Elsevier

Phytomedicine

Volume 16, Issues 2–3, March 2009, Pages 161-171
Phytomedicine

Inhibition of inflammation-induced alterations in rat small intestine by the herbal preparations STW 5 and STW 6

https://doi.org/10.1016/j.phymed.2008.10.011Get rights and content

Abstract

Inflammation is a common mechanism of many gastrointestinal diseases. Therefore, it is interesting to know, whether complex phytopharmaceuticals known to modulate gastrointestinal motor function reveal also anti-inflammatory properties. We tested the fixed herbal combination product STW 5 (Iberogast®) and its main component Iberis amara fresh plant extract (STW 6) to characterize their protective potential in an experimental inflammation model in vitro. The test system consisted of ileum/jejunum segments from male Wistar rats. Inflammation was evoked by intraluminal instillation of 2,4,6-trinitrobenzenesulfonic acid (TNBS) for 30 min. Preincubation of TNBS together with STW 5 and STW 6 prevented the TNBS-induced inhibition of ACh-induced contractions. No differences were found between water-dissolved and ethanol-dissolved extracts. STW 5 and STW 6 reduced morphological changes induced by TNBS in mucosal and muscle layers. The IL-10 mRNA measured by qRT-PCR was not influenced by TNBS but increased by STW 5 and STW 6. The TNBS-induced increase in the TNFα-mRNA expression was suppressed by STW 5 but not by STW 6. Additionally, STW 5 decreased TNFα release in LPS-stimulated human monocytes. STW 6 influenced neither the TNFα-mRNA nor the TNFα release. These findings demonstrate that STW 5 reduced inflammation-induced alterations in ileum/jejunum segments. The effects were associated with a restoration of the disturbed ACh-induced contraction, pathohistological protection and inhibition of TNFα. STW 6 may contribute to the protective effect of STW 5 mainly by increasing IL-10 pathway but not by influencing TNFα.

Introduction

Inflammatory bowel diseases induce sensory-motor changes in the gastrointestinal systems that have been shown to persist during remission. These changes may contribute to the pathogenesis of irritable bowel syndrome (IBS) in at least a subset of patients (Collins, 2001). Neuroimmune interactions have been found to play an important role in the pathogenesis (Barbara et al., 2002), resulting from tissue injury produced by neutrophils and macrophages, which has been attributed to the ability of these cells to release reactive metabolites, cytotoxic proteins and cytokines and to their disrupting effects on the epithelial integrity (Cho, 2001; Stokkers and Hommes, 2004). Cytokines have multifaceted functions in the intestinal recruitment of inflammatory cells, stimulation of inflammatory mediator release and in the generation of imbalanced immunologic effector pathways (Fiocchi, 1998). These processes can lead to a reduced gastrointestinal contractility as seen in animal models and in human inflammatory bowel diseases such as Crohn's disease and ulcerative colitis (Grossi et al., 1993; Snape et al., 1991; Sethi and Sarna, 1991).

Experimental inflammatory bowel diseases can be induced in 2,4,6-trinitrobenzenesulfonic acid (TNBS) sensitized rats by intrajejunal challenge with TNBS. This treatment induces an inflammation of the distal small intestine, characterized by gross hyperaemia and oedema, as accessed by macroscopic score. Histologically, the inflammatory response induces cell infiltration by immune cells (Selve, 1992). Experimental inflammation can also be induced by intraluminal application of TNBS or lipopolysaccaride (LPS) into preparations of the rat small intestine in vitro (Warstat et al., 2004; Warstat and Nieber, 2004). TNBS or LPS induced a concentration- and time-dependent decrease of the acetylcholine (ACh)-induced contractions, which were partly prevented by methotraxate. Additionally, infiltration of macrophages and monocytes was shown after antigen staining (Warstat et al., 2004). Microscopic observations revealed comparable histopathological changes as shown after in vivo application of TNBS (Selve, 1992).

Various drugs and herbal extracts influencing the motility in different ways are commonly used in the therapy of gastrointestinal disorders. Among these is STW 5 (Iberogast®), a fixed combination of nine herbal extracts consisting of a hydroethanolic fresh plant extract from Iberis amara totalis and drug extracts from peppermint leaves (Menthae piperitae folium), chamomile flower (Matricariae flos), liquorice root (Liquiritiae radix), angelica root (Angelicae radix), caraway fruit (Carvi fructus), milk thistle fruit (Silybi mariani fructus), lemon balm leaves (Melissae folium) and greater celandine herb (Chelidonii herba). It is a well-established gastrointestinal phytotherapeutic medication and successfully used in the therapy of motility-related disorders of the gastrointestinal tract and dyspepsia (Rösch et al., 2002, Rösch et al., 2006). A number of independent controlled trials have shown clinical efficacy of STW 5 in patients with functional dyspepsia in comparison to placebo (Madisch et al., 2001; Nicolay, 1984) or to the synthetic drugs metoclopramide (Hanisch et al., 2005) and cisapride (Rösch et al., 2002). There were significantly more symptom-free patients after therapy with STW 5 compared to metocolpramide, and STW 5 showed equivalent efficacy to cisapride in the treatment of patients with functional dyspepsia of dysmotility type. Supportive data from retrospective and postmarketing surveillances reported no adverse events or interactions with other medications (Sassin and Buchert, 2000). Additionally to the clinical trails, many experimental data are available indicating the spasmolytic and tonicising effects of the herbal extract STW 5 in different regions of the gastrointestinal tract (Ammon et al., 2006; Heinle et al., 2006; Hohenester et al., 2004), less is known about the influence of STW 5 on inflammation-induced processes in the gut.

The primary aim of this study was to investigate the effects of STW 5 and its main component STW 6 (Iberis amara totalis) on an experimental in vitro inflammatory model using rat ileum/jejunum preparations pretreated with TNBS. Especially, the effect of STW 5 and STW 6 on the ACh-induced contraction as well as on pathohistological changes of the tissue, and gene expression of interleukine-10 (IL-10) and tumor necrosis factor alpha (TNFα) were investigated. Additionally, the effects of the herbal extracts were tested for their ability to modulate the basal and lipopolysaccharide (LPS)-stimulated TNFα release from human monocytes, an established model to test pro-inflammatory or anti-inflammatroy properties of drugs.

Section snippets

Animals

All procedures used throughout this study were conducted according to the German Guidelines for animal Care and approved by the Institutional Review Board of Animal Care Committee.

Adult male Wistar rats (8–10 weeks old, 150–220 g body weight) were obtained from the Biomedical Centre, Medical Faculty, University Leipzig, and were maintained at room temperature in a light (12 h light/12 h dark) controlled environment with free access to food and water ad libitum. The rats were anaesthetized with

Effects of STW 5 and STW 6 on TNBS-damaged ACh-contraction

The preincubation of ileum/jejunum segment with TNBS (0.01 M, 30 min) induced a damaging effect accompanied by lowering the phasic and tonic activity and suppression of ACh-evoked contractions (Fig. 1A). The maximum contractile response in the TNBS-pretreated segments was approximately 40% in comparison to intact segments of the same animal. The combined preincubation of the ileum/jejunum segments with TNBS (0.01 M, 30 min) and water-dissolved STW 5 (64–512 μg/ml) or water-dissolved STW 6 (3–24.1 

Discussion

Treatment of functional dyspepsia is hampered by the lack of an accepted pathophysiological knowledge. Presently, various drugs influencing motility or hypersensitivity as well as herbal extracts are used to treat these states. Several clinical studies showed that herbal extracts like STW 5 are potent antidyspeptic agents (Gundermann et al., 2003; Madisch et al., 2001; Rösch et al., 2002, Rösch et al., 2006). Disappointing less is known about the potential underlying mechanisms of a possible

Disclosure statement

Olaf Kelber is a scientific staff member of Steigerwald Arzneimittelwerk GmbH, the producer of Iberogast®. All other authors have no conflict of interest. There is no conflict to disclose.

The study was financially supported by Steigerwald Arzneimittelwerk GmbH, Darmstadt, Germany.

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