to the present time, in box 1 is summarized some of the points
of editorial articles of the prestigious journal Science of the years 2012
and 2016, that attempt to describe advances and milestones in the
knowledge of the microbiota study so booming in recent times [5, 6 ].
We leave behind these advances in this field and return with René Dubos,
starting with a very brief biography with the sole purpose of highlighting
the validity of his ideas in an incessant search of the ecological thinking of
the humanist scientist, who carefully used the experimental methods he
had within his reach.
Box 1: Selected items that are postulated to have arrived by advances in
Dubos began studying agronomy in Paris. But a few coincidences, which
are described in the book "The world of René Dubos"  led him to make
Editorial Science 2012:
Research.. .it reveals how crucial these inhabitants are for our
susceptibility to a multiplicity of infections and noncommunicable diseases
Research… prompts tu turn to ecological theory to gain an understanding of the
dynamics at work in gut communities
Microbiota is major contributor to host metabolism through nutrient release
Editorial Science 2016:
A select few microbes cause great harm, but most are benign, some essential - The
normal plant and animal development require benign microbial colonization
The microbes that colonize colonize mucosal tissues after birth play a pivotal role in
shaping the development of the host immune system
Long term effects on susceptibility to inflammatory diseases, such as allergies and
Maintaining a healthy microbiota is no easy task:
The role of diet, disease and medications can all wreak on the microbiota
Probiotic development shows great promise
the jump to the United States and finish studying Microbiology at Rutgers
University (New Jersey). At age 26 he was already working at the
Rockefeller Institute in New York, an institution in which he stayed most of
his life. Little known is the fact that it was Dubos who obtained the first
clinically useful and commercially available antibiotics (gramicidin and
Based on the basic idea that agronomic studies should take into account
the influence of soils, he had observed that the number of bacteria with
the same substrate (the soil) was stable and he deduced that some
bacteria would have to inhibit the growth of others . So he actively
sought an inhibitory enzyme, arriving at the discovery that pneumococci
lost their capsule in the soil and were no longer infectious in mice [8, 9].
Subsequently, his work on the mentioned antibiotics stimulated the study
and subsequent isolation of streptomycin by Albert Schatz in 1943, an
antibiotic drug widely used for the treatment of tuberculosis. Waksman
was awarded the Nobel Prize with much controversy about the real
authorship of the discovery .
René Dubos, an underrecognized pioneer of Evolutionary
Two titles of the many books that Dubos has written in understandable
language should call attention to the student of Evolutionary Medicine,
Man adapting published in 1966  and So human an animal in 1969
, which has been awarded the Pulitzer prize for Works of General Non-
Fiction. In them the study of the disease and its causes are given special
relevance. He insists repeatedly on the relationship and interaction of the
human being with the environment in all its facets and considers the
disease as a response to new environments. It is nevertheless the book
Man, Medicine and Environment (1968) , which condenses in its own
title the pretension of placing disease and medicine always in an
environmental context. This also includes the psychosocial and cultural
environment that affects the risk of suffering from disease. Here many of
the ideas that are part of the Evolutionary Medicine program are
It describes some of the characteristics that characterize the human being
compared with other living beings or animals. The first is the great ability
to adapt to environments, which is explained by being a species with little
biological specialization. Further, the human being also has the ability to
change its own environment, which has made it possible to live almost
anywhere in the world.
Here comes into play the role of culture as one of the mechanisms of
adaptation. What is not apparent at first sight is the fact that the
environment that we have molded will easily create a dependence on it in
a feedback mechanism. We can apply this idea also to Medicine, which
helps us to alleviate, cure or prevent diseases, but in turn a use of drugs
can cause in some cases undesirable effects for health, hence new forms
of relief are sought, etc.
In relation to the cultural environment and man’s dependence on it, it
becomes clear when the drives and urges of Paleolithic man break
through the coating of civilization, being the result of the mismatch
produced by the complex interaction between current conditions
(environment) and the inherited and acquired characteristics. The latter do
not only refer to the cultural and genetic inheritance, but also to their in-life
experiences. He emphasizes that the human beings are more a product of
their environment than of their genes and in many experimental works the
role of irreversibility of the pathological effects of very early experiences is
shown [12,13]. Thus, it would be explained that many organic and mental
diseases arise from the mismatch between paleolithic responses and the
modern life conditions.
Dubos' concept of health is noteworthy because it defines it as a way of
life that allows the imperfect human living an acceptable and rewarding
existence when facing an imperfect world. Hence, it does not consider
possible the complete elimination of disease. These considerations are
fundamental in the biological philosophy of Evolutionary Medicine, which
considers organisms as partially unadapted beings simply because the
environment is changing. Dubos is aware of the great achievements of
Medicine in the fields of Infections and Nutrition, but chronic diseases with
high prevalence have appeared, the result of continuous imbalance and
readjustment to the environment at ever faster speeds.
Regarding his ideas about medicine, he stressed that doctors should learn
to work in a multidisciplinary way with biologists, engineers, etc. in an
approach that includes through holistic research the environment,
because as we change our environment, we always risk the appearance
of disease due to maladaptation. This is in contrast to the fact that
medicine has emphasized the study and knowledge of pathological and
biochemical lesions, rather than the response to the "total environment"
. He postulates that multiple approaches to alternative medicine have
emerged that he criticizes, when they are not based on scientific evidence,
but he is aware that they have arisen as a response to the widespread
feeling that some of the most important problems in medicine are not
being adequately addressed.
The ruling paradigm and the origins of its hypothesis
In the late nineteenth century Louis Pasteur and Robert Koch were the
proponents of the Germ Theory of Disease, which for the first time
postulated that specific germs are the cause of infectious diseases. Robert
Koch applied this idea to tuberculosis and also proposed the famous of
Koch’s postulates that are cited in box 2. The fact acquires relevance
because the agenda of experiments that spread for a long time in medical
research was based on the idea of the specific cause of disease. Not only
has it affected the microbiologists of the first half of the 20th century who
have been searching for the etiological agents of disease . Moreover,
it has influenced the concept of other diseases, prioritizing a study of
structures or biochemical mechanisms. Thus, citing Dubos, disease has
been analyzed in its different specialties according to chemical molecules,
immunological, metabolic, endocrinological mechanisms, but also applying
research in nutrition, genetics, etc., with the result of a reductionist
analysis. Dubos does not criticize progresses gained undoubtedly by
these methods, but rather opposes the absence of a holistic vision . In
an essay in the journal with such a suggestive name Perspectives in
Biology and Medicine of the year 1966, Dubos recalls how Hippocrates in
the treatise Airs, Waters and Places highlights the importance of climate,
topography, food, water, etc. for health or disease. Dubos, who had been
denouncing how medicine was unilaterally applying mechanistic
explanations in the study of the pathophysiology of diseases and thus
forgetting the role of the environment, postulated the need for a neo-
Hippocratic era .
Box 2: Koch's postulates
Turning to the field of infectious diseases, it is noteworthy that neither the
discovery of Koch's bacillus, nor the discovery of streptomycin or other
anti-tuberculostatics have been scientific achievements that have
significantly contributed to the decline in the morbidity and mortality of
The micro-organism must be present in all cases of disease
The pathogen can be isolated and cultivated
The cultivated pathogen must cause the disease
The pathogen must be re-isolated
tuberculosis in the XIX to XX century. Dubos insists that the improvement
of the state of health at the epidemiological level regarding this and other
epidemic diseases took place before these discoveries and was due to
great efforts in public health with improvements in nutrition and hygiene
So it describes a model, in which the specific agent causing the disease,
in order to produce not only the infection (which may be asymptomatic),
must be accompanied by other factors to produce it. This explains why
many pathogens persist in the host without causing disease. Examples
such as herpes or the "common cold" produced by certain types of
viruses, show that they produce disease only in special circumstances.
There is a wide-spread confusion between infection and disease, thus he
postulates that infection is the norm for many pathogens, while disease is
the exception. This has been the case for a long time in the case of
tuberculosis and other diseases. Today we can apply this idea also to
agents such as Helicobacter pylori, or the Hepatitis A virus .
The experiments that demonstrate his hypotheses
As for his ideas about microorganisms and contrary to the studies of
microbiologists who sought to isolate the specific pathogen for each
disease, he Dubos states that the true nature of them cannot be known by
studying them in isolation [16, 17]. What appears to be a pathogen that
necessarily produces disease, in many cases does not find the in vivo
environment favorable for its proliferation, partly because the
microorganisms inhibit or potentiate each other and communicate with
each other, or because they change their environment, which may be the
environment of the gastro-intestinal tract.
The problems arise when attempting to apply these ideas to the design of
experiments. One example of the practical problems of microbiologists is
the fact, that they have always seen more microorganisms under the
microscope than those that can be cultivated.
In the article Infection into Disease, written as early as 1958, he insists on
the necessary factors for an infectious disease to occur, that is, in which it
is necessary not only the presence or infection by the specific pathogen,
but also factors of the environment . So in his experiments he
analyzed in murine studies the role of diet on infection, of antibiotics, of
stress factors, and as he progressed in time involved in the studies the
intestinal flora. The studies described below have been published mostly
in the Journal of Experimental Medicine in the 50s and 60s of the last
First, he addressed the possible effect of nutritional alterations on
susceptibility to infection. In one experiment, he compared mice on a free
diet with others under fasting conditions for 36 to 48 hours before infecting
them with pathogenic staphylococci. The measured parameter was the
death of the mouse by infection. He was able to verify a greater
susceptibility to infection after fasting. However, if the mice were put on a
dietary restriction for a longer time of 4 weeks the mice remained resistant
to infection .
Another subsequent study aimed to investigate different diets as modifiers
of resistance to infection . Different diets were compared for 15 days
before proceeding to experimental infections with two different pathogenic
bacteria (Klebsiella pneumoniae and staphylococci). The diets were
formed by only corn, complete diet in two variants (+ 20% casein, or + 5%
casein), only 20% casein, or only 5% casein. The objective was to
observe the effect of the diets on the infecting organisms in the tissues, as
well as the ability of the host to resist the toxic effects of the infection. It
was found that insufficient nutrition regimen (in this case only corn)
increased the susceptibility to infections, especially determining the
resistance. This interpretation was the result of the observation that while
the bactericidal capacity was maintained, the administration of LPS
(lipopolysaccharide) and its toxic effect produced such stress in these
mice that they did not resist when fed an incomplete diet [19, 20].
Taking this experience to evaluate the role of intestinal flora, the effect of
antimicrobials and diet on it was studied. In these experiments it was
possible to observe a decrease in lactobacilli and an increase in
enterococci and gram-negative bacilli after the use of several types of
antibiotics (Penicillin, Terramycin, Chloramphenicol). Recovery of
lactobacilli was slow (observation for 12 weeks) . The experiments
were extended by modifying the diet in these mice, observing a
modulation regarding the recovery of intestinal flora after the use of
antimicrobials: those mice fed enriched bread took longer to recover than
those with a more adequate complex diet. Thus they presented one of the
first evidences of the influence of nutrition on the intestinal flora .
It remained to be studied the role of the intestinal flora on the resistance to
infections. The experiment was designed such that the mice received
different diets (commercial pellets, Sherman diet with 33% whole milk and
66% whole wheat, complete semi-synthetic diet with 15% casein,
complete semi-synthetic diet with 15% gluten) and were then
experimentally infected with murine pathogens (Staphylococcus aureus,
Klebsiella pneumoniae) [23,24]. The effect on the number of lactobacilli in
feces, duration and reversibility of changes, as well as resistance to
infection were analyzed. Diets with casein or gluten decreased the amount
of lactobacilli quickly (after only a few days), while the Sherman diet and
pellets (complete diet) increased the resistance to infections. The group by
Dubos was able to verify a correlation between lactobacilli and resistance.
Contributions for the understanding of human microbiota and
tribute to René Dubos
Already in a 2001 review that aimed to identify pioneer researchers in the
field of intestinal biota, the team of R. Dubos points out in several points
. The knowledge about the presence of microorganisms (at least
transiently) in the upper gastro-intestinal tract, the ecological succession
of neonatal communities, the fact that some microorganisms form
communities in the intestinal mucous gel lining the epithelium, the
ecological laws and interaction among species and within the host, and
especially the fact that the intestinal flora is considered practically an
indispensable organ for life .
In his 1959 book "Mirage of Health" he says "... Our recent studies have
revealed that there exists in normal animals an abundant and
characteristic microflora, not only in the large intestine, but also in all the
other parts of the digestive tract, including the mouth, the stomach and the
small intestine. These microorganisms should not be regarded merely as
contaminants. Rather, they become so intimately associated with the
various digestive organs that they form with them a well-defined
ecosystem of which each component is influenced by the others, and by
the environmental conditions".
If we look again at box 1, we can see how almost 50 years ago Dubos
already experimentally demonstrated most of the ideas that are now
postulated as advances. Dubos had the merit that he not only maintained
common sense in the elaboration of his hypotheses, but also made an
important bibliographical research work, ensuring that many of these ideas
were already pre-existing by previous thinkers. He remembered how even
L. Pasteur was involved in an important debate, and an anecdote
describes how shortly before his death he said: "Le microbe n'est rien.
C'est le terrain qui est tout "[The microbe is nothing, the terrain is
everything] to describe that the virulence of possible pathogens depends
on the environment. Dubos used his research facilities in a laboratory that
is still very prestigious to underline the hypotheses with currently accepted
scientific methods. And finally, not only was he a great thinker and
experimenter, but he also put a lot of effort into spreading his acquired
knowledge. This facet has frequently been criticized as superficial, but
importantly opens the interest for the subjects to a much wider audience
than the specialized one. Perhaps the most important matter is that ideas,
accompanied by common sense and with a broadly plausible base, which
further present themselves cyclically through the history of thought and
observation, are those, that have the ability to be transmitted in both
specialized scientific language but also in an informational manner.
The new sophisticated methods of metagenomic sequencing have helped
to the knowledge of more species, their interrelations and the relationships
with the metabolism. There are countless publications that now associate
diseases, phenotypes, etc. with characteristics of the human, especially
intestinal, microbiota, The ecological alterations are now studied as risk
factors for the appearance of chronic diseases. But in reality, these ideas
about the intestinal ecology, the relation of nutrition with the microbiota
and with the susceptibility to the disease, as we have seen, are not new.
We must now take advantage of these recent "advances", precisely
because they are not so novel. Throughout history, similar ideas have
repeatedly been postulated. They have not been labeled with names like
ecology, microbiota, etc., but in its essence they bore the same germ, just
as Dubos predicted about the new Hippocratic era. He was also able to
predict the application of his own discoveries. In a 1967 article he cites "...
The gastrointestinal microbiota, especially that acquired during early life,
influences so profoundly the morphologic and physiologic characteristics
of its host that many characteristics of the adult, which appear to be the
expression of the genetic endowment, commonly turn out to be
determined, in reality, by the microbial environment. In view- of this fact,
and for therapeutic purposes, it would be highly desirable to develop
procedures for modifying at will the composition of the indigenous
microbiota.. ". In medicine we look for treatments for diseases, but we
must also be involved in prevention. The knowledge that is currently
published in the field of microbiota clearly highlights the importance of
certain groups of microorganisms for the maintenance of health, growing a
field of diagnostic and therapeutic application, such as the possible use of
probiotics. Here, however, we must not stop and especially not forget the
role of the environment, to which food belongs, and as a more specific
example fermented foods  in the ecology of the intestine and health.
1. Daschner A, Gómez Pérez J, Trujillo Tiebas M, Las diferentes caras de la
Medicina Evolucionista. Niveles de adaptación y el origen de las
enfermedades. In: Daschner A, Gómez Pérez J, Trujillo Tiebas M eds.
Medicina Evolucionista Aportaciones pluridisciplinares Volumen III. Madrid:
2. Gould SJ, Ontogeny and phylogeny. Cambridge, Mass.: Belknap Press of
Harvard University Press, 1977.
3. Zuk M, Paleofantasy: What Evolution Really Tells Us about Sex, Diet, and
How We Live. New York, London: W.W. Norton & Company, 2014.
4. Dubos RJ, Man, medicine, and environment. New York,: Praeger, 1968.
5. Ash C, Mueller K, Manipulating the Microbiota. Science 2016;352: 530-1.
6. Mueller K, Ash C, Pennisi E, Smith O, The gut microbiota. Introduction.
Science 2012;336: 1245.
7. Dubos RJ, Piel G, Segerberg O, Rene Dubos Center for Human
Environments., The world of René Dubos : a collection from his writings. 1st
Edn. New York: H. Holt and Co., 1990.
8. Avery OT, Dubos R, the protective action of a specific enzyme against type iii
pneumococcus infection in mice. J Exp Med 1931;54: 73-89.
9. Dubos R, Influence of Environmental Conditions on the Activities of Cellulose
Decomposing Organisms in the Soil. Ecology 1928;9.
10. Dubos RJ, Man adapting. New Haven,: Yale Univ. Press, 1965.
11. Dubos RJ, So human an animal. New York,: Scribner, 1968.
12. Dubos RJ, Savage DC, Schaedler RW, The indigenous flora of the
gastrointestinal tract. Dis Colon Rectum 1967;10: 23-34.
13. Dubos R, [Man and his environment. Biomedical knowledge and social
action]. Bol Oficina Sanit Panam 1965;59: 471-80.
14. Dubos R, Hippocrates in modern dress. Perspect Biol Med 1966;9: 275-88.
15. Daschner A, Una visión evolucionista de la hipótesis de la higiene en alergia
y las enfermedades inflamatorias crónicas. In: Pérez ADJ-LG ed. Medicina
Evolucionista Aportaciones pluridisciplinares Volumen I. Madrid: MedEvo,
16. Houtman J, The human microbiome: your own personal Ecosystem.
Breakthroughs in Bioscience 2012.
17. Dubos RJ, Infection into disease. Perspect Biol Med 1958;1: 425-35.
18. Smith JM, Dubos RJ, The effect of nutritional disturbances on the
susceptibility of mice to staphylococcal infections. J Exp Med 1956;103: 109-
19. Dubos RJ, Schaedler RW, Effect of nutrition on the resistance of mice to
endotoxin and on the bactericidal power of their tissues. J Exp Med 1959;110:
20. Schaedler RW, Dubos RJ, The susceptibility of mice to bacterial endotoxins.
J Exp Med 1961;113: 559-70.
21. Dubos RJ, Schaedler RW, The effect of the intestinal flora on the growth rate
of mice, and on their susceptibility to experimental infections. J Exp Med
22. Dubos R, Schaedler RW, Stephens M, the effect of antibacterial drugs on the
fecal flora of mice. J Exp Med 1963;117: 231-43.
23. Dubos RJ, Schaedler RW, The effect of diet on the fecal bacterial flora of
mice and on their resistance to infection. J Exp Med 1962;115: 1161-72.
24. Schaedler RW, Dubos RJ, The fecal flora of various strains of mice. Its
bearing on their susceptibility to endotoxin. J Exp Med 1962;115: 1149-60.
25. Savage DC, Microbial biota of the human intestine: a tribute to some
pioneering scientists. Curr Issues Intest Microbiol 2001;2: 1-15.
26. Dubos RJ, Mirage of health, utopias, progress, and biological change. 1st
Edn. New York,: Harper, 1959.
27. Daschner A, Alimentos fermentados: ¿Pueden igualmente conseguir los
efectos postulados de los probióticos? In: Daschner A, Gómez Pérez J,
Trujillo Tiebas M eds. Medicina Evolucionista Aportaciones pluridisciplinares
Volumen II. Madrid: MedEvo, 2014:119-32.