FEED Business Worldwide - December, 2011
Potential of Phytogenics in Animal Nutrition
by Dr. Basharat SYED, MICRO-PLUS Konzentrate GmbH, Am GÃ¼terbahnhof 7a D-37627 Stadtoldendorf, Germany
digestaromÂ® belongs to the group of phytogenic feed additives and has been classified as a flavour according to the EC Regulation No 1831/2003 of the European Parliament and Council. Essentially, digestaromÂ® is a combination of essential oils, herbs, extracts and spices including onion, garlic, caraway, fennel, gentian, melissa, peppermint, anise, oak bark and clove.
In addition to the flavouring effect, which arouses the animal's appetite, digestaromÂ® stimulates the digestive tract's internal secretions. This increased secretion of the endogenous digestive enzymes optimizes digestion and the degradation of metabolic products. As a result, the absorption and metabolic conversion of the supplied feed nutrients is optimised.
For many years Micro-Plus has considered not only the animal performance improvement induced by the supplementation of digestaromÂ®, but also its influence on genetic expression and inflammatory processes in the intestine.
Mode of action
Several pathological stimuli, including bacteria and viruses, are known to stimulate inflammatory processes in the intestinal mucosa through their cytokine-mediated activation of the pro-inflammatory transcription factor NF-kB.
NF-kB is considered the master regulator of inflammation because its activation switches on a series of genes that mediate inflammatory response. (Cytokines, chemokines, adhesion molecules, Collins et al.1995)
Through the subsequent release of inflammatory mediators including TNFa, IL-6, or INFy, which enter the animal's circulatory system, inflammatory responses can spread beyond the intestine itself to affect other tissues.
For instance, the resulting inflammatory mediators cause a stimulation of protein catabolism in skeletal muscle through their activation of the ubiquitin-proteasome-system, which is the most important system for intracellular protein degradation in mammalian cells.
This in turn leads to an increase in the formation of acute phase proteins in the liver. Considering that such processes lead to an impairment of animal performance, inhibition of inflammatory intestinal processes is a reasonable approach to maintaining the performance and health of livestock animals.
In this respect, a large body of evidence exists in the literature to show that phytochemicals, which are important constituents of essential oils, are capable of mitigating inflammatory instestinal processes. For such essential oils, their main mode of action is by blocking the pro-inflammatory transcription factor NF-kB.
In addition, recent studies demonstrate that phytochemicals exert protective effects on tissues including the intestine by activating the Nrf2 pathway (Wagner et al.2010, Boesch-Saadatmandi et al.2011). Activation of the Nrf2 pathway leads to the activation of genes responsible for cellular defence against reactive oxygen pathogens and the detoxification of xenobiotics (Niture et al.2010).
In this University of Giessen study, the objective was to explore the anti-inflammatory potential of the phytogenic additive digestaromÂ®, which is rich in essential oils, by using Caco-2 intestinal epithelial cells. Caco-2 cells express characteristics of enterocytic differentiation upon reaching confluence, and are therefore an established in-vitro model for intestinal epithelial cells (Jumarie and Malo, 1991).
To evaluate the anti-inflammatory action of digestaromÂ®, its effect on TNFa-induced transactivation of NF-kB and TNFa-induced mRNA levels of selected NF-kB target genes was investigated. These included its effect on genes responsible for regulating interleukin-8 (IL-8), chemokine (C-X-C motif) ligand 10 (CXCL 10), intercellular adhesion molecule-1 (ICAM-1) and monocyte chemoattractant protein-1 (MCP-1).
To study the effect of digestaromÂ® on activation of the Nrf2 pathway, the mRNA levels of selected Nrf2 target genes, heme oxygenase-1 (HO-1), cytochrome P450 isoform 1A1 (CYP1A1) and UDP-glucuronosyltransferases isoform 1A1 (UGT1A1) were determined.
Supplementation of digestaromÂ® in feed rations reduced the activation of the complex transcription factor NF-kB, such that the damages caused by inflammatory processes are substantially reduced. NF-kB's mode of functioning of is represented in Figure 1.
During the research trial, digestaromÂ® significantly reduced the mRNA levels of the NF-kB target genes IL-8, ICAM-1, and MCP-1. These genes initiate and maintain inflammatory reactions in Caco-2 cells contracted with lipopolysaccharides, thereby functioning as antigens which provoke inflammatory reactions and added TNF-a (tumour necrosis factor alpha), which intensifies the inflammation.
digestaromÂ® is also able to stimulate and raise the activity of the transcription factor Nrf-2 responsible for anti-oxidative activity
The following positive effects were observed and can be concluded from the above research.
First, digestaromÂ® is capable of inhibiting transactivation of the pro-inflammatory transcription factor NF-kB, thus it is able to counteract the inflammatory processes.
Second, digestaromÂ® is able to activate the transactivation of Nrf2 and thus stimulate the expression of antioxidant enzymes and enzymes of xenobiotic metabolism (phase 1 and 2 enzymes) in the liver.
Third, digestaromÂ® is able to reduce the hypersensitivity of the intestines due to inflammation and, eventually, reduce the incidence of the onset of enteric diarrhoea provoked by the activity of inflammatory transcription factor NF-kB.
Fourth, digestaromÂ® assists and promotes the immune system to enhance its resistance capacity to defend any potential inflammatory or oxidative factors.
Practical and economic benefits
Through its prophylactic nature, digestaromÂ® prevents excess inflammation and, eventually necrosis, in the intestinal tract thereby promoting optimal animal performance and reduced mortality. It also helps in the reduction of sub clinical gastro-intestinal disorders during feed changes, which reduces production loses.
Due to its stimulation of Nrf2, digestaromÂ® indirectly prevents the hypersensitivity of intestines to oxidative stress. The extra-hepatic detoxification, in which Nrf2 plays an important role by promoting the formation of detoxifying enzymes, then helps in the breakdown of undigested feed and metabolic toxins, thereby assisting the liver in performing this function.
By stabilising the immune system, digestaromÂ® plays an important role in situations of peak production performance when the organism is metabolically burdened, stressed and unstable, thus saving energy and therefore production costs.
A graphic representation in Figure 5 shows the cardinal signs of inflammation, the appearance and damages of these are mitigated by the continuous supplementation of digestaromÂ® in the diet, which prevents economic loses caused by these classical signs and symptoms.
In sum, regular digestaromÂ® supplementation of feed rations acts as a prophylactic against inflammatory reactions in the gastro-intestinal tract by inhibiting the NF-kB factor and stimulating the anti-oxidative factor Nrf2. This activity interrupts the damaging circle of the release of inflammatory mediators that otherwise would provoke more intensive, body-wide inflammation and subsequent necrosis.
Boesch-Saadatmandi C, Loboda A, Wagner AE, Stachurska A, Jozkowicz A, Dulak J, DÃ¶ring F, Wolffram S, Rimbach G (2011) Effect of quercetin and its metabolites isorhamnetin and quercetin-3-glucuronide on inflammatory gene expression: role of miR-155. J Nutr Biochem. 22:293-299.
Collins T, Read MA, Neish AS et al. (1995) Transcriptional regulation of endothelial cell adhesion molecules: NF-ÎºB and cytokine-inducible enhancers. FASEB J. 9:899-909.
Jumarie C, Malo C (1991) Caco-2 cells cultured in serum-free medium as a model for the study of enterocytic differentiation in vitro. J Cell Physiol. 149:24-33.
Niture SK, Kaspar JW, Shen J, Jaiswal AK (2010) Nrf2 signaling and cell survival. Toxicol Appl Pharmacol. 244:37-42.
- Wagner AE, Ernst I, Iori R, Desel C, Rimbach G (2010) Sulforaphane but not ascorbigen, indole-3-carbinole and ascorbic acid activates the transcription factor Nrf2 and induces phase-2 and antioxidant enzymes in human keratinocytes in culture. Exp Dermatol. 19:137-144.
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