Anti-Inflammatory Activities of a Chinese Herbal Formula IBS-20 (IBS/IBD Support) In Vitro and In Vivo

Yang Zh, Grinchuk V, Ip SP, et al. Evidence-Based Complementary and Alternative Medicine. Volume 2012 (2012). doi:10.1155/2012/491496

Irritable bowel syndrome (IBS) is a functional bowel disorder and the aetiology is not well understood. Currently there is no cure for IBS and no existing medication induces symptom relief in all patients. IBS-20 is a 20-herb Chinese medicinal formula that offers beneficial effects in patients with IBS; however, the underlying mechanisms are largely unknown. This study showed that IBS-20  potently inhibited LPS- or IFNΓ-stimulated expression of pro-inflammatory cytokines, as well as classically activated macrophage marker nitric oxide synthase 2. Similarly, IBS-20 or the component herb Coptis chinensis decreased LPS-stimulated pro-inflammatory cytokine secretion from JAWS II dendritic cells. IBS-20 or the component herbs also blocked or attenuated the IFNΓ-induced drop in transepithelial electric resistance, an index of permeability, in fully differentiated Caco-2 monolayer. Finally, the up-regulation of key inflammatory cytokines in inflamed colon from TNBS-treated mice was suppressed significantly by orally administrated IBS-20, including IFNΓ and IL-12p40. These data indicate that the anti-inflammatory activities of IBS-20 may contribute to the beneficial effects of the herbal extract in patients with IBS, providing a potential mechanism of action for IBS-20. In addition, IBS-20 may be a potential therapeutic agent against other Th1-dominant gut pathologies such as inflammatory bowel disease.

Control of intestinal permeability is critical to host defence because enhanced permeability facilitates passage of large numbers of intraluminal bacteria, antigens, or other pathogen-generated molecules across the mucosal barrier that trigger immune activation (Turner, 2009). Evidence indicates that IBS patients exhibit increased mucosal permeability in the small intestine or colon irrespective of IBS subtype, and that is often correlated with the disease severity. In addition, changes in mucosal barrier function and the resulting immune activation are involved in triggering visceral hypersensitivity in patients with IBS (Piche et al, 2009).

This study showed that IBS-20 or the component herbs are able to preserve normal mucosal barrier function, providing another mechanism for the beneficial effects in patients. It would be interesting to identify the molecular targets of IBS-20 acting through the intracellular signaling and tight junction proteins that may contribute to herbal effects on epithelial barrier function. TNBS-induced colonic inflammation in mice is a commonly used chemically induced model that features up-regulation of pro-inflammatory cytokines (IL-1β, IFNγ, TNFα, IL-12, IL-17A). This model has been used for investigating the pathogenesis of IBD and testing the anti-inflammatory activities of agents with therapeutic potential (Wirtz & Neurath, 2007). Macrophage activation with increased levels of Th1 cytokines in the colonic mucosa is another feature of mice treated with TNBS. In addition, TNBS treatment mimics several key aspects of symptoms in patients with IBS, including the increase in mucosal permeability and visceral hypersensitivity in response to colorectal distension (Fioramonti & Gebhart, 2007).

The underlying mechanisms for the hyperalgesia are not fully understood but may involve the release of pro-inflammatory mediators interacting with, and sensitizing, the sensory and motor neurons (Hughes et al, 2009). Administration of IBS-20 with TNBS simultaneously abolished or significantly attenuated the up-regulation of pro-inflammatory cytokines in the inflamed colon consistent with its anti-inflammatory activities. It was surprising to see that the clinical symptoms or histological abnormalities of the colon in TNBS-treated mice were not improved by IBS-20. This could be attributed to a number of factors relating to the use of IBS-20 in vivo including the inability to inhibit the TNBS-induced epithelial barrier breakdown or to block production of IL-1β, a major pro-inflammatory cytokine implicated in TNBS-induced colonic inflammation.

Collectively, this study demonstrates that IBS-20 possesses strong anti-inflammatory properties. The herbal extracts not only inhibit the pro-inflammatory cytokine production from the immune cells but also block the inflammatory mediator-induced epithelial cell barrier disruption. Moreover, IBS-20 is capable of suppressing the up-regulation of inflammatory cytokine in the inflamed colon in vivo. Thus, the beneficial effects of IBS-20 in patients with IBS may be attributed to its anti-inflammatory activities. It should be noted that IBS patients are heterogeneous and inflammation may only occur in certain subtypes of patients particularly those with histories of previous infection. These factors should be taken into account when applying anti-inflammatory therapies to IBS patients. Given the fact that there are similarities and clinical overlaps between IBS and other gut inflammatory diseases (Bercik et al, 2005), IBS-20 may also be a potential therapeutic agent against other Th1-dominant gut pathologies such as IBD.

There is an absolute relationship between IBS and stress. This has do with the way that our bodies respond to internal or external changes. This stress response, also known as the fight-or-flight response, appears to have developed so as to allow us to respond to life-threatening situations in a way that would maximize our chances for survival. The stress response is a complicated process. It involves our nervous and endocrine systems and it stimulates changes in a variety of body processes, including blood pressure, heart rate, muscle tension and bowel functioning. It is the changes in bowel functioning that tie the stress response and irritable bowel syndrome (IBS) together.

The Brain-Gut Connection

In response to a perceived stressor (external or internal), various parts of the brain begin to communicate with one another, including the sensory cortex, the thalamus and the brain stem. This process then triggers a response along two major bodily paths. The first is the hypothalamic-pituitary-adrenal axis, resulting in an increase in hormonal secretions, particularly the hormone cortisol. The second path is the autonomic nervous system, which releases adrenaline (epinephrine) and noradrenaline (norepinephrine) causing cardiovascular, muscular and digestive system changes. These two pathways directly affect the network of nerves found within the bowel, known as the enteric nervous system. This process, which starts with a perceived stressor, followed by a brain response, and resulting in stimulation along the two pathways down to the gut, illustrates the importance of looking at the stress response in trying to understand the dysfunction that manifests as IBS symptoms.

Physical Changes in the Stress Response

The stress response triggers the following physiological changes:

    Heart rate increases

    Increased respiration

    Increased muscle tension

    Inhibition of the immune system

    Delay in stomach emptying

    Increase in the speed of colonic contractions

    Relaxation of bladder muscles 

Research on the Stress Response and IBS

In an attempt to find effective treatments for the symptoms of IBS, researchers have been investigating the various substances that are released during the stress response. One substance that appears to have major significance in the stress response is corticotropin-releasing-factor (CRF). CRF is a family of peptides (molecules that link amino acids) that are found in both the brain and the gut. In the brain, CRF receptors are found in the areas related to digestion, emotions and the autonomic nervous system. In the gut, CRF act within the colon to increase mucous and water secretion, affect the speed of colon contractions (motility), and appear to be related to the experience of abdominal pain.  Treating the HPA axis will directly impact gut disorders.

Anxiety and IBS

Regardless of whether they have IBS, people with anxiety tend to worry greatly about issues such as health, money, or careers, according to the Anxiety Disorders Association of America. Other symptoms include stomach upset, trembling, muscle aches, insomnia, dizziness, and irritability.

There are several theories about the connection between IBS and stress and anxiety:

Although psychological problems such as anxiety do not cause IBS, people with IBS may be more sensitive to emotional troubles.

Stress and anxiety may make the mind more aware of spasms in the colon.

IBS may be triggered by the immune system, which is affected by stress.

Coping with Stress and Anxiety

There's proof that stress management can help prevent or ease IBS symptoms. Some people use relaxation techniques such a deep breathing or visualization, where they image a peaceful scene. Others reduce stress by doing something enjoyable, such as talking to a friend, reading, listening to music, or shopping. 

References

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Fioramonti and Gebhart GF, “In vivo and transgenic animal models used to study visceral hypersensitivity,” Neurogastroenterology and Motility, vol. 19, no. 1, pp. 20–28, 2007.

Hughes PA, Brierley SM, Martin CM, Brookes SJH, Linden DR, and Blackshaw LA, “Post-inflammatory colonic afferent sensitisation: different subtypes, different pathways and different time courses,” Gut, vol. 58, no. 10, pp. 1333–1341, 2009.

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