Management Strategies: Why Sick Animals Don't Grow

Conventional environments lead to slower growth compared to germ-free environments.
Germ-Free Faster growth
Conventional environments with antibiotics lead to improved growth.
- The increase in growth is greater in conventional environments than in germ-free environments when antibiotics are added.
- Antibiotics minimize the number and severity of interactions (referring to pathogen-host interactions).
- Antibiotics minimize pathogen-induced growth inhibition on the host.

Microbial invasion can lead to:
- Loss of appetite
- Fever
- Depression/sleepiness, lethargy
- Protein catabolism

Microbial invasion leads to inflammation and local tissue damage.
The body mounts both local and systemic responses.
- The local response addresses the immediate incursion.
- The systemic response protects the whole body.
The systemic response involves three macrophage-derived pro-inflammatory cytokines: interleukin-1 (IL-1), interleukin-6 (IL-6), and tumor necrosis factor (TNF).

Pro-inflammatory cytokines: IL-6, TNF, IL-1
Inflammation: Some cytokine responses are designed to protect the body as a whole.
Anti-inflammatory responses occur during the recovery period

Low molecular weight proteins.
Regulate all important biological processes (e.g., cell growth, cell activation, inflammation, immunity, tissue repair).
Secreted by a range of cells (e.g., T cells, B cells, macrophages, neutrophils).
Examples:
- Interleukins (1-19): Regulate interactions between lymphocytes and other leukocytes.
- Transforming growth factors: Involved in cell differentiation, embryonic development, and regulation of the immune system.
- Tumor necrosis factors: Programmed cell death.
- Interferons: Response to viral infection.

Immune cells usually make more than one cytokine when activated.
Cytokines affect a wide variety of cells and tissues.
Each cytokine can have several different functions, depending on which cell it binds to.
Different cytokines may act on a single target cell.
Many cytokines work best in association with other cytokines (i.e., synergy).
Cells can only respond to cytokines if they express the appropriate receptor.
Effective at low concentrations.
Tend to act locally (paracrine) or control the activity of cells that produced them (autocrine), but they can also act systemically (endocrine).
Short half-life.
Can be inhibited by receptor antagonists.

Illustrates the complex interactions between various immune cells (e.g., Eosinophils, T cells, B cells, Mast cells, Macrophages, Neutrophils) and the cytokines they secrete (e.g., IL-1, IL-2, IL-3, IL-4, IL-5, IL-6, IL-7, IL-8, IL-10, IL-11, IL-12, IL-13, IL-15, IFN-α, IFN-γ, TNF-α, TNF-β, TGF-β, GM-CSF, G-CSF).
Highlights the role of cytokines in processes such as clonal expansion of T cells, B cell differentiation into plasma cells, hematopoiesis, and activation of endothelial cells and fibroblasts.

Pro-inflammatory cytokines (IL-1, IL-6, TNF) act on the brain to increase body temperature, induce sleep, and suppress appetite.

Pro-inflammatory cytokines (IL-1, IL-6, TNF) induce metabolic changes such as increased protein catabolism, mobilizing a pool of amino acids.
This eventually leads to muscle wasting, but the amino acids are available for protein synthesis.

Pro-inflammatory cytokines (IL-1, IL-6, TNF) induce liver cells to increase protein synthesis and secretion.
Acute phase proteins are produced within hours of injury, with a rapid rise in concentration (1000x) that subsides within 24-48 hours.
Function in host defense (e.g., C-reactive protein (CRP)).
CRP binds to invading organisms and damaged tissue, promoting their phagocytosis.
CRP inhibits neutrophil release of damaging radicals, reducing tissue damage and enhancing tissue repair.

Aim: Track the development of immunoregulatory cytokines during the development of and recovery from swine dysentery.
Methodology:
- Challenged 10 pigs with Brachyspira hyodysenteriae.
- Took blood samples pre-inoculation, during acute dysentery, and during the recovery period.
- Measured cytokines IL-1, IL-6, IL-10, TNF, and IFN, and APP – serum amyloid A.
Results:
- 8 pigs developed diarrhea with compromised body function.
- 2 pigs remained clinically healthy.
- Acute phase protein – Serum amyloid A – (SAA) increase coincided with the first 3 days of clinical signs of dysentery
- Induced by pro-inflammatory cytokines, especially IL-1 and IL-6.
- Chemotactic for neutrophils and mast cells.
- Experimentally induced swine dysentery induced detectable levels of some cytokines, differing with the stage of the disease.
- No IFN-gamma detected.
- Observed neutrophilia, monocytes, and CD8 lymphocytes.
- Detected bacteria-specific antibodies.
- IL-10 is anti-inflammatory.
- IL-6 in serum is not a reliable marker for swine dysentery, as only 3 of 8 sick pigs had elevated levels in the blood, possibly due to production outside the sampling time or local production dealing with local incursion.
- The presence of IL-6 and TNF in clinically healthy animals indicates possible subclinical infection.

Antibiotics have a greater effect on growth in conventional environments than in germ-free environments.
Antibiotics minimize the number and severity of pathogen-host interactions.
Pathogen-induced growth inhibition on the host is mediated by pro-inflammatory cytokines.

Pigs grown in clean and dirty environments showed a 12% difference in growth.
High levels of pro-inflammatory cytokines and APP – C reactive protein were found in pigs in the dirty environment.
Treatment with IL-1 improved growth and reduced C-reactive protein release in the dirty environment, blocking aspects of the host-pathogen interaction axis.