The connection between the digestive system and the brain is not something new to scientists; the term “gut-brain axis” has been around ever since studies showed that information flow between the gastrointestinal tract and the brain is not restricted to efferent (downstream) mechanisms — as when stress induces diarrhea (1) — but that the information goes upward as well.
The gut has its very own “little brain,” the enteric nervous system (ENS), which constantly informs the “big brain” (central nervous system, or CNS) about its status and well-being. Much of this communication seems to occur through the vagus nerve — comprised of mostly afferent (upward-projecting) nerves.
The gut microbiota: New kid in town
More recently, however, the picture has become increasingly complex with the intestinal microbiota as the “new kid in town.” This community of microorganisms is a zoo of many different bacterial species (more than 1000), along with viruses, fungi, and other microbes. Only after the human genome project were many new ‘omics technologies available that allowed for exploration of the microbiota and their genes.
Life without a microbiota
Scientists working with germ-free mice noticed something that was at first incidental: these mice, bred and raised under highly sterile conditions without a resident microbiota, behaved abnormally. That is, compared to normal (non-sterile) animals, they showed less fear and shyness in new situations, such as an open field or maze; they were more exploratory, not avoiding bright lights in their cages, and were relatively asocial and aggressive toward their littermates. But when scientists began to investigate this further, they found that colonizing these mice with a normal intestinal microbiota — from other mice, from another animal species, or from humans — their behavior normalized. Sometimes the behavior became normal even when the germ-free mice were colonized by only a single bacterial species.
By now, many research laboratories around the world are following up on this line of study. At least for mice, the presence of bacteria in the gut are clearly needed for the development of normal behaviors. We know the microbiota (whether rich and diverse or poor and limited) takes part in the development of various organs and functions and also contributes to brain development.
Some have reasoned if the presence or absence of bacteria in the gut affects the brain and its functioning, then other manipulations of the intestinal ecosystem might change brain function as well. These manipulations could include probiotics (“live microorganisms that, when administered in adequate amounts, confer a health benefit on the host”) (2), or prebiotics (“ a substrate that is selectively utilized by host microorganisms conferring a health benefit”) (3), or synbiotics, a combination or pro- and prebiotics. The term “psychobiotics” was coined to describe how these kinds of interventions could affect the brain (4).
But delivering these compounds to a sterile gut may not be the only way to affect brain function and development; depleting or eliminating the commensal microbiota by excessive use of antibiotics has a detrimental effect in laboratory animals. Also, transferring the microbiota of sick animals to healthy animals makes the recipients show similar symptoms and behaviors as the sick ones. And sometimes the reverse can be true: transferring a healthy microbiota to diseased animals is beneficial.
Translation into humans
In at least one case — recurrent C. difficile infection — transferring the fecal microbiota from a healthy person to a sick person cures the infection (5). But not all of these techniques are easily applicable in humans. So far, no “psychobiotic” exists — nor is there irrefutable evidence for the existence of a microbiota-gut-brain axis.
In humans, many researchers are taking a different approach: to investigate microbiota composition, diversity, and relative abundance of single strains in diseases associated with CNS functions or originating in the CNS — predominantly neurological and psychiatric diseases. By now, the list of diseases associated with microbiota “dysbiosis” include major depressive disorders, anxiety and panic disorders, attention-deficit hyperactivity disorders, autism spectrum disorders, Parkinson’s disease, Alzheimer’s disease, and other neurodegenerative disorders, as well as multiple sclerosis and amyotrophic lateral sclerosis (6), not to mention all the diseases in which high psychiatric comorbidity is common — such as functional bowel disorders (7). But correlations and one-time assessments cannot prove a causal relationship between a dysbiotic microbiota and a brain-related disorder.
The psychobiotic path
If neurological or psychiatric disorders could be successfully treated with psychobiotics, we would have evidence that the microbiota was in some way causally related to the disorder.
On the other hand, if commonly-available probiotics, on the market for many years, had consistent effects on CNS functions, we would already know; these probiotics have not been successful in general, as shown in many systematic reviews and meta-analyses of even more randomized placebo-controlled trials (8).
For psychobiotics, we may have to turn to other bugs — those found in the human microbiota and administered back therapeutically. The development of these “next generation” probiotics has to follow a pathway known from pharmacological research: selecting one specific strain out of many with promising CNS action, testing it in animal disease models, and exploring its pathways (mediation). From there, the test should be carried out in healthy humans with comparable read-outs (behaviors) before exploring the same in a selected patient group. The final step is a clinical trial with careful evaluation of individuals’ disease-associated behaviors and psychological symptoms.
Several recent “psychobiotic” developments have followed this path, and some have not survived the translation from (successful) animal testing to humans (9). To review the current literature, the Enck lab conducted a systematic review (10) and identified one compound suitable for further development: Bifidobacterium longum 1714, tested for central effects in animals (11) and humans (12). Stay tuned for the story of this promising bacterial strain.
This is part 1 of a series covering “microbiota” provided by Paul Enck from the Tübingen University Hospital and science writer Kristina Campbell. Continuous updates on microbiota research can be found at www.gutmicrobiotaforhealth.com.
- Elsenbruch S, Enck P. The stress concept in gastroenterology: from Selye to today. F1000Research. 2017;6:2149.
- Hill C, Guarner F, Reid G, Gibson GR, Merenstein DJ, Pot B, et al. Expert consensus document. The International Scientific Association for Probiotics and Prebiotics consensus statement on the scope and appropriate use of the term probiotic. Nature reviews gastroenterology & hepatology. 2014;11:506-14.
- Gibson GR, Hutkins R, Sanders ME, Prescott SL, Reimer RA, Salminen SJ, et al. Expert consensus document: The International Scientific Association for Probiotics and Prebiotics (ISAPP) consensus statement on the definition and scope of prebiotics. Nature reviews gastroenterology & hepatology. 2017;14:491-502.
- Dinan TG, Stanton C, Cryan JF. Psychobiotics: a novel class of psychotropic. Biological psychiatry. 2013;74(10):720-6.
- Quraishi MN, Widlak M, Bhala N, Moore D, Price M, Sharma N, et al. Systematic review with meta-analysis: the efficacy of faecal microbiota transplantation for the treatment of recurrent and refractory Clostridium difficile infection. Alimentary pharmacology & therapeutics. 2017;46:479-93.
- McFarland LV, Dublin S. Meta-analysis of probiotics for the treatment of irritable bowel syndrome. World journal of gastroenterology. 2008;14:2650-61.
- Enck P, Mazurak N. Dysbiosis in Functional Bowel Disorders. Annals of nutrition & metabolism. 2018;72:296-306.
- Mazurak N, Broelz E, Storr M, Enck P. Probiotic Therapy of the Irritable Bowel Syndrome: Why Is the Evidence Still Poor and What Can Be Done About It? Journal of neurogastroenterology and motility. 2015;21:471-85.
- Kelly JR, Allen AP, Temko A, Hutch W, Kennedy PJ, Farid N, et al. Lost in translation? The potential psychobiotic Lactobacillus rhamnosus (JB-1) fails to modulate stress or cognitive performance in healthy male subjects. Brain, behavior, and immunity. 2017;61:50-9.
- Wang H, Lee IS, Braun C, Enck P. Effect of probiotics on central nervous system functions in animals and humans – a systematic review. Journal of neurogastroenterology and motility. 2016;22:589-605.
- Savignac HM, Kiely B, Dinan TG, Cryan JF. Bifidobacteria exert strain-specific effects on stress-related behavior and physiology in BALB/c mice. Neurogastroenterology and motility. 2014;26:1615-27.
- Allen AP, Hutch W, Borre YE, Kennedy PJ, Temko A, Boylan G, et al. Bifidobacterium longum 1714 as a translational psychobiotic: modulation of stress, electrophysiology and neurocognition in healthy volunteers. Translational psychiatry. 2016;6:e939.
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