Conclusions and future directions
Looking back at the first three decades of the 20th century is an experience, for the modern scientist interested in the gut-microbiome-brain connection, akin to an anthropological archeologist discovering an ancient civilization. Superficially, the historical markings are dominated, as they often are in medicine, by the myopic and biased view toward the so-called ‘great/infamous men, great/infamous discoveries and claims’. Medical historians focus on heroes and anti-heroes in the fights against ignorance and disease. Yet the complete chronicles are never as simple as Lane vs. Alvarez. Psychiatrist and medical historian Iago Galdston warned against losing context and understanding with such chronicles - ‘
The essential deficiencies in academic medical history derive from its commitment to the “great man, great discoveries” view of medical history and of medical progress…
those who labour long at such gathering are prone to mistake their miscellany of accumulations for real knowledge and deep understanding’ [
116]. Sifting through the archives, moving past the outer walls of intestinal autointoxication dominated by Metchnikoff, Lane, Cotton and non-physician opportunists, one finds rational works that were in line with modern-day ‘discoveries’ - antecedents to what we are now, in many ways, relearning and constructing related to the importance of the gut integrity and its microbial residents. An examination of the early history of oral bacteriotherapy reveals hundreds of studies dedicated to the intestinal flora and its transformation. Although many of these studies reported conflicting findings, and the methodologies were most certainly based on rudimentary technique by the standards of today, there were more than enough clues to suggest that the primary premise – i.e. gut-derived microbes and/or microbial breakdown products
may play a role in mental health – was correct.
Related concerns of intestinal permeability, SIBO, hypochlorhydria, carbohydrate intolerance, endotoxins, modernity and dietary matters, gut microbe vaccines, the oral administration of lactic acid bacteria, colonic microbiota transfer, and qualitative/quantitative changes to the intestinal microbiota were all discussed as being relevant to mental health and cognition. For a variety of reasons, not the least of which included lack of human evidence and broad claims that autointoxication was the exclusive root of all neuropsychiatric disorders, these discussions disappeared from mental health publications. One cannot say that the disappearance of autointoxication was driven exclusively by the emergence of evidence-based medicine because in many cases it would be supplanted by unverifiable Freudian psychoanalytic viewpoints. Still, clinicians pleaded for more than studies in rodents, rabbits and monkeys – they needed convincing human research so that medicine could be practiced not by hypothesis - and yet none would be forthcoming. Unwarranted colectomies and unfounded marketing promissory notes for good health via friendly microbes would obscure legitimate research pathways that might have otherwise been followed with vigor. They also created a superficial and simplified medical history based on great or infamous men. Over time, autointoxication would become known only for these surgical and marketing extremes, ultimately becoming a medical outcast – or, as it was written just prior to our hypotheses papers, ‘a triumph of ignorance over science’. Yet, as the French physiologist Claude Bernard wrote, “That which we know is a great hindrance to our learning that which is yet unknown to us”. By the year 2000 we “knew” intestinal toxemia and friendly microbes for mental health to be exclusively a medical folly, one associated with charlatans and so-called colon cleansers.
All of this contemporary work, as described above, forces us to have a fresh look at the inner dialogue within the historical intestinal toxemia publications. Obviously the modern advances are not a validation of colectomy, L. bulgaricus as a fountain of youth, or colon cleansers as a solution to all the potential ills of what may indeed be a type of intestinal ‘toxemia’. However, modern historical reviews that stick exclusively to the redundant and superficial narrative of “autointoxication was the arena of charlatans, it was wrong and disproven by Alvarez” contribute little, and indeed provide a disservice to the medical minds that were on a rational path. Of course, reminders of the dangers of practicing medicine by hypothesis alone have their place. However, it may be time to re-write some of the history books or at least qualify them; the legacy of Lane and Cotton should not negate that of those who found that a high fat diet and stress increased intestinal permeability and bacterial translocation, or those who reported successful outcomes with simple fecal transplantation. Why should the legacy of those who instilled fears into healthy adults regarding autointoxication, as a means to sell pseudoscientific contraptions, obscure that of rational physicians who saw some legitimacy to intestinal toxemia as relevant to unhealthy populations? It is fairly obvious many of those physicians rationally discussing intestinal toxemia a century ago were confronted with unhealthy patients (IBS, ME, FM, migraine, mood and anxiety disorders) that would today be classified with elaborate diagnostic criteria and codes.
Top-down, psychosomatic-oriented theorists [
117] continue to haul out Lane and Cotton as exhibits A and B to exclaim that autointoxication as it relates to mental health was nonsense [
118] - with nary a mention of the history of the other not-so-Great Men, and the emerging gut-brain-microbiome research. Psychosomatic researchers continue in their quest to show that IBS is provoked by neuroticism – non-prospective, x-sectional population studies show high degrees of neuroticism correlate with IBS severity, and the Pubmed abstracts boldly conclude that ‘
These results suggest that neuroticism is involved in the pathophysiology of IBS’ [
119]. These strong assertions are accompanied by nary a mention of gut microbiota. What if it were the opposite? What if the bottom-up microbiota is involved in the provocation of neuroticism among IBS patients? Or what if, as is more likely the case, it lays somewhere in the middle ground? Once again, psychiatrist and historian Iago Galdston, provided advice for research and direction (in 1954) of what he hoped would be a new era in psychosomatic medicine, one without labels of “type” (e.g. Alvarez’s go-getter “ulcer” type etc.) as they pertain to disease. He advised a shift to the middle ground – ‘
we will learn to understand the experiences of man in terms of multidirectional relations, and with a simultaneity that is free of the naiveté and artificiality of straight line sequential causality…when we have come to such an understanding, psychosomatic medicine will be truly holistic. But then, may I whisper it softly, it will no longer be psychosomatic medicine. It will be medicine such as Hippocrates could comprehend, and Paracelsus might celebrate – a keen reflection on the interrelations of Microcosm and Macrocosm’ [
120].
With all our modern advances, we once again arrive at a place of theory, albeit slightly more sound in its support. In order to truly advance from the days of Metchnikoff we must expand the bench and rodent work and bring it into the clinical investigative setting, and not to do so, of course, for the purpose of yet more anecdote. The undoing of intestinal toxemia and the idea of probiotics for brain health was not Alvarez, it wasn’t the charlatans and the high colonics, nor was it for the want of more rodent and laboratory studies - its undoing was the lack of convincing controlled clinical work. It seems remarkable, given the supporting scientific rationale, that there has been so little in the way of clinical research. At this point, as highlighted throughout this series, we already have extensive experimental research from which to guide probiotic strain selection for clinical experimentation – e.g. strains that can lower LPS burden; strains that lower oxidative stress, and systemic inflammatory cytokines; strains that have a beneficial influence on stress resiliency; strains that can influence neurotransmitter precursor levels via amino acids and neuronal membrane structure via fatty acids; strains that can attenuate intestinal permeability; strains that can lower uremic toxin burden. It may take decades to further elucidate the divergent ways in which these and other specific probiotic strains may interact, alone and in combination with each other, to influence markers relevant to animal models of depression and/or anxiety. This critical work should, of course, continue. However, the mouse models will always be lacking the clinically-relevant context of mood-related diet, physical activity, environmental toxin exposure and other variables within lifestyle medicine. Probiotics, even if they do influence the human GABA system, are not synthetic benzodiazepines; as discussed throughout this paper, orally administered microbes are much more likely to converge with lifestyle variables within the gut lumen.
This presents a quandary for experimental researchers examining the use of probiotics in the behavior of animals as a means to inform clinical utility. Since environmental enrichment factors are known to interact with psychological stress and diet, both of which interact with gut microbiota, a near-endless combination of animal housing and dietary variables related to microbes must be investigated - from running wheels, tunnel positioning, wood, plastic and soil materials [
121‐
123]. To put it more clearly, a high-fat diet can compromise brain function as previously described, however, the detrimental cognitive effects of too much fat can be significantly offset by the degree of naturalistic environment [
124] in which the animals reside! Could there be probiotic strains that might appear to be without value in one model, yet provide value when interacting with environmental variables such as physical activity? As for diet itself, a multitude of dietary variables could potentially interact with probiotic administration in animal behavioral studies. The potential value of a specific strain or groups of strains of probiotics may be dependent, or put another way, may be obscured, by a host of dietary variables. Despite more than ample scientific justification, only our own group [
112] and a few others have begun to explore the potential of probiotics to influence
human mood, cognition and fatigue. The results from these early studies, in concert with what is now a fairly robust body of experimental research, would suggest that we have now passed the time in which clinical investigations should be approached with vigor. Moreover, the work of Michaël Messaoudi [
113,
114] and colleagues from France deserve special accolades, for this group has been simultaneously sampling the effects of probiotcs on behavior in animal models and mental health in clinical settings. Human intervention studies with probiotics related to allergy risk, including prenatal/early life administration, have been ongoing for more than a decade – perhaps it is time for neuropsychiatric researchers to catch up.
The strain specific focus is clearly justifiable in the scientific examination of a particular probiotic preparation or commercial ‘functional food’ for mental health. Research not only shows that heat-killed bacteria may have strain-specific benefit, the research also indicates that there are broad and divergent effects of lactic acid bacteria in their interaction with the immune system [
125]. If we isolate single strains, we should indeed have a good degree of certainty that its potential influence is that which is desired in immune function over the long term. Less known is the extent to which an individual strain might influence the overall microbial ecology of the gut when consumed for extended periods of time. Could a single strain diminish diversity? The isolated strain approach also carries a less speculative caveat; it tells us little about the potential synergistic benefits of multi-species lactic acid and other bacterium found in traditional diets and fermented foods. Are we obscuring microbial benefits with a myopic view to single patented and/or commercial strain? Beneficial microbes are abundant in indigenous diets, and an estimated 35% of all lactic acid bacteria isolated from raw fruits and vegetables can survive gastric conditions [
126]. Beyond lactic acid bacteria we can consider the previously mentioned studies on live
M. vaccae added to the dietary of animals – as a soil-derived organism,
M. vaccae can easily find its way onto plant foods. It seems the links between traditional dietary patterns, mental health and microbiota, are far more complex than generally appreciated. We simply cannot view the gut-brain-microbiota axis as isolated from diet, the context of its macro and micronutrient as well as phytochemical composition. This fact underscores the potential futility of probiotic administration to a sedentary individual with depression that may be co-consuming a fast-food style diet with the addition of pharmaceuticals and/or dietary chemicals (e.g. sucralose) that are otherwise capable of altering the intestinal microbiota [
127]. These are just some of the clinical realities not addressed in simple experiments with rodents in an elevated plus maze.
Have we advanced, will we advance?
In the real-world of mental healthcare provider and patient, one that occurs in a holistic setting involving lifestyle factors, the odds of a single strain of probiotic bacterium providing clinically meaningful and long-lasting benefit, not simply statistically significant differences vs. placebo, could not be estimated to be high. Yet, probiotic experiments with rodents, just as they did in the day of Metchnikoff (“Yoghurt – the anti-toxin of old age” May, 1913) [
128], generate headlines such as “Forget Prozac – Try Probiotics” (Sept 10, 2012) [
129]. Widely disseminated inferences that, based on current rodent research, probiotics are a substitute for fluoxetine are not only alarming, such headlines should ultimately force us to ponder to what extent we have truly advanced from Metchnikoff.
Today, in the new era of Autointoxication II, what is old is new again – preliminary non-clinical research efforts, based on metagenomics and microbiome projects, are commercially co-opted to support a financially lucrative probiotic business wherein unsubstantiated claims abound [
130]. Metchnikoff’s history is repeating itself - in a 2011 study published in
PLoS One, Japanese researchers showed that a strain of
Bifidobacterium animalis can increase longevity in mice via its influence on gut polyamine production [
131]. In 2012 researchers linked negative mood, social anxiety and distressed personality type, if you can imagine, to indoxyl sulfate levels in a healthy (n = 1502) population [
132]; meanwhile, in other news, there are now commercially available probiotic formulas in North America that are clearly positioned, in their direct product names and associated claims, as anti-aging and anti-stress formulas [
130]. It seems fair to ask, at this juncture, when will this research pathway truly enter and
emerge from phase I of translational medicine? Will all of this work become another clinically meaningless forgotten city in the future, one destined to once again be explained away by conflicts over toilet training? If there is a future role of probiotics in cognitive and mental health, one relevant for clinicians, and one that can only be proven or disproven by human intervention studies, it is almost certainly as our group hypothesized it to be – an adjuvant to well-established first-line care.
Competing interests
ACB and EMS have no competing interests. ACL has received consulting fees from Genuine Health, Toronto, Canada.
Authors’ contributions
ACB, ACL and EMS contributed equal time and effort in the investigation, research and drafting of this manuscript. All authors read and approved the final manuscript.