Jeremy Appleton, ND

Vis Medicatrix Naturae

The gut-brain axis is a communication network that links the central nervous system (CNS) with the enteric nervous system. The anatomical network includes the brain and spinal cord (CNS), autonomic nervous system (ANS), hypothalamic-adrenal-pituitary (HPA) axis, and the innervation of the gastrointestinal (GI) tract, or enteric nervous system. Both neural and hormonal routes of communication allow the brain to influence intestinal activities, including activity of functional effector cells (ie, immune cells, epithelial cells, enteric neurons, smooth muscle cells, interstitial cells, etc).

The Gut-Brain Axis

These cells are simultaneously under the direct influence of the gut microbiota,¹ leading some to refer to the network by the longer name “microbiota-gut-brain axis.” As these immune, endocrine, and neural pathways are increasingly detailed in the medical literature, linkages are being established between emotional and cognitive centers of the brain and peripheral intestinal functions, modulated by the gut microbiota.²

The gut-brain axis not only ensures the proper maintenance of GI homeostasis, but also appears to influence psychological features such as affect, motivation, and higher cognitive functions.² Clinically, several disorders of the CNS (eg, depression, anxiety, and especially autism spectrum disorders) have well-established links to functional disorders of the GI tract, and disorders of the GI tract often have psychological comorbidities.³

The traditional view has been that microorganisms are not of particular importance in the development and function of the CNS, or in the physiology and regulation of mood. Although gut-brain connections have been studied for decades – providing extensive research insight and information about the axis connecting the gut-associated immune system, enteric nervous system, and gut-based endocrine system⁴ –these findings have yet to gain broader acceptance by the conventional psychiatric and neurological research communities. Nonetheless, evidence now makes clear that psychological state (eg, stress) directly affects the composition of the gut microbiota and, conversely, that the microbiota is involved in controlling mood-related behaviors.^5-9 Gut microbes may even be critical in the development of the brain itself.¹⁰ By extension, it should not be surprising that diet also influences cognitive function via its effects on the gut microbiome.¹¹

Mechanisms of the Gut-Brain Axis

“Emotional Motor System”

The concept of an “emotional motor system” was introduced in 1996 as a way of conceptualizing CNS-mediated processes on bodily functions, including the immune response of the gut.¹² According to this model, several systems operate in parallel to mediate the effect of emotional states on bodily systems, including GI function. These include the ANS (sympathetic and parasympathetic branches), HPA axis, and various pain pathways. Consider the role of the ANS in controlling GI mucus secretion, which governs the composition and quality of the intestinal mucus layer. This mucus layer is habitat for the majority of enteric microbiota, which reside within the secreted matrix of biofilm.¹³ The ANS also influences immune activation in the gut, for example by directly modulating macrophage and mast-cell responses to luminal bacteria. In the other direction, the gut microbiota appear to be critical for normal gut intrinsic primary afferent neuron excitability.¹⁴ HPA axis dysregulation is a common feature of major depression, characterized by elevations in cortisol in the plasma and corticotropin-releasing factor (CRF) levels in the cerebrospinal fluid, along with a failure to suppress cortisol in response to dexamethasone challenge.¹⁵

Stimulation of Signaling Molecules

Gut microbes communicate within their self-secreted biofilm via quorum sensing, but are also able to sense signals directly from gut epithelial cells. The various signaling molecules and their role in host immune modulation have been characterized extensively. The secretion of cytokines, catecholamines, serotonin, and opioid peptides, such as dynorphins, into the gut lumen is stimulated by neurons and carried out by immune cells and enterochromaffin cells. (Enterochromaffin cells line the gut lumen and play a critical role in GI regulation, especially intestinal motility and secretion. They are activated by the vagus nerve.) The CNS plays a major role in stimulating and governing the release of these molecules. Serotonin secretion into the stomach lumen, for example, is modulated, at least in part, by thyrotropin-releasing hormone, a central mediator of the stress response to cold temperatures.^16-17 Stress induced by cold temperature also causes secretion into the jejunum of mast-cell products, such as tryptase and histamine.¹⁸ Other mast-cell products, such as serotonin and CRF, may also be secreted into the gut lumen. Both norepinephrine and dynorphins are thought to be released into the gut lumen when gut homeostasis is disrupted.¹⁹

Epithelial Barrier Function

While it was once a theoretical notion, it has now been amply demonstrated that stressful stimuli alter permeability of the intestinal epithelium, allowing bacterial antigens and lipopolysaccharides to leak into the circulation and become humoral influencers, stimulating immune responses in the intestinal mucosa and beyond.^20-24 These stress-induced alterations in epithelial cell junction permeability can be seen as actual morphological changes to colonic epithelial cells, altered colonocyte differentiation, decreased expression of mRNA encoding tight junction proteins (ie, reduced genetic expression of tight junction protein 2), overproduction of interferon-γ, and activation of glial and mast cells in the gut.²⁵ Resultant intestinal permeability defects are thought to underlie the chronic, low-grade inflammation observed in disorders such as depression.²⁶

The Role of Probiotics

Inflammation Metabolism

Probiotics represent an attractive intervention for patients with depression, in part because patients with depression frequently exhibit increased expression of pro-inflammatory cytokines, such as interleukin (IL)-1β, IL-6, tumor necrosis factor-alpha (TNFα), and interferon-gamma (IFN-γ), as well as C-reactive protein (CRP).^27-29 These markers have been associated with specific symptoms of depression.^30,31 The transcription of some of these same cytokines is also known to be “primed’ by gut microbiota, triggering the so-called inflammasome pathway. Short-chain fatty acids (eg, butyrate, propionate), produced via fermentation of dietary fiber by gut bacteria, inhibit NF-κB, thus diminishing production of pro-inflammatory cytokines.^32,33

Gut microbiota are well known to help maintain tight junctions between gut epithelial cells. It should therefore come as no surprise that dysbiosis and associated increases in intestinal permeability are now recognized features of rheumatoid arthritis, Alzheimer’s disease, asthma, autism spectrum disorders, and other systemic ills, both inflammatory and otherwise. In recent years there has been an explosion of research validating the mechanisms and role of the microbiome and probiotics in managing inflammatory conditions, particularly inflammatory bowel disease (IBD), but also throughout the body.^34-41

Depression is increasingly recognized as having an inflammatory component. Anti-inflammatory drugs, such as cyclooxygenase (COX)-2 inhibitors, have previously demonstrated efficacy in major depression.⁴² Even the mainstream media has picked up on the connection between depression and inflammation.^43-45 An inflammatory phenotype contributes to depression in a number of ways, notably by altering neurotransmitter metabolism, reducing the availability of neurotransmitter precursors, and by activating the HPA axis.⁴⁶ This inflammation is thought to be caused by intestinal permeability defects. In particular, gut-derived endotoxins called lipopolysaccharides (LPS), which originate from the outer membranes of gram-negative bacteria, trigger immune activation through Toll-like receptor 4 (TLR4).⁴⁷ Reducing inflammation of this origin may thus lead to improved regulation of the HPA axis and neurotransmitter activity.

The Serotonergic System

In the CNS, serotonin is involved primarily in regulating emotions and stress, sleep, and appetite. In the GI tract, serotonin modulates intestinal secretions, GI motility, and other critical functions. Changes to the gut microbiome have been shown to profoundly influence neurotransmission of serotonin in both the PNS and CNS.³² Probiotics could potentially improve CNS symptoms by promoting the production of free tryptophan, which then serves to increase the availability of serotonin.

However, many questions remain about how bacteria signal the brain; the general mechanisms described above are slowly being unraveled and elaborated. We still lack a definitively demonstrated microbiome-endocrine-based mechanism that can account for the influence of gut microbiota on behavior. Is it actual in-vivo production of a neurochemical by specific microorganisms that is responsible for changes in behavior, or is it non-neurochemical aspects of the microorganisms, such as cell wall components interacting with immune cells in the gut? When will researchers demonstrate receptor-specific binding within the gut, or at some extraintestinal site, for specific neurochemicals produced by organisms of the microbiota? What individual components of bacteria are mediating their effects? When will the nascent field of metabolomics advance sufficiently to clarify the signaling cascades and roles of bacterial products?⁴⁸

Research in Animals

As early as 1998, oral administration of a single, unique bacterium in the gut (Campylobacter jejuni) to rats in subclinical doses was found to lead to anxiety-like behavior without an accompanying immune response.⁴⁹ Later research confirmed that introduction C jejuni caused anxiety-like behavior in mice, with concomitant activation of neuronal regions in the brain that were dependent on information received from the gut via the vagus nerve.⁵⁰ Around the same time, Sudo and colleagues showed that administering commensal Bifidobacterium species could reverse exaggerated HPA axis responses to restraint stress.⁵¹ This revolutionary observation motivated other research groups to investigate the role of the host gut microbiota on CNS function. While earlier animal studies had suggested such effects were only possible during a critical time-frame of early life and adolescence, more recent research challenged this hypothesis, demonstrating success in adult mice as well.^52,53

Diverse gut microbiota-directed approaches – eg, studies in germ-free rodents, antibiotics, probiotics, GI infection studies, fecal microbiota transplantation studies, etc – have suggested several possible gut-brain signaling pathways influenced by the gut microbiota and capable of modulating brain and behavior.^6,14,54-57 For example, changes in gene expression in brain regions of germ-free mice have been documented, including hippocampal expression of brain-derived neurotropic factor (BDNF), a key protein involved in neuronal plasticity and cognition.⁵⁸ Administration of the commensal bacterium Lactobacillus rhamnosus beneficially altered brain expression levels of BDNF and of genes involved in serotonin signaling and metabolism in zebrafish.⁵⁹

Behavioral and biochemical parameters have also been significantly modulated by recolonizing the gut with probiotics. Of the probiotics that have been investigated thus far, Bifidobacterium and Lactobacillus species have the most extensive data sets supporting beneficial effects on mood behaviors.⁵⁷ In one study, 40 male rats were randomized to either a control or high-fat diet for 10 weeks. After 5 weeks, the rats were randomized to receive either placebo or a multi-strain probiotic combination (Ecologic BARRIER, Winclove, Amsterdam; containing Bifidobacterium bifidum, B lactis, Lactobacillus acidophilus, L brevis, L casei, L salivarius, Lactococcus lactis, and Lc lactis). Forced swim test results demonstrated, independent of diet, this probiotic combination to significantly improve mood by 34% (p<0.001) in the treatment group. In addition, the probiotic group had decreased levels of inflammatory cytokines and increased indole-3-propionic acid, a potential neuroprotective agent.⁶⁰

Animal Models of ASD

Animal studies have also provided evidence of alterations in microbiome-gut-brain axis in models of Autism Spectrum Disorder (ASD). The pathophysiology of ASD is multifactorial, complex, and incompletely understood. Changes in the composition and metabolic products of the gut microbiome could alter how the gut communicates with the brain.⁵⁷ Clinically, this hypothesis is supported by several observations: GI symptoms are common in adults and children with ASD; some ASD individuals have dysbiosis of the gut microbiota, and some have increased intestinal permeability. Are observed microbiota changes in people with ASD secondary to altered neural regulation of key gut functions like motility and secretion? Or do they represent primary peripheral alterations that later affect brain development and function? This remains to be determined.⁶¹ ASD is a heterogeneous group of disorders, so it is unlikely that any single mechanism will offer a unifying etiology. Nonetheless, the microbiome offers up some intriguing avenues of research. Using a mouse model of ASD, offspring born following maternal immune activation during pregnancy were supplemented with the human commensal B fragilis. Supplementation corrected gut permeability defects and ameliorated defects in behavior and communication, particularly stereotypic, anxiety-like and sensorimotor behaviors seen in human-variant ASD.⁶²

The Missing Link in Depression?

The gut-brain axis is now thought to be critical in our understanding and treatment of depression.^63,64 Amazingly, this concept was proposed as early as 1910,⁶⁵ although research has taken nearly a century to catch up with the hypothesis. As noted earlier, HPA axis dysregulation is a feature of depression, and microbes can influence the functioning of the HPA axis and immune system. Thus, seeking to establish the links between microbiota and depression is a credible endeavor.

To date, most of the research linking the microbiota with anxiety and depression has come from animal models. Experimentally elevated HPA axis response and depression in germ-free (GF) rats has been shown to be reversed by administration of mono-strain, commensal Bifidobacterium infantis.⁶⁶ (B infantis is now considered a so-called “psychobiotic” because of these antidepressant effects.)⁶⁷ Studies from 3 independent research groups have all shown alterations in the levels of key monoamines (or their receptors) involved in depression (ie, serotonin, norepinephrine) in the cerebral cortex and limbic regions of the brain.^68-70

Such research has laid the groundwork for clinical trials of probiotics in humans.

Clinical Evidence

As clinical trials validating these concepts have begun to emerge in the last decade, a new class of probiotics also emerged – the so-called psychobiotics, or psychomicrobiotics – which hold significant promise for new, nontoxic treatment of psychiatric disorders.^71,72 Several human clinical trials have now investigated the effects of probiotics for mood disorders such as depression and anxiety.

• In a randomized, double-blind study (n=40), Akkasheh and colleagues found that administration of a combination of Lactobacillus acidophilus, L casei, and Bifidobacterium bifidum for 8 weeks improved scores on the Beck Depression Inventory.⁷³
• In a randomized, double-blind study (n=124), Benton and colleagues found no effect from consumption of probiotic-containing yogurt on Profile of Mood States scores, although there was improved self-reported mood of those whose mood was initially poor.⁷⁴
• In a randomized, double-blind study (n=36), Chung and colleagues found that administration of a L helveticus for 12 weeks had no significant effects on the Perceived Stress Scale or Geriatric Depression Scale. Consumption of probiotics did, however, improve digit span test, story recall test, verbal learning test, rapid visual information-processing, and Stroop Tasks scores.⁷⁵
• In a pre- and post-intervention assessment of adults suffering from stress or exhaustion (n=34), Gruenwal and colleagues found that 6 months’ intervention with a combination of L acidophilus, B bifidum, and B longum improved subjects’ general condition by 40.7%. Seventy-three percent of participants rated the effect of treatment as “good” or “very good.”⁷⁶
• In self-report questionnaires related to fermented food consumption, neuroticism, and social anxiety in 710 young adults (mean age 19 years), consumption of fermented foods containing probiotics was negatively associated with symptoms of social anxiety and interacted with neuroticism to predict social anxiety symptoms. Those at higher genetic risk for social anxiety disorder (indexed by high neuroticism) showed fewer social anxiety symptoms when they consumed more fermented foods.⁷⁷
• In a prospective, randomized, controlled, parallel study (n=136 healthy students), Marcos and colleagues found no significant effects of L casei supplementation on anxiety levels. Probiotics did modulate lymphocyte and CD56 cell counts.⁷⁸
• In a double-blind, randomized, controlled, parallel study (n=55), Messoudi and colleagues found that consumption of L helveticus and B longum reduced the global severity index of the Hopkins Symptom Checklist, due to lower somatization, depression, and anger-hostility; it also reduced Hospital Anxiety and Depression Scale global scores. Consumption of probiotics reduced self-blame scores on a coping checklist and increased focus on problem-solving. There was no effect noted on the Perceived Stress Scale.⁷⁹
• In a sub-population of the above sample, including 25 subjects with the lowest urinary free cortisol levels, Messaoudi et al found that consumption of the probiotics reduced scores on the Hospital Anxiety and Depression Scale and the Hopkins Symptom Checklist.⁸⁰
• In a double-blind, randomized, placebo-controlled pilot study (n=35 chronic fatigue syndrome patients), Rao and colleagues found that 2 months’ supplementation with L casei significantly improved Beck Anxiety Inventory scores. There was no effect on Beck Depression Inventory scores.⁸¹
• Finally, Steenbergen and colleagues studied the effects of a multi-strain probiotic formula (Ecologic BARRIER, Winclove, Amsterdam) in a randomized, triple-blind, placebo-controlled trial (n= 40 non-smoking healthy young adults, mean age 20 years). The formula contained specific strains of B bifidum, B lactis, L acidophilus, L brevis, L casei, L salivarius, and Lactococcus lactis and was administered at a dose of 5 billion CFU per day. Consumption of this multispecies probiotic significantly reduced overall cognitive reactivity to depression, in particular aggressive and ruminative thoughts, as assessed by the Leiden index of depression sensitivity (LEIDS-R).⁸²

This last clinical trial is noteworthy because many psychiatrists and other healthcare professionals would prefer non-pharmaceutical interventions as first-line therapy, especially among young people with no prior history of depression but who are at risk due to cognitive reactivity to sad mood. It demonstrates that supplementation with a well-formulated probiotic might actually prevent depression in susceptible individuals.

In Wallace and Milev’s systematic review of 10 studies that met their inclusion criteria (summarized above), 5 studies assessed mood symptoms, 7 studies assessed anxiety symptoms, and 3 studies assessed cognition.⁴⁶ Most of the studies found positive results on all measures of depressive symptoms; however, the studies were heterogeneous in terms of strain of probiotic used, the dosing, and duration of treatment. The authors concluded that further randomized controlled clinical trials are warranted to validate the efficacy of this intervention.

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Jeremy Appleton, ND, has been a well-known writer and speaker on topics in natural medicine for nearly 20 years. A graduate of the National University of Naturopathic Medicine (NUNM), Dr Appleton is a licensed naturopathic physician, author, educator, and Vice President of Scientific and Regulatory Affairs for SFI USA, which manufactures dietary supplements under the Klaire Labs brand.