Both Hypothalamic-Pitutary Axis axis (HPA) and SMA (Sympatho Adrenal Medullary axis) play key role in regulating the effects of physical/psychological stress. Infective agents can activate this system through pro inflammatory cytokines. Recent studies have shown that HPA is tightly regulated to respond efficiently to gut pathogens such as Escherichia coli. (Zimomra et al,2011). Adrenal cortex can be directly activated by PGE2 from the immune system stimulated by gut pathogens.
What about the non pathogenic microorganisms living inside us? Do they play with our brain and mind?
The human gut is inhabited by 1000- 10000 trillion micro-organisms, which is ten times the number of human cells in our bodies and contains 150 times as many genes as our genome consisting of more than 1000 species and 7000 strains mostly dominated by bacteria.
Colonisation of the infant gut commences at birth. Complex adult-like microbiome is evident by year one. Infection, disease, diet and antibiotics might alter this, though the tendency is to restore a stable diversity after these challenges. With age, the composition changes and some of it is linked to adverse health effects in the host.
There is now an expanding volume of evidence to support the view that these commensal organisms within the gut play a role in early programming and later responsivity of the stress system (Grenham et al., 2011). The brain-gut axis is bidirectional in nature.The vagus nerve provides an important line of communication between the gut microbes and the HPA. Experiments have shown that CRF mRNA in the hypothalamus increases 2 h after vagal stimulation and subsequently the plasma levels of ACTH are markedly elevated. The Enteric Nervous System (ENS), is a complex neuronal network with multiple neuro- transmitters and neuromodulators including 5-HT, acetylcholine and CRF. CRFR1 and CRFR2 receptors here act as signalling peptides in the brain—gut axis. Stress results in the recruitment and activation of CRF receptors in the colon to induce the stress-related changes in gut function.
Germ free animal studies (Animals born via surgical methods as against vaginal delivery would have no gut microbia if kept in sterile environment or by using broad spectrum antibiotics to clean up the gut ) showed that their gut structure become different from controls. (eg greatly enlarged cecum, reduced intestinal surface area, increased enterochromaffin cell area,smaller villous thickness etc ). What about brain? … Toll-like receptors (TLRs) present on cells of the innate immune system is key to recognition of pathogens and in initiating a cascade of reactions that end in activating HPA. In the absence of the resident enteric flora, these receptors show low or absent expression profiles in the gut and this compromise the appropriate immune and neuroendocrine responses to pathogenic threats.
These microbia may also be playing a role in development or early tuning of the HPA axis.The germ free mice produces an exaggerated release of corticosterone and ACTH to a mild restraint stress compared to controls. This exaggerated response can be reversed by introduction of microbial colonies. Studies suggest that microbial content of the gut is critical to the development of an appropriate stress response later in life. This should occur during a narrow window in early life.Hippocampal receptors, BDNF levels ( which is crucial in neuro plasticity), serotonergic system etc are shown to be different in germ free animals. Some of these change also correlate with decreased anxiety in germ free animals.
We know that maternal separation, an early life stressor, can result in long-term HPA changes (O’Mahony et al., 2011) , it is now shown that this can cause a significant decrease in faecal lactobacilli on day 3 post separation. Studies also show that such early stressors during critical periods can cause in microbial changes in measurable later in adult life.
Can we modulate this axis?
Probiotics: These are live organisms and health benefit claims are exaggerated . Some recent work has suggested antianxiety property.(Bercik et al., 2011, Messaoudi et al., 2011) in rodents. Authors caution that many such effects in rodents do not show that in human beings. Another study found that chronic treatment with the Probiotic Lactobacillus rhamnosus over 28 days produced animals with lower levels of corticosterone. They showed reduced depressive behaviours and anxiety. This was accompanied by changes in brain GABA expressions (Bravo et al., 2011). Interestingly , these benefits and changes were not seen in vagotomised animals indicating that the Vagus is a key route of communication between Probiotic bacteria and the brain. Another study has shown that specific Lactobacillus strains could induce the expression of m-opioid and cannabinoid receptors in intestinal epithelial cells and mimic the effects of morphine in promoting analgesia (Rousseaux et al., 2007).
Martin et al. (2009) using NMR and mass spectroscopy based studies in 30 human subjects (2 weeks), showed that human subjects with higher anxiety were distinct in their gut microbial activity, energy homoeostais etc and a dietary intervention reversed these changes.
Just like these microbes influence our brain, brain can alter them also. Signalling molecules released into the gut lumen from cells in the lamina propria that are under the control of the CNS can result in changes in gastrointestinal motility and secretion as well as intestinal permeability, thus altering the environment in which the bacteria reside (Rhee et al., 2009). Psychological stress can increase permeability of the gut allowing bacteria and bacterial antigens to cross the epithelial barrier and this can activate a mucosal immune response which in turn alters pro-inflammatory cytokines and perhaps activate the HPA.
It would be of great significance to know the mechanism through which stress change the gut permeability. Clark (2005) showed that a rise in the pro-inflammatory cytokine interferon g play a key role here with the cascade of actions ending in disruption of tight junctions.
Depression and Gut Microbes: Significant differences in serum IgM and IgA against LPS of enterobacteria were found in patients with major depression than in normal volunteers (Maes et al 2008), indicating increased translocation of Gram- negative bacteria playing a role in this.
Gut microbes can activate the HPA. They might also have a role in early programming and subsequent responsivity of the HPA. Probiotics could have a role in decreasing the behavioural and endocrine components of stress. Prospective studies in patients with mood disorders examining the gut microbiota, immune parameters and HPA activity can throw further light on this emerging area. Therapeutic agents targeting the gut microflora useful in treatments for stress-related psychiatric and gastrointestinal disorders could emerge from such research.
Would these research prove the detailed biology behind ‘butterflies in stomach’? .Would all this prove what Ludwig Feuerbach wrote: “Der Mensch ist, was er ißt.” ie ‘man is what he eats'”?….My own “gut instinct” is that may be some day!
Summary of the article:
Regulation of the stress response by the gut microbiota: implications for psychoneuroendocrinology. Dinan TG, Cryan JF. Psychoneuroendocrinology. 2012 Sep;37(9):1369-78