Thursday, 20 March 2014

Probiotics produced within the fish microbiome: A more effective strategy than commercial human antibiotics?

Marine invertebrates, and the symbiotic and mutualistic microbial communities living inside them, have traditionally been used for discovering novel natural products, although the microorganisms are the true producers of the majority of compounds. These chemicals are significant in the pharmaceutical industries for manufacturing new drugs. Previously unexplored bacterial niches and whole genome sequences may harbour new compounds and activate silent biosynthetic gene clusters, respectively. This particular study was influenced by the human microbiome project to determine whether marine vertebrates can harbour a potential source of new types of marine Actinobacteria. Intestinal bacterial diversity is higher than was first thought, but the diversity of Actinobacteria can vary depending on which discrete environmental niche they are located in.

Vibriosis is one of the most dominant diseases that affects both wild and farmed fish, and is induced by many different Vibrio species, which are all fast-growing, opportunistic bacteria that quickly colonise the gut in fish. In some cases, antibiotics can cause organisms (i.e. humans) to become more susceptible to infection by bacteria, so commensal bacteria are important in controlling the onset of disease.

Vertebrates have been largely ignored in studies aiming to discover natural microbial products, so this is the first to focus on the fish microbiome acting as a source of bacterial diversity, and to isolate culturable and taxonomically-distinct Actinobacteria for new compounds. The commensal microbes being tested in this study use a large number of biological activities to inhibit the growth, and effects, of both Gram-positive and Gram-negative pathogens on fish.

Intact whole dead fish were bought from commercial vendors and dissected. Three main phyla, Actinobacteria, Firmicutes and Proteobacteria, were found in the phylogenetic tree that was created after the stomach and intestinal contents were analysed. As all marine fish are susceptible to at least one Vibrio species, there are limited types of treatment that can be applied specifically for fish pathogens, which is why traditional antibiotics have been over-used in aquaculture.

The discovery and development of compounds for drug synthesis can be used against protozoan parasites and bacteria, and the capacity of these isolates to produce bioactive natural products against them was tested by producing large-scale liquid cultures. Five out of the 21 extracts inhibited the growth of one or more Gram-positive strains, and eight of the nine stopped one or more Gram-negative strains from growing, so some compounds may have broad spectrum efficacy for treating vibriosis in aquaculture.

One certain isolated strain, FI-1004, showed even lower sequence identity to published sequence data (97.8%), which implied that they had significantly diverged from known cultured isolates. Secondary screening of fractions of FI-1004 showed that only sebastenoic acid, a novel bioactive lipid, was responsible for the bioactivity. Branched chain fatty acids are universally found in all bacteria and are common substrates for phospholipid synthesis for bacterial cell membranes. Although saturated anteiso fatty acids containing 15 carbon atoms are relatively rare, sebastenoic acid was discovered with a unique unsaturation pattern (3 particular sub-units) for this compound class. Sebastenoic acid displayed moderate activity against the three Gram-positive test strains. In addition, because strain FI-1004 can produce an antibiotic to act against common pathogens, it may be a type of probiotic within the fish microbiome.

Maintaining a healthy microbiota has been linked to maintaining the general health of the fish host, as they are in direct contact with opportunistic pathogens in the marine environment, and probiotic bacteria are thought to provide more benefits to the health of fish in aquaculture than commercially available products typically used for humans. Therefore, it is critical in understanding the microbial composition of commercial fish to determine the appropriate probiotics for protection against harmful bacteria such as many Vibrio species, as it is species-specific and it may prove to be a more effective management strategy.

This research represents the first study into the discovery of natural products from the fish microbiome. The authors have managed to decipher a large gap in the literature in terms of the role of the microbial community in vertebrates to produce novel bioactive secondary metabolites, so this should be used as a springboard for further investigations. However, they also used a range of fish, such as lantern fish, mackerel and Canadian rock cod from different regions like Moss Landing, California and Seattle, Washington, when they already mentioned that the diversity of gut microbiomes in fish are known to vary widely between species and distributions. Therefore, they seem to imply that these novel bioactive compounds are ubiquitous across many or all fish taxa, but the probiotic effect on common pathogens may differ between species, if for example, higher concentrations of these compounds are needed to act against bacteria in some fish species more than others.

 Sanchez, L.M., Wong, W.R., Riener, R.M., Schulze, C.J., and Linington, R.G. (2012) Examining the fish microbiome: Vertebrate-derived bacteria as an environmental niche for the discovery of unique marine natural products. PLoS ONE, 7(5): e35398. doi: 10.1371/journal.pone.0035398

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