IJE Advance Access originally published online on January 13, 2005
International Journal of Epidemiology 2005 34(1):13-15; doi:10.1093/ije/dyh380
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IJE vol.34 no.1 © International Epidemiological Association 2005; all rights reserved.
Commentary |
Commentary: Remembrance of microbes past
Department of Microbiology and Immunology, University of Otago, PO Box 56, Dunedin, New Zealand. E-mail: gerald.tannock@stonebow.otago.ac.nz
Sigmund Freud (1856–1939) established a central theme of psychoanalysis: the past is alive in the present. Influences experienced in the past are not something that can be completely outgrown by the individual or society; they remain vital parts of existence.
Rene Dubos (1901–1982), French-born American microbiologist, experimental pathologist, environmentalist, humanist, and Pulitzer Prize-winning author, explored in a number of books the interplay between environmental forces and the physical, mental, and spiritual development of humankind. His article in the journal Pediatrics entitled ‘Biological Freudianism: lasting effects of early environmental influences’ and written in collaboration with his postdoctoral fellows Dwayne Savage and Russell Schaedler (soon to be eminent scientists in their own right) encapsulated this theme.1 Drawing on results obtained from experiments with specific-pathogen-free mice, the authors concluded that ‘From all points of view, the child is truly the father of the man, and for this reason we need to develop an experimental science that might be called biological Freudianism. Socially and individually the response of human beings to the conditions of the present is always conditioned by the biological remembrance of things past’. With this two-sentence statement the works of William Wordsworth, Sigmund Freud, and Marcel Proust were deftly wedded to biology.
Only touched upon in the Pediatrics article was the pioneering work of the Dubos group concerning the impact of the diverse collection of bacterial species (the microbiota) that inhabit the gut of mice from soon after birth. As recalled by Dwayne Savage, the NCS (New Colony Swiss) mouse colony derived at The Rockefeller University was the first murine colony in the world in which the animals, while harbouring a gut microbiota, were nevertheless free of certain mouse pathogens and could be bred in sufficient quantity for major experiments.2 Dubos and colleagues soon realized that NCS mice differed in several characteristics from SS mice (Standard Swiss, from which the NCS colony had been derived). NCS mothers bore on average more infants per litter, and their offspring grew faster and were larger than SS mice (even when fed diets low in lysine and threonine). It was suggested that the differences between NCS and SS mice were the result of mutations (in other words, that a new mouse strain had been selected); however, astoundingly, NCS mice housed with SS mice reverted to the characteristics of SS mice in all properties tested. The faecal microbiota of the two colonies of mice were different when analysed by bacteriological culture. Unlike SS mice, NCS animals did not harbour facultatively anaerobic gram-negative bacteria such as Escherichia coli among the members of their gut microbiota. Remarkably, NCS mice were tolerant to parenteral doses of endotoxin that were lethal within a few days of administration to SS mice. Exposure of NCS animals to SS mice during early life, or prior injections with small doses of heat-killed cells of gram-negative bacteria that thus exposed the animals to sub-lethal amounts of endotoxin, increased the susceptibility of NCS mice to match that of SS animals. Dubos and colleagues concluded that the enterobacteria, present in relatively high numbers in the gut of infant SS mice, sensitized the animals so that, as adults, they were highly susceptible to endotoxin. These observations led Dubos and colleagues to devote almost 20 years to the study of gut microbiota composition and gut microbial ecology. They established experimental methods and observations that, as Savage has appropriately stated, ‘should endure in history’.2
Many clues to the influences of bacteria on the mammalian host have been obtained from comparisons of the biochemical and physiological characteristics of germ-free (raised in the absence of demonstrable microbes) and conventional (colonized by microbes) animals.3 The impact of even a single bacterial species on the host animal can also be ascertained using this approach. Gnotobiotic (‘defined biota’) work like this can now be done at a sophisticated level because of the availability of advanced imaging technology, as well as genome sequences of experimental animal species and the consequent preparation of DNA microarrays that can be used to measure gene expression. The potential for obtaining exciting knowledge of the mechanistic influences of gut microbiota on a host using this approach has been demonstrated by the work of Gordon and colleagues, who have studied the impact of colonization of formerly germ-free mice by the bacterial species Bacteroides thetaiotaomicron.4 Perhaps most striking have been their observations concerning angiogenesis in the murine gut. Quantitative three-dimensional imaging studies showed that a plexus of branched and interconnected blood vessels developed postnatally in small bowel villi of conventional mice. Angiogenesis coincided with the establishment of the gut microbiota. Vascular development was arrested in germ-free mice, but could be restarted by colonization of the gut by a conventional gut microbiota or by B. thetaiotaomicron, which had been shown in other experiments to up-regulate expression of the murine angiogenin-3 gene in the ileal mucosa. Other observations showed that interaction between the gut microbiota and Paneth cells was essential for the regulation of angiogenesis.4,5
The gut of newborn human infants resembles those of germ-free animals because it is not yet colonized by a microbiota. This germ-free state is short-lived, however, because within minutes of birth bacteria in the faeces that have been involuntarily expelled by the mother during labour, together with environmental microbes, have the opportunity to colonize the neonate. Suckling, kissing, and caressing the infant after birth provide additional assurance that members of the microbiota are transmitted from one generation to another. Seemingly unchecked proliferation of bacteria proceeds initially in the neonatal gut, resulting in a heterogeneous collection of bacterial species. Subsequently, regulatory mechanisms generated within the ecosystem (autogenic factors) and by external forces (allogenic factors) permit the persistence of some bacterial populations but the elimination of others in a continuous succession. It takes several years to produce a climax community reminiscent of that of adults.6
Members of the bacterial genus Bifidobacterium are numerically predominant in the gut of infants during the first months of life, a phenomenon first described in 1905 by Henri Tissier.7 In his observations of infant faeces, he noted that the bacterial collection seemed ‘to be constituted, by microscopic examination, of only one species, Bac. bifidus, a strictly anaerobic bacterium. It is necessary to do a complete bacteriological examination to see that there exists, besides this species, other facultatively anaerobic bacteria in very limited numbers...’.7 Bifidobacterium species could be of particular relevance to biological Freudianism because they are the numerically predominant bacteria during the first months of life, regardless of diet. Using modern, nucleic acid-based methods of analysis, bifidobacteria have been shown to form between 60 and 91% of the total bacterial community in the faeces of breast-fed babies and 28–75% (average 50%) in formula-fed infants, whereas in the faeces of adult humans they comprise, on average, only a few per cent of the microbiota.8,9 Thus these bacteria could have an important role in early life on the development of host characteristics.
In recent decades, many affluent countries have experienced an increase in the prevalence of atopic diseases, including asthma.10 Several aspects of lifestyle have changed in these countries over the same period and theories have been advanced to explain the altered prevalence of allergies. The ‘Hygiene Hypothesis’ proposes that atopic diseases could be prevented by infections in early childhood because the neonatal immune system would be driven towards a T helper 1 (Th1) response; however, a specific ‘infectious protective factor’ has not been identified.11 Attention has turned to the gut microbiota and the possibility that colonization of the gut by specific bacterial species may be more important than the impact of sporadic infections. For example, the composition of the gut microbiota has been reported to differ in terms of the numbers of lactobacilli and clostridia in the faeces of Estonian and Swedish children.12 Atopic diseases were less prevalent in the Estonian population than the Swedish population. Ouwehand and colleagues have reported that the prevalence of Bifidobacterium adolescentis differed in the faeces of healthy and allergic Finnish children aged 2–7 months. Six out of seven allergic children harboured B. adolescentis in the faeces whereas this species was not detected in six healthy children.13
The environmental conditions under which babies are born and nurtured may affect which microbes they are exposed to and subsequently influence the composition of their gut microbiota. Differences in neonatal gut microbiota might occur as a result of the frequency of hospital deliveries, caesarean sections, special-care baby unit admissions, smaller family size, widespread use of antibiotics, good hygiene, and differences in maternal diet in affluent countries. The lack of exposure of babies to particular bifidobacterial species and/or the elimination of bifidobacterial species from the gut through the use of antibiotics might reduce the exposure of children to important bacterial antigens at a critical time in the maturation of the immune system. Hence, the difference in national prevalence of allergies among children offers scope for investigating the possible preventive role of specific gut bacteria against atopic diseases.
Young and colleagues have recently published the results of a study which compared the faecal populations of bifidobacteria from children aged 25–35 days in Ghana (low prevalence of atopy) and New Zealand and the United Kingdom (high prevalence countries).14 Natal origin influenced the detection of bifidobacterial species: faecal samples from Ghana contained almost exclusively Bifidobacterium infantis whereas those of the other children did not. Choosing species on the basis of the bacteriological results, the authors tested bifidobacterial preparations for their effect on cell surface markers and cytokine production by dendritic cells harvested from cord blood. Dendritic cells were used because they are principal antigen-presenting cells that are present at mucosal surfaces, including that of the gut, and are therefore likely to have an important role in the interplay between the gut microbiota and the immune system.
Bifidobacterial species-specific effects on dendritic cell activation were observed insofar as CD83 expression was increased and interleukin-10 production was induced by Bifidobacterium bifidum, Bifidobacterium longum, and Bifidobacterium pseudocatenulatum. One or more of these species were detected in the faeces of 40 out of 46 New Zealand and United Kingdom children but in only a few (B. longum: 2 out of 32) of the samples from infants living in Ghana. B. infantis, common in the faeces of babies from Ghana, failed to produce these effects. It was concluded that B. infantis would not trigger the activation of dendritic cells, thus effectively down-regulating the immune response and favouring immunological tolerance. B. bifidum, B. longum, and B. pseudocatenulatum, on the other hand, in susceptible infants (basis not yet known) would probably drive the development of T helper 2 (Th2) cells which are implicated in allergic responses. In support of this view, germ-free mice tolerized to ovalbumin have been reported to produce IgE after subsequent systemic challenge with this antigen, whereas formerly germ-free mice whose gut was colonized by B. infantis did not produce IgE.15 Further investigations of the molecular interplay between bifidobacteria, human dendritic cells, T cells, and allergens are clearly required and may provide the first clear evidence of ‘immunological Freudianism’ in relation to human diseases.
The prescience of Dubos and colleagues in the development of experimental science based on the concept of biological Freudianism is admirable. Freud postulated that an ‘unconscious’ mental process or event was not just one that was out of consciousness at a given time, but was one that cannot, except through psychoanalysis, ever be brought to mind. Nevertheless, the unconscious exerted a dynamic and determining influence upon the conscious mind. Like a magnificent iceberg, the bulk of which is below the surface of the sea, the gut microbiota of early life, unseen and unfelt, just like the ‘unconscious’, conditions and shapes its host for later life. To Dubos and colleagues, and now to scientists of the twenty-first century, the physiology of the mature animal is but the tip of the iceberg and a reflection of time and biological memory.
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