br Conclusions Collectively extensive in vivo

Collectively, extensive in vivo data have demonstrated that orally administered low-dose IFN has rapid and systemic beneficial biological effects in animals and humans. In the present study, it was demonstrated that oral IFN statistically modulated the expression of 12 genes within a specific KEGG pathway (cytokine–cytokine receptor interactions). In turn, these data suggest that low-dose oral IFN exerts systemic and largely beneficial anti-viral effects by up- or down-regulation of specific immune response genes and their products likely needed for recovery from any viral disease, including FMDV. The accumulated evidence from this and other studies suggests that adoption of orally administered bovine IFNα or HuIFNα as a therapeutic modality to suppress viral replication in livestock at risk for FMDV exposure is an inexpensive, easily dispensed and widely available alternative and adjunct to vaccinations for FMDV. In addition to the obvious antiviral effects of oral IFN, systemic immune modulating effects are also part of the overall beneficial responses to IFN and it is the latter that may well provide prolonged systemic beneficial effects in virus-susceptible livestock populations. The results are intended 5 aminolevulinic acid to stimulate further testing using delivery in feed or water, potentially helping the livestock industry manage viral respiratory disease and protect against an FMDV outbreak.


Microbial colonization begins immediately after birth with facultative anaerobes, such as lactobacilli, enterococci and enterobacteria, being the first colonizers. Colonization by anaerobic microorganisms follows, including Bifidobacterium, Bacteroides and Clostridium, resulting in a gradual decrease of the ratio of facultative anaerobes to strict anaerobes over time (Arboleya et al., 2012). Bifidobacteria, along with lactobacilli, are an important part of normal intestinal microbiota of various mammalian species and are also the best characterized and widely commercialized probiotics. Both lactobacilli and bifidobacteria are non-spore-forming, gram-positive, lactic 5 aminolevulinic acid producing bacteria (LAPB). Lactobacilli have limited biosynthetic abilities and ferment refined sugars, generating lactic acid as the major end product (Wells, 2011), whereas bifidobacteria are important producers of short chain fatty acids (SCFA) (Tojo et al., 2014). Despite some common properties, lactobacilli and bifidobacteria belong to two taxonomically distinct groups: the genus Lactobacillus in the phylum Firmicutes and the genus Bifidobacterium in the phylum Actinobacteria, respectively. In adults, Firmicutes and Bacteroidetes phyla usually dominate the intestinal microbiota, whereas Actinobacteria, Proteobacteria and Verrucomicrobia are considerably less abundant. However, in naturally delivered, breast-fed infants, bifidobacteria (Actinobacteria) appear between days 2 and 5 after birth and reach a maximum of up to 99% of all bacteria within one week becoming the predominant bacterial component of the infant fecal microbiota (Kurokawa et al., 2007; Mitsuoka and Kaneuchi, 1977; Turroni et al., 2012; Yatsunenko et al., 2012). Some studies report that Bifidobacterium infantis and Bifidobacterium breve were the most common species found in healthy infants (He et al., 2001).
Although not the most dominant in adulthood, lactobacilli and bifidobacteria remain stable elements of the normal intestinal microbiota, maintaining their important functions throughout life, and their dysbiosis is associated with a plethora of pathological conditions (Gerritsen et al., 2011). Numerous studies with different strains of Lactobacillus and Bifidobacterium have been performed in vitro and in vivo, in humans and animal models to investigate their immunomodulatory properties and probiotic potential to treat various infectious, allergic and inflammatory conditions (Grimm et al., 2014; Picard et al., 2005; Tojo et al., 2014; Wells, 2011) (Fig. 1). While not always conclusive, most of them emphasized the beneficial effects of these probiotic bacteria, that appear to be pathogen/condition, bacteria and sometimes host species-specific. In most clinical trials, lactobacilli and bifidobacteria probiotics were demonstrated to be safe with the rare exception of probiotic-associated infections in immunosuppressed patients (Saarela et al., 2002). Historically, the most usual application of probiotics is to treat gastrointestinal disorders, including infectious diarrhea (de Vrese and Marteau, 2007).