Anti-Inflammatory Effect for Successful Antibiotic (AGP) Alternative
Inflammation reduces profitability, endangers health and product quality. Inflammation occurs frequently in intensive, modern animal production systems, particularly when routine antibiotics are being reduced. Controlling inflammation promises ROI in terms of feed conversion and health benefits to the livestock. This control is now the proposed mode of action (MOA) of commonly used antimicrobials in feed (AGPs). By managing triggers of inflammation and actively downregulating inflammation, excellent results can be achieved with alternatives to antibiotics in terms of productivity and even welfare. It is all about changing focus from anti-microbial effects to anti-inflammatory.
Where and when does inflammation occur?
As livestock production has intensified across many countries, inflammation has become a common side effect. An increase has been observed in productions systems where routine antibiotic usage has been discontinued. It is a natural process and has been connected to desirable outcomes, such as controlled apoptosis, however, it can get out of hand. Inflammation becomes a challenge when the up- and down-regulations of the process are not well matched. There are different triggers that can start this process such as oxidative stress, certain mycotoxins, social stress, fast growth rates, and certainly dysbiosis of the gut microbiome. Several of these inflammation starting points also trigger each other (e.g. social stress leading to dysbiosis) which can lead to a vicious cycle of inflammation.
Once inflammation has gone beyond the normal level, it becomes very challenging for the animal to regulate it again back to normal levels. While inflammation has likely always posed a challenge in livestock production, its significance is certainly increasing in modern systems.
The mode of action (MOA) of antibiotic growth promoters
Originally, the discovery of the antibiotic growth promoting effect was accidental. Afterward, several explanations were suggested (after Niewold, 2007):
- Inhibition of subclinical infection
- A reduction in undesirable metabolites (e.g. ammonia)
- Less use of primary nutrients by microbes
- Improved nutrient absorption by gut-wall thinning effects
However, none of these could explain the growth promoting effect over a wide range of very different antibiotic substances. One factor all efficient AGPS have in common is a non-antibiotic effect. Even in low doses, they act as an anti-inflammatory. Regional laws governing antibiotic use have either banned antibiotics or are considering bans in many countries. Because the effect was found to have been anti-inflammatory and not anti-microbial, livestock antimicrobial supplements are being selected based on their anti-inflammatory potential instead of the anti-microbial potential.
Why is modulating inflammation relevant for livestock production?
Anti-inflammatory effects in the intestinal wall are now the proposed mode of action of antibiotic growth promotion. This alone should make anti-inflammatory effects worth a second look.
Heating while keeping your windows open
First, inflammation costs energy. Simply raising the body temperature of an animal by one degree does not appear to be a big effect. It is the first visible sign of any inflammation typically triggered by IGFα. However, such a small increase comes with a large energy expenditure, particularly in relatively small animals such as poultry. All energy expenditure comes at the cost of feed conversion affecting the bottom line of any production.
Driving with the handbrake on
While the exact hierarchy is under much debate in the scientific community, it is agreed upon that animal physiology prioritizes energy utilization. There is no dispute, however, that growth and the specific immune response are of low prioritization. As long as an animal experiences a shortage of energy due to increased exertion from inflammation, it cannot reach its full genetic potential in terms of growth or yield of milk or eggs, respectively.
Illustration: Damaged villi, a gateway for pathogens
Opening the door for anyone to enter
Inflammation always causes a weak area in the intestinal wall. In cases of severe dysbiosis this can be seen in necropsies with the naked eye. On a cellular level the effects can range from imperfectly closed tight junctions, over reduced mucus, loss of gut structure (decreased villi length and crypt depth), all the way to open lesions. These weakened areas make is much easier for pathobionts such as Enterococcus cecorum or Campylobacter to translocate past the epithelial wall. While pathobionts are frequently present in broilers, they become a severe problem when they translocate. At the same time, additional substances such as mycotoxins or contaminants will transverse into the animal at a higher rate when inflammation has weakened the structures.
How can anti-inflammatory effects be characterised?
There are a variety of tests in use to evaluate pro- and anti-inflammatory responses. Natural periods of high inflammation risk can also be used (i.e. weaning in piglets). The best standard to evaluate anti-inflammatory effects is to induce inflammation, with TNBS (Foligné et. al 2012) for example, and control the harmful effects with a known and clearly defined anti-inflammatory drug such as prednisolone. In the cited study, the test substance PB6 spores (CLOSTAT ®) was directly compared to prednisolone with significantly positive results. Equally specific essential oils, such as ORSENTIAL, also show promise to have anti-inflammatory effects.
Inflammation directly affects productivity, the health status of the final product (e.g. potential invasive salmonella or campylobacter) and animal welfare. The best solution utilizes natural feed additives that have proven ROI. Anti-inflammatory solutions will have a positive impact on economics and health while targeting the exact cause of excessive inflammation. However, due to the multi-factorial nature of inflammation, a complete solution should ideally rely on more than one substance. Genetics, intelligent mycotoxin management by binding mycotoxins in the animal rather than mitigating the effects afterwards (e.g. Toxfin™), and managing the microbiome to prevent dysbiosis should all be considered. CLOSTAT has shown its efficacy in managing dysbiosis and inflammation in several studies (Abdelqader, et al. 2012 and Foligné et. al 2012). Inflammation can only be managed successfully if several of the factors that trigger it are actively managed.
Abdelqader, 2012 Trop Anim Health Prod. 2013 Apr;45(4):1017-24. doi: 10.1007/s11250-012-0326-7. Epub 2012 Dec 28.
Abdelqader A1, Irshaid R, Al-Fataftah AR. Effects of dietary probiotic inclusion on performance, eggshell quality, cecal microflora composition, and tibia traits of laying hens in the late phase of production.
Niewold T.A. 2007. The nonantibiotics anti-inflammatory effect of antimicrobial growth promoters, the real mode of action? A hypothesis. Poult. Sci. 86(4).
Foligné et. al 2012, Clinical Nutrition 31 (2012) 987-994, Spores from two distinct colony types of the strain Bacillus subtilis PB6 substantiate anti-inflammatory probiotic effects in mice