Recently, there has been an increased interest in finding the cause of Inflammatory Bowel Diseases (IBD) and elucidating an effective treatment. Within this field of study, much of the focus has been on determining the composition of the gut microbiome and its role within the disease pathologies.

IBD is relatively common, with approximately 1-1.3 million Americans affected.2 IBD encompasses both Ulcerative Colitis (UC) and Crohn’s Disease (CD), which are both characterized by chronic inflammation of the gastrointestinal (GI) tract. This inflammation interferes with proper digestive processes, resulting in symptoms such as diarrhea, bloating, cramping, and rectal bleeding. Although the exact cause of IBD is unknown, it is generally accepted that these diseases arise from the body mounting a prolonged immune response against harmless bacteria and microorganisms, which ultimately results in inflammation.3 These harmless microorganisms, along with the disease causing variants, make up the human microbiome. The recent trends in the field of GI research have appropriately focused on studying the complex interactions between the host and the microbiome that resides within the digestive tract, revealing a strong connection and even reliance on these microorganisms. Furthermore, these host-microbiota interactions have been shown to have diverse impacts throughout the body, including in interactions with key molecules that are part of the neuroendocrine axes, and in genetic regulation by the host on microbial growth.

The neuroendocrine axes refer to biochemical pathways in the body that originate in the brain (usually in a structure called the hypothalamus), and the propagation of these chemical signals via hormones and other second messengers to a target organ. In the case of IBD, this refers to the brain-gut interaction, with chemical signals originating in the brain and traveling down to the gut. Numerous studies have shown a relationship between stress and digestive function. These studies focused on the corticotropin-releasing factor (CRF), a primary molecule released due to stress. Stress has been found to affect the permeability of the digestive tract, secretion of digestive enzymes, and local inflammatory responses in the GI tract. A study by Stengel et al. that was performed on rats found that chronic stress is associated with worsening colitis symptoms.1 However, this was due to the fact that the body adapts to these chronic stress conditions and actually decreases the CRF output over time. The study found that CRF took on a protective role in the gut, decreasing the inflammatory response that is mediated by stress. Thus, the lower CRF levels in the body worsened colitis symptoms and caused an increase in inflammation in the large intestine.

Further investigations with CRF release in the gut found that stress and CRF increase the permeability of the colon in rats to various microorganisms.1 The increased permeability of the colon was hypothesized to also contribute to inflammation by allowing more foreign bodies, including harmful bacteria, to penetrate the intestinal walls. The infiltration of these bacteria into the colon in turn results in the heightening of the immune response, which causes increases in inflammation. The mediators of the hyperpermeability of the intestinal walls are specialized cells known as mast cells. These cells communicate with vagus nerve and sympathetic nerve fibers that travel to the intestine from the brain by release their products onto these neurons. These products then bind to alpha and beta adrenergic receptors on these neurons. These processes have been linked to the increase of permeability of the intestine.1

Additionally, the structure of the microbiota layout throughout the colon changed with stress induction in mice.1 These alterations in structure interfere with proper defense against pathogens by the colon. Similarly, the release of a class of chemicals called catecholamines (primarily norepinephrine) under stressful conditions may alter the pattern of bacterial growth in the colon. As expected, changes in growth patterns were seen to lead to a greater susceptibility of the colon to infection.1

However, more interestingly, researchers found that the microbiota of the gut is able to act as a mediator between the colon and the brain, sending chemicals signals backwards (i.e. from the gut to the brain).1 The brain is able to communicate with organs via chemical signals (in the form of neurotransmitters) that are released from neurons that originate in the brain and end at some target organ. The gut is no different– there are numerous neurons that will send signals to the gut that will regulate the process of digestion. There is a subset of neurons that are associated with the senses, appropriately termed “sensory neurons,” will initiate a chemical cascade that sends a chemical signal back to the brain after the experience of some smell, sound, flavor, etc and are separate from the rest of the neurons. Generally, these are the only neurons that can communicate with the brain in this manner, by sending efferent signals to the brain. Thus, it is quite noteworthy that researchers were able to show that when healthy mice that were treated with the bacterium Campolybacter jejuni, specific brain areas were seen to be activated via signals sent by the vagus nerve.1 This experiment proved the presence of efferent signals being sent from a non-sensory organ up to the brain, which is contrary to the way signals usually travel on the brain-gut axis. The introduction of this bacteria into mice resulted in increased levels of Brain Derived Neurotrophic Factor (BDNF) within a brain structure called the hippocampus. This was in turn correlated with a reduction in stress and anxiety-like behaviors in these mice, relative to the germ-free control mice.1 It can be inferred that with the onset of IBD and the subsequent alterations in the gut microbiome, the protective signals that are mediated by having adequate levels and proper distribution of bacteria within the intestine (as with the C. jejuni-treated mice) are lost. Further experimentation with mice exhibiting depressive-like behaviors (likely from an altered gut microbiome), were shown to be more susceptible to intestinal inflammation relative to controls.1

The gut microbiome has also been seen to interact with the human genome. Lamas et al. investigated the gene CARD9, which is implicated in IBD. This gene is found to promote the recovery from ulcerative colitis by upregulating the production of a group of molecules named interleukins.4 These molecules are implicated in the immune response, especially to specific fungi. The researchers found that mice that are homozygous for CARD9 mutations, (both the mother’s and father’s copies being mutated), were much more susceptible to colitis. Although CARD9 does not directly impact the metabolism of the amino acid tryptophan (Trp), it was hypothesized that the CARD9 mutants had impaired breakdown of tryptophan given their altered microbiome. The metabolism of Trp byproducts are important for the production of interleukins, which in turn leads to an increased susceptibility to inflammation and colitis given the inability to produce these key molecules.4 The gut bacteria metabolize Trp, and these Trp metabolism byproducts (metabolites) serve as ligands for the aryl hydrocarbon receptor (AHR). The metabolites bind to the receptor, leading to the upregulation of the production of interleukins. Fecal matter that was transferred to wild type, germ-free mice from the CARD9 mutants was seen to be defective in its ability to activate the AHR in the wild type mice, likely by the failure to produce the necessary AHR ligands.4

The composition of the gut microbiota was also altered in these mutant mice. The investigators noted dysbiosis in these mice, which is defined as an imbalance in the number and type of bacteria compared to baseline levels. The mutant CARD9 mice were observed to have a greater amount of fungi in the colon.4 Such results were used to determine the role of CARD9 as a regulator of fungal growth in colitis-diseased mice. Their susceptibility to colitis was likely attributed to both the overpopulation of fungi in the colon, as well as the fact that the fungi excluded other species of the microbiota from growing. These other species were hypothesized to either have regulatory roles in controlling microbial growth or protective roles against inflammation. To focus on the effects of the microbiota, the scientists transferred the microbiota from mutant CARD9 mice into germ-free mice.4

These mice were seen to have downregulated interleukin-22 production, and they exhibited greater rates and susceptibility to inflammation. This confirmed the previously stated postulate that CARD9 mutant mice have a deficient interleukin-22 mediated immune response, thus suggesting that the microbiota of the mutant mice may have proinflammatory effects. This results directly from the altered metabolism observed in the CARD9 mutant mice, in turn inhibiting the protective effects of the microbiome. Moreover, mutant mice were seen to exhibit lower levels of AHR activation by tryptophan metabolites, leading to decreased interleukin activation.4 When treated with strains of the bacterium Lactobacillus, germ-free mice treated with CARD9 microbiota were seen to return to baseline levels of AHR activation and thus, interleukin production, further strengthening the results of the study. Given these results, the researchers hypothesized that mice containing CARD9 mutations have an altered immune response. This altered immune response then interferes with the metabolism of tryptophan, which affects the immune response and further increases dysbiosis.4 The gut of the IBD patient is in a constant vicious cycle that ultimately leads to the disruption of homeostasis in the colon.

Despite there being much research on IBD, there is much more left to learn. For instance, it is still unclear whether dysbiosis is a cause or a result of IBD. Although the gut-brain axis signaling is well documented, there is a plethora of other effects that are mediated by the microorganisms of the gut on other physiological systems. Decoding the mystery of how the human body interacts with the microbiome it houses will undoubtedly enhance our understanding of IBD, and possibly other diseases as well.


REFERENCES

  1. Bonaz, Bruno L., and Charles N. Bernstein. “Brain-Gut Interactions in Inflammatory Bowel Disease.” Gastroenterology 144 (2013): 36-49. Web. 5 Mar. 2017.
  2. “Epidemiology of the IBD.” Centers for Disease Control and Prevention. N.p., 31 Mar. 2015. Web. 05 Mar. 2017.
  3. “Facts About Inflammatory Bowel Diseases.” Chron’s and Colitis Foundation. N.p., 1Apr. 2011. Web. 05 Mar. 2017.
  4. Lamas, Bruno, et al. “CARD9 Impacts Colitis by Altering Gut Microbiota Metabolism of Tryptophan into Aryl Hydrocarbon Receptor Ligands.” Nature Medicine 22.6 (2016): 598-605. Web. 5 Mar. 2017.

Related Posts