How much do intestines (gut) control our brain? Psycho Neuro Endo: 2012 Sept.


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

4 thoughts on “How much do intestines (gut) control our brain? Psycho Neuro Endo: 2012 Sept.

  1. Very interesting! People with anxiety also complain of multiple GI problems – IBS, it is interesting to think that they all may be interconnected through gut flora

  2. Puts some meat on the bones of the notion that there really a brai-mind split..could open up new preventative and management approaches for mental distress.

  3. It makes sense to me. I found that i can not think well if i took too much red peppers. saying that i continously take red pepper for two days. My wife and my friends do not believe my story and laughed at me. However, I know that it is true to my body. Now thanks this article which talks about the connection between gut and brain. This connection makes more sense to my situation.

  4. SAVE THE DATE : The 2013/MARCH/28 , will be held the EGOCREANET WORKSHOP c/o Province of Florence (IT) se in Italian Preliminari Motivation in

    ONE of Principal THEME of the NUTRA-SCIENCE EVENT will be to develop the issue:

    Who has the best diet from the perspective of your gut microbiome?

    During all life time , from born to the elderly, people with better diets have much better healthy outcomes .
    In spite of that ancient knowledge , till today we don’t know if those good outcomes are due throughout an important part to the heathy microbial activity. Human diets vary to the extreme, from complete herbivory (vegans) to something close to pure carnivory. The FUTURE HORIZON of NUTRITION research would analyze, through a epidemilogic trial and subseguent stidies in microbiome genetics and metabolomics to understand how some types of diets prevent health from diet-related metabolic diseases and brain .behavioural impairments ( as stress or depression). Thus the FUHONU European project will expect to have a high impact to favor dietary strategies to enhance an healthy gut microbiome to disseminate a broad range of information to prevent health for having an active population and to advance in HORIZON 2020 prioriries on food quality production for a better life. For the above goal the project FUHONU need to go beyond of the state of the art of the traditional genetics. In fact the model that places our genes at the root of all human development is no sufficient to explain our effective live. For instance genetics cannot explain the incidence of many diseases has risen this because we till now we are not able to take into a clear account the symbiosis in our genetics fucused on the healthy gut microbiome development ; the last contain at least four million genes, and they work constantly on our behalf if the symbiosis is well co-organized by Gemome end Microbiome

    Symbiontic Microbiome produces some vitamins and protect our digestion system and the intestinal tract to prevent infections and inflammation ; an healthy microbiome help us to form and bolster our immune systems, and to correcly absorb nutritional components of food.

    More recent research discover that gut- bacteria may even alter our brain communication, thus affecting our moods and behavior ….etc.. etc…


    I hope that your curiosity on those themes will be very entusiastic , s that you would actively participate EGOCREANET WORKSHOP c/o Province of Florence (IT) the 2013/MATCH/28 ,. Write to me please :

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