Category Archives: Brain-gut axis

SIRT1 and Stress Suppress Regulatory T Cells

High traffic
Is it actually our stressful lives that are setting the stage for inflammatory bowel disease?
This week on TIBDI: Human stem cell transplantation redefines T cell repertoires, SIRT1 blocks the development of induced regulatory T cells, and stress sets the stage for intestinal inflammation.

Stem Cell Transplantation Wipes CD4+ T cell Memory

Human stem cell transplantation (HSCT) is a potential treatment for severe cases of inflammatory bowel disease (IBD). One way that HSCT works is by resetting the adaptive immune system. However, few studies have looked in depth at changes in the T cell repertoires. Dr. Paolo Muraro from the Imperial College of London has now addressed this question. In a HSCT trial for multiple sclerosis (MS) patients, he and his team used high-throughput sequencing to assess T cell receptor changes in 24 patients. They found that CD4+ and CD8+ T cells responded differently to HSCT. The patients’ CD4+ T cells were redefined and had a new repertoire of clones, while the CD8+ T cells reflected pre-HSCT clones. Resetting CD4+ T cells could be one reason why that HSCT is also successful for IBD.

SIRT1 Suppresses Suppressor Induction

Regulatory T cells (Tregs) are known to be important in IBD, and work from animal models shows that they can regulate the severity of symptoms. Previous work by Dr. Tatiana Akimova and her colleagues at the Children’s Hospital of Philadelphia demonstrated a connection between SIRT1 and Tregs. To investigate this more in induced Tregs, they used SIRT1 deficient cells in the T cell transfer model of colitis. Loss of SIRT1 increased the induction of Tregs and effectively attenuated colitis development. This result was mirrored in dextran sodium sulfate colitis using an inhibitor of SIRT1 (EX-527). It will be interesting in the future to see if targeting SIRT1 will work in a therapeutic setting.

Stress Hinders Regulatory T Cells

Most IBD patients are quite aware that stress plays a role in their disease progression. However, the connection between stress and IBD remains shaky. Dr. Wei Wu of Tongji University considered that the missing link could be Treg function. To test this concept, they stressed mice and investigated the Tregs both in vitro and in vivo. Tregs from stressed mice were unable to function as normal, and some expressed IL-17 and TNFα. Prolactin, a stress mediator, mediated this change via dendritic cells. Stressed mice were highly susceptible to colitis, however, blocking prolactin reduced colitis. The authors feel that stress and prolactin set the stage for IBD development by the conversion of Tregs from effective suppressors to harmful pro-inflammatory T cells.


Early Anti-TNF Has Benefits and the Nervous Gut Unraveled

George Caleb Bingham - Stump Speaking
Mast cells could be behind public speaking-induced intestinal disturbances.
This week: anti-TNFα treatment shows promise in early Crohn’s disease, rifaximin takes on over-sensitive gut nerves and mast cells might be behind stress-induced tummy troubles.

Hit Them Early and Hit Them Hard

Specialists treating newly diagnosed cases of Crohn’s disease (CD) in children usually follow a specific treatment regimen: corticosteroids followed by immunomodulators, like azathioprine. However, scientists funded by the Crohn’s and Colitis Foundation of America wondered if better results could be obtained with another protocol, a protocol including early use of anti-TNFα. In a huge collaborative study using patients that were matched for age and disease severity, CD severity was followed for a year after initial treatments. It was discovered that early treatment with anti-TNFα led to a significantly better clinical and growth outcomes than the typical regimen.

Rifaximin Settles Gut Nerves

Some intestinal disturbances, including irritable bowel syndrome (IBS), can be attributed to what is called “visceral hyperalgesia,” a situation of heightened nerve sensitivity. The antibiotic rifaximin has shown promise for IBS treatment, but little was known about its mechanism. Using two visceral hyperalgesia models in rats based on chronic stress, scientists from the University of Michigan determined that these models were associated with alterations in the microflora, increased intestinal permeability and mucosal inflammation. Rifaximin, unlike a control antibiotic, eliminated these dysfunctions. The benefits appeared to be linked to an increase in beneficial bacteria species in the gut after treatment that was not found after other kinds of antibiotic treatment.

Mast Cells Behind Nervous Gut Permeability

Most of us are familiar with nervous gut trouble, especially when we have to speak in front of a crowd. Belgium scientists suspected that corticotropin-releasing hormone (CRH) could be playing a role in stress-induced gut permeability. After administering CRH to volunteers, they found changes in gut permeability similar to those found after public speaking. One target of CRH is the mast cell, which has all of the right tools to cause a good case of tummy trouble. To find out if the mast cell could be the culprit behind stomach butterflies, they asked volunteers to take the mast cell blocker disodium cromoglycate and either give a presentation or take CRH. Blocking mast cells alleviated intestinal permeability in both situations.


Th17 in the Human Gut and Bacteria Talk to Neurons

Unipolar Sensory Neuron
Bacteria can cause pain by interacting directly with neurons in the gut.
Crohn’s disease patients have more T helper 17-inducing lamina propria cells, bacteria activate pain neurons and retinoic acid determines the fate of pre-dendritic cells.

T helper 17 Cell Induction in the Human Gut

It’s easy to forget with the all the mouse immunology research that many things about gut Th17 cells haven’t been described with human cells. Now we are one step further. The journal Gastroenterology has an article in press that describes the induction of Th17 cells from human-derived, lamina propria cells. Using cells isolated from Crohn’s disease patient and control intestinal samples, Japanese scientists found an antigen-presenting cell population with a monocyte/macrophage lineage that was extremely good at inducing Th17 cells from naïve T cells. While both patient and control cells both could induce Th17, Crohn’s disease patient cells were the most effective. Th17 cells are suggested to play a role in Crohn’s disease, and this result supports this idea even more.

Bacteria and Nociceptors, Talking Together

Most of us have heard the term, “the second brain,” when people are referring to the neural networks within the intestinal system. Sensory neurons called nociceptors are responsible for the pain sensation. During intestinal Staphylococcus aureus infection, pain is induced, and, for a long time, it was assumed to be caused inflammatory mediators interacting with the pain neurons. Chiu et al, in the most recent issue of Nature, have now shown that, in actuality, it’s the bacteria that are directly activating the nociceptors. Furthermore, in neuron ablation experiments, they discovered that the nociceptors could influence inflammation. Interestingly, the communication wasn’t via pattern recognition receptors. Instead, the communication mediators were formylated peptides and α-haemolysis, a pore-forming toxin, produced by S. aureus. In the future, it will be interesting to find out how friendly commensals interact with nociceptors. They could form a novel way of modulating the immune response during intestinal inflammation.

Choosy Pre-Dendritic Cells Choose Retinoic Acid

Retinoic acid has a variety of effects within the gut-associated immune system, and it is known to influence the generation of different kinds of dendritic cells (DCs). However, it wasn’t known precisely when retinoic acid was having an effect on DC generation from pre-DCs or how it was affecting systemic DC populations. Scientists from the National Institute of Health now know the answer to both questions. They found that a retinoic acid deficiency caused a reduction in pre-DC-derived conventional DCs in both the spleen (CD11b+CD8α-Esamhigh DCs) and the gut (CD11b+CD103+ DCs), while populations of several other DC types were not affected. By transferring pre-DCs to different hosts with different retinoic acid levels, the scientists determined that ambient retinoic acid levels controls the fate of pre-DC. As conventional DCs are necessary for sufficient protective immune responses, this highlights the importance of vitamin A (precursor of retinoic acid) supplementation during mucosal stress.



New Findings on the Brain-Gut Axis

The vagus nerve’s connection with the spleen may play a role in IBD.
The brain-gut axis is receiving more attention as a possible target for modern inflammatory bowel disease (IBD) drugs. A recent publication shows an interesting vagus nerve-spleen axis role in colitis, while older publications indicate several other brain-gut associations in ulcerative colitis (UC) and with gut microbiota.

Vagus nerve-spleen axis in colitis

The vagus nerve is mainly responsible for communicating information from the visceral organs to the brain. It also is known to promote anti-inflammatory immune responses. In a study looking at the influence of the vagus nerve on murine colitis models, Ji et al. found that increasing centrally stimulating the vagus nerve led to decreased symptoms of murine colitis and that these effects were mediated mainly via release of acetylcholine in the spleen, which interacted with a7 nicotinic acetylcholine receptor (α7nAChR) on CD11c+ cells, lowering their activation state. In general, CD11c+ cells are considered to be antigen presenting cells, which open the door for brain control of the adaptive immune response. More information about the vagus nerve and immune regulation can be also be found in a recent review by Matteoli and Boeckxstaens in July’s issue of Gut.

Different Emotional Responses in Ulcerative Colitis

To answer the question if IBD patients have different brain responses, two years ago researchers performed brain scans on patients with ulcerative colitis. Agonstini et al. imaged brains from both patients and controls after exposing them to emotional visual stimuli. It was found that the UC patients were less sensitive to positive emotional stimuli. This may play a role in why IBD sufferers have an increased incidence of depression.

Intestinal Bacteria Influence Brain Activity

In a more recent study with only healthy women, Tillisch et al. looked at the effects of the consumption of fermented milk on brain function. After four weeks of daily probiotics, changes were observed in the areas of the brain associated with emotional processing and sensation. On a practical level, this could mean that the women were more resistant to pain and stress. However, a larger study would need to be performed to be certain.

What’s your opinion regarding the brain’s involvement with IBD or do you have any personal experiences that show a link? Please share in the comment section below.


Agostini, A., Filippini, N., Cevolani, D., Agati, R., Leoni, C., Tambasco, R., et al. (2011). Brain functional changes in patients with ulcerative colitis. Inflammatory Bowel Diseases, 17(8), 1769–1777. doi:10.1002/ibd.21549

Ji, H., Rabbi, M. F., Labis, B., Pavlov, V. A., Tracey, K. J., & Ghia, J. E. (2013). Central cholinergic activation of a vagus nerve-to-spleen circuit alleviates experimental colitis. Mucosal Immunology, 1–13. doi:10.1038/mi.2013.52

Matteoli, G., & Boeckxstaens, G. E. (2013). The vagal innervation of the gut and immune homeostasis. Gut, 62(8), 1214–1222. doi:10.1136/gutjnl-2012-302550

Tillisch, K., Labus, J., Kilpatrick, L., Jiang, Z., Stains, J., Ebrat, B., et al. (2013). Consumption of Fermented Milk Product With Probiotic Modulates Brain Activity. Gastroenterology, 144(7), 1394–1401.e4. doi:10.1053/j.gastro.2013.02.043



The Role of NLRP6 in Stress Induced Intestinal Inflammation

TIBDI blog post 14-01Many inflammatory bowel disease patients know that stress can complicate and worsen their symptoms. Even though this has been generally known for years, the study of the relationship between the gut and the brain is just now gaining popularity. In the most recent issue of Gastroenterology, we finally get a glimpse of how stress leads to intestinal inflammation.

The study, performed by American, Chinese and Taiwanese researchers, investigated the signals induced by stress that lead to inflammation in the small intestine. For this work, they used a stress-induced model of enteritis in mice. The mice were placed on a small platform surrounded by water for one hour each day, for a total of ten days. The resulting disease was characterized by intestinal damage, reduced weight gain and intestinal permeability. Although, IL-17 and IL-6 were found to be increased in the small intestine, there was also striking loss of IL-1β expression, which is what apparently first sparked their interest in inflammasomes.

Inflammasomes are large multi-protein complexes that are needed to activate a family of enzymes known as the caspases, which are involved in cell death and inflammation functions. One of the most well-known caspases is caspase-1. It’s needed to activate IL-1β, which is done by cleaving an inactive precursor of IL-1β. Interestingly, the inflammasomes belong to the (NOD)-like receptor (NLR) family, which many of you might realize also includes NOD2, a receptor that is highly associated with Crohn’s disease.

After some real-time PCR work, they found that the mRNA expression for Nlrp6 was considerably downregulated. They could also eliminate the pathology just by forcing the expression of NLRP6, further supporting its importance.

NLRP6 is an interesting NLR. Previous studies using Nlrp6-/- mice have shown that loss of this inflammasome in colonic epithelial cells disturbs the intestinal flora, which leads to an overgrowth of the bacterial family, Prevotellaceae and the candidate bacterial phylum, TM7. Both of these bacteria types are suspects in IBD, and the knockout mice also displayed a mild intestinal inflammation and extreme susceptibility to chemically induced forms of colitis.

However, other studies with the same knockouts hint that NLRP6 is even more complex. It also seems to have the potential to downregulate signaling via the pro-inflammatory factors NF-κB and ERK making the knockout inherently pro-inflammatory. Which might lead one to believe that the intestinal pathology is only caused by an overactive immune system. However, one most also remember that the microflora community that develops in the knockouts also can induce the same intestinal problems in wild type mice.

In my opinion, these conflicts could be a result of immunological compensation in the knockout. The knockout studies  emphasize the importance of this current study, which was performed in wild type mice and represents what can happen with a normal complement of genes.

The next question of the researchers was how did stress translate into the reduction of NLRP6. They looked at corticotropin-releasing hormone (CRH), an important stress signal in the brain-gut axis. They found that during stress the levels skyrocketed, and the levels were indirectly correlated with NLRP6 expression. More importantly, injecting mice with CRH was enough to mimic the pathology, and blocking it eliminated the stress-induced inflammation.

However, the previous study with the Nlrp6-/- mice indicated that the pathology was caused by the ultimate overgrowth of bad bacteria, which was transmissible by co-housing. Co-housing stressed mice with unstressed mice led to the development of intestinal problems in the unstressed mice. Simple probiotic therapy was enough to protect the co-housed unstressed mice. A detailed investigation of the bacterial populations in the intestines of the stressed mice showed that it, indeed, was changed, and both the small and large intestine had an increased bacterial load.

To sum it up, this study shows that stress can lead to increased CRH, which reduces NLRP6 expression. NLRP6 expression is important for the activation of IL-1β and IL-18. Both of these cytokines are important for the control of bacterial infection, and, thus, loss of NLRP6 could possibly lead to loss of control of bacterial growth. In this study, this appears to be the case, and mice with stress have a changed intestinal flora that, on its own, appears to cause intestinal inflammation in unstressed mice.

This study is intriguing. Could it be that many intestinal pathologies are caused by long-term stress that changes one’s intestinal microbiota? I think it could be the case. However, the chance that this causes inflammatory bowel disease by itself is highly unlikely. One mustn’t forget that there is still a genetic component to inflammatory bowel disease. Yet, it wouldn’t surprise me if it were discovered that those with inflammatory bowel disease have experienced more stress at critical periods in their lives than healthy individuals.


Anand, P. K., Malireddi, R. K. S., Lukens, J. R., Vogel, P., Bertin, J., Lamkanfi, M., & Kanneganti, T.-D. (2013). NLRP6 negatively regulates innate immunity and host defence against bacterial pathogens. Nature, 488(7411), 389–393.

Elinav, E., Strowig, T., Kau, A. L., Henao-Mejia, J., Thaiss, C. A., Booth, C. J., et al. (2011). NLRP6 Inflammasome Regulates Colonic Microbial Ecologyand Risk for Colitis. Cell, 145(5), 745–757.

Kuehbacher, T., Rehman, A., Lepage, P., Hellmig, S., Folsch, U. R., Schreiber, S., & Ott, S. J. (2008). Intestinal TM7 bacterial phylogenies in active inflammatory bowel disease. Journal of Medical Microbiology, 57(12), 1569–1576.

Sun, Y., Zhang, M., Chen, C. C., Gillilland, M., Sun, X., Zaatari, El, M., et al. (2013). Stress-Induced Corticotropin-Releasing Hormone-Mediated NLRP6 Inflammasome Inhibition and Transmissible Enteritis in Mice. Gastroenterology, 144(7), 1478–1487.e8.