Gaining Acceptance of Microbial Endocrinology

As can often be the case in any endeavor that seeks to introduce a paradigm-shift in thinking, the introduction of neuroendocrine-bacterial interactions as a hitherto unrecognized mechanism in the pathogenesis of infectious disease was met not only with initial skepticism, but also downright hostility. At a mid-1990s meeting




Fig. 1.3 The experiment that launched the field of microbial endocrinology. Yersinia enterocolitica culture plates in 1991 showing that bacterial growth in serum-based medium was enhanced in the presence of the neuroendocrine stress hormone norepinephrine, but not epinephrine or control diluent

in Toronto that focused on the role of neuroendocrine mediators and immunity in drug addiction, I gave a microbial endocrinology-based lecture as part of a session on stress and its relationship to drug addiction sequelae such as increased prevalence of infectious disease in drug addicts. At the conclusion of my talk before I could take any questions, the session chair addressed the audience and said that my ideas were so radical that they should not be taken seriously, and the audience should in essence forget what I just presented. More than one member of that audience has approached me over the years to recount that episode and the shock of the audience being told to disregard what they had just heard as well to ask why I did not get mad (which I did not). Such opposition, although admittedly more restrained, was also encountered during the early years in terms of gaining acceptance into the scientific literature. I have been told by more than one individual that the integration of microbial endocrinology into mainstream infectious disease research would have been accelerated if I had chosen to publish in more microbiology-oriented journals. However, my choice to publish in journals not typically read by microbi-ologists was dictated not by choice, but instead by necessity. My early attempts to publish in basic microbiology-based journals were universally met with rejection. Undoubtedly, while one may take the convenient road of blaming the reviewer for failure to consider a highly interdisciplinary approach where it is often not possible to address all the questions regarding each of the fields, I shall instead take a fair share of the blame since it is also the responsibility of the author to educate the reader of the need to go beyond traditional thinking.

With that said, I have also come to recognize that one of the defining reasons that these early papers were rejected from basic microbiology-centric journals was the reliance on phenomenology rather than mechanisms. My own training in the clinical laboratory sciences and subsequent work in hospital laboratories before entering graduate school in 1977, ingrained in me a powerful sense of the clinical side of microbiology. And that side is one that is grounded in growth, for without evident growth and sufficient numbers of bacteria, little can be done, even today, to diagnose suspected bacterial disease. Thus, it seemed to me at the time (and still does today) that the ability to show growth-related effects of neuroendocrine hormones on bacteria would have profound implications for the study of the host factors, which influence susceptibility to infectious disease. However, I was surprised that this was generally not the case. A similar refrain ran through those early reviews that the demonstration of effects on growth were phenomenological in nature and what was needed to be shown was the mechanism(s) by which neuroendocrine hormones could influence bacterial physiology. Due largely to the availability of an ever growing arsenal of molecular biological techniques, phenomenology was to be eschewed in favor of dissecting molecular mechanisms. While I do not mean to begrudge nor demean the value of mechanistic studies, one may argue that many of the advances in the treatment of disease have been made through the observation of phenomena for which no mechanism at the time of discovery was available. Antibiotic development owes itself largely to the observation of phenomena. While the requirement for molecular analyses currently reigns dominant in the majority of first-tier microbiology journals, the relegation of phenomenological studies to the status of second-class research ignores its historically pivotal role in fueling scientific and medical advances. A number of recent articles examining the failure of genomic-based strategies to lead to the discovery of new antimicrobials that ultimately make the transition from the lab bench to the clinic have addressed this very point (Barrett 2005; Finch 2007).

My reasoning for discussing the relative merits of phenomenology versus molecular analyses is not to point out my own shortcomings in the area of molecular analysis, but to offer a cautionary note to other researchers who may choose to explore microbial endocrinology. Catecholamines, which to date have been the principal neuroendocrine hormones that have been examined in the microbial endocrinology field by virtue of their prominence in the stress response, represent but a tiny sliver of the spectrum of neuroendocrine hormones that can be examined for potential interaction with both pathogenic as well as commensal bacteria. For example, gamma amino butyric acid (GABA), the primary inhibitory neurotrans-mitter in the mammalian brain, is produced in such large amounts by bacteria in the gut that a role for bacterial-derived GABA has been proposed to account for the altered organ function (encephalopathy) that is part of the pathogenesis of advanced liver disease and sepsis (Minuk 1986; Winder et al. 1988). In fact, GABA produced by bacteria, such as those contaminating a distilled water apparatus, have been found not only to confound neurotransmitter binding studies with mammalian cells (Balcar 1990), but also to possess a high affinity binding protein that resulted in one of the first bioassays for GABA that was entirely bacterial-based (Guthrie and Nicholson-Guthrie 1989; Guthrie et al. 2000). In this book, Chap. 2 by Victoria Roshchina provides an exhaustive review of the wide breadth of neurohormones that are found in prokaryotes that we otherwise only associate with multicellular eukaryotic systems.

By utilizing a microbial endocrinology approach, researchers can further our understanding of how host and bacteria, both commensal and pathogenic, interact in the gut (or at other sites). That approach, in turn, could provide insights into not only homeostasis but also other medical conditions that involve gut pathology that upon verification could enable the design of new, innovative medical interventions. Although researchers realized more than 100 years ago that the mammalian gut is innervated, how this system interacts with the gut microbial flora remains largely a mystery. Further, large amounts of neurochemicals are produced within the gut that find their way into the gut lumen where the possibility of interactions with the gut microflora exist and remain largely unexplored. For example, milligram quantities of serotonin are produced by the gut that can be recovered from the lumen, although the physiological reason for this production is not well understood. Could it be that serotonin produced by the mammalian gut has some hitherto unknown interaction with a specific part of microbial population? Thus, examination of any such serotonin-bacterial interaction will depend on both phenomenology and molecular analyses to provide as complete a picture as possible of the relevance of microbial endocrinology to both homeostasis and disease.

Further, the bidirectional nature of bacterial neuroendocrine interactions contained within the theory of microbial endocrinology also suggests that bacteria can influence mammalian function. More recent work utilizing metabolomics to compare the blood metabolic profile of conventional-reared and germ-free mice revealed that the gut microbiome contributed to the concentration of neuroactive components in the circulation (Wikoff et al. 2009). That the presence of a micro-bial community within the gut, and inherent interactions between the host and gut microflora, is crucial to an animal's neurological health was demonstrated in 2004 when Nobuyuki Sudo and colleagues at Kyushu University in Japan examined the role of microbial colonization on the hypothalamic-pituitary-adrenal response to stress in gnotobiotic, germ-free, and conventionally-reared mice (Sudo et al. 2004). Not only did the development of host neural systems that control the physiological response to stress depend on postnatal microbial colonization of the gut, but also reconstitution of gnotobiotic mice with feces from specific pathogen-free mice altered their subsequent neurohormonal stress response. And more recently, Li et al. (2009) at Texas Tech University showed that diet-induced alteration of gut microbial diversity can even affect memory and learning in mice. Thus, we are just beginning to understand the degree to which microbial diversity is crucial not only to the development and regulation of normal gastrointestinal function, but also to how it may interface with the host's neurophysiological system.

And crucially, does this bidirectional nature of bacterial-neuroendocrine interactions contained within microbial endocrinology also imply that gut neuronal activity may as well influence local bacterial ecology and vice versa? In attempting to answer this question, a new hypothesis has recently been proposed based on the ability of bacteria as well as other microbes to both recognize and synthesize neuroendocrine hormones. According to this hypothesis, the microbiota within the intestinal tract comprise a community that interfaces with the mammalian nervous system that innervates the gastrointestinal tract to form a microbial organ which enters into a symbiotic relationship with its mammalian host that is governed by bacterial-neuroendocrine (microbial endocrinology) interactions (Lyte, 2009a). The consideration of a microbial organ within the gut that interfaces with the host through microbial endocrinology-based interactions involving the host's nervous system provides for a new paradigm with which to understand and design new therapeutic approaches for a range of clinical diseases.

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