*1.3. Use of Organic Extracts and Natural Supplements as an Alternative Holistic Strategy*

Another approach against nosemosis is the use of organic extracts and natural supplements. The major advantage is their lower toxicity for both bee colonies and the environment, compared to other chemical compounds [47]. Many investigations have shown that various organic and aqueous natural products do not show any toxicity to honey bees and lead to a decrease in both parasite load and mortality rate caused by *N. ceranae* infection [56–58]. Natural compounds, mostly flavonoids and polysaccharides contained in a number of medicinal plants, demonstrate anti-microsporidian activity in honey bees and are applied most often as alcoholic extracts, although some studies dispute the role of the biological activity of flavonoids against *N. ceranae* infection [58]. Propolis, a mixture of resins, wax, and pollen from buds and flowers of plants, enriched with enzymes and subjected to lactic acid fermentation in the digestive system of bees, has strong antimicrobial, antiviral, and antifungal properties [59]. These properties provoke the interest of the scientific community in propolis as an anti-microsporidian drug. In this relation, an ethanolic extract of propolis has been tested in different bee species experimentally infected with *N. ceranae* [59–61]. The obtained results from these investigations support the hypothesis that propolis represents an effective and safe product to control *N. ceranae*, while it is interesting to note that bees seem not to use it to self-medicate when infected with these microsporidia [61]. Some studies have indicated that honey and pollen from sunflowers (*Helianthus annuus* L.; Asteraceae) may also reduce the microsporidian infection and increase survival rate in honey bees [62,63].

A number of commercial supplements (HiveAliveTM, Api-Bioxal® and ApiHerb®, "BEEWELL AminoPlus", Nozevit®, BeePro®, MegaBee®, etc.) have been tested for anti-*N. ceranae* activity as well [64–68]. For instance, administration of HiveAliveTM and ApiHerb® significantly reduces *N. ceranae* spores load [64,65]. Application of the dietary amino acid and vitamin complex called "BEEWELL AminoPlus" decreases *N. ceranae* spore and protects honey bees from immune suppression by upregulating the expression of genes for immune-related peptides (abaecin, apidaecin, hymenoptaecin, defensin and vitellogenin) [66]. The investigation of Nozevit® (a natural product from plant polyphenols) has shown that this commercial phytopharmacological supplement may improve bee health by decreasing colony spore loads [67]. However, DeGrandi-Hoffman et al. [68] have found that bee colonies fed with the commercial protein supplements BeePro® and MegaBee® exhibited higher levels of black queen cell virus and *N. ceranae* incidence and greater queen losses in comparison to bee colonies feeding on natural forage (*Brassica rapa*—rapini).

#### *1.4. Probiotics and/or Prebiotics*

The negative consequences associated with the use of antibiotics in the treatment against nosemosis are primarily related to the disruption of the host microbiota and, in some cases, the increased susceptibility to *N. ceranae* infection [69,70]. The use of microbial supplements (probiotics or prebiotics) represents another innovative approach not only for maintaining or restoring intestinal microbiota, but also in the combat against nosemosis. In this aspect, endogenous gut bacteria belonging to *Lactobacilliaceae*, *Bifidobacteriaceae*, and *Acetobacteraceae* families have been found to suppress the development of *N. ceranae*, by reducing the spore load [70,71]. Different commercial probiotics strains (Bactocell® and Levucell SB®, Lallemand Inc., "Biogen-N", "Trilac", "Lakcid", etc.) have also been tested as an alternative therapy against *N. ceranae* infections in honey bees [72–76]. The obtained results from these investigations have shown endogenous bacterial strains to be as efficient as commercial strains in terms of survival of honey bees infected with *N. ceranae*, without a pronounced antagonistic effect on the parasite development.

However, some studies have indicated that uncontrolled and unbalanced administration of probiotics to honey bees may cause dysbacteriosis and increase pathogen susceptibility [76,77].

Some prebiotics are also used to control *N. ceranae* infection in honey bees. For example, prebiotic mannan-oligosaccharides (MOSs) are easily fermentable by gut microbiota and their accelerated reproduction allows them to compete with pathogenic bacteria for both nutrients and space in the gut. The β-glucans (glucose homopolymers) are known for their immune-modulating impact on different species, including honey bees [78]. The polysaccharide chitosan stimulates the bee immune system, leading to a decrease in the degree of infection with *N. apis* and to increased bee survival [79].
