The Blis Story
Blis Technologies are the developers of the world’s first advanced oral probiotics.
We currently market two strains of probiotic bacteria – BLIS K12™ and BLIS M18™ – both of which occur naturally in the oral cavity. However, only around 2% of the population have these healthy bacteria at levels high enough to be effective.
BLIS K12™ was our first discovery. It was originally developed into a probiotic supplement to support throat health. But the benefits of BLIS K12™ have been found to be more wide-reaching as more studies have been completed. We know that BLIS K12™ also supports the ear nose and throat health of infants and children, and is also effective in improving bad breath (halitosis).
The second strain – BLIS M18™ – was discovered later and this promotes the healthy bacterial balance for dental health. Both strains were discovered by Professor John Tagg while at the University of Otago Microbiology Department. His story is both fascinating and inspiring. Professor Tagg extensively catalogued a collection of more than 2000 of these bacteria strains over a period of more than 30 years. Those bacteria were then acquired by Blis Technologies with the first product – ThroatGuard – launched in 2002.
Today the Blis portfolio consists of:
- DailyDefence – a daily advanced probiotic containing BLIS K12™ to support throat immunity
- DailyDefence Junior – a daily powder formulation of BLIS K12™ to support ear, nose and throat health of infants and small children
- ElitePRO – our WADA tested products for high performance athletes, developed in collaboration with High Performance Sport NZ (https://hpsnz.org.nz/about-us/commercial-partners/)
- ThroatGuard PRO - a high dose of BLIS K12™ to give boosted immunity support to help protect against winter ills
- TravelProtect – a higher dose formulation of BLIS K12™ with a specialised regimen to help support the immune system when travelling;
- FreshBreath Kit – a regime that re-populates the mouth with BLIS K12™, thereby replacing the bad ‘smelly’ bacteria in the mouth, not simply masking it;
- HoneyBlis – a great tasting honey lozenge with BLIS K12™ to soothe and protect a scratchy or dry throat;
- ToothGuard and ToothGuard Junior – our advanced probiotic with BLIS M18™ for the health of teeth and gums, helping to prevent cavities in children and maintaining healthy gums in adults.
All our products are developed and manufactured at our headquarters in Dunedin, New Zealand.
The John Tagg Story
Professor Tagg’s first significant encounter with Streptococcus pyogenes – the bacteria that causes a strep sore throat – was as a 12-year old living in Melbourne. A series of sore throats culminated in him developing rheumatic fever. He then had to consume penicillin tablets daily over the following decade to help prevent any follow-up attacks of the disease. Fortunately, due to this antibiotic regime, he did not suffer any of the residual heart damage that can occur from recurrent episodes of rheumatic fever.
Nevertheless, it just seemed to the young John Tagg that there must be a better way to defend against streptococcal sore throats.
Following high school, John studied at Melbourne University, and in the third year of his Microbiology degree, he became influenced by the teachings of Dr Rose Mushin concerning the potential applications of bacterial interference as a targeted and natural means of infection prevention. Dr Mushin had become a devotee of an old-world strategy for infectious disease control, the origins of which pre-date the discovery of antibiotics and indeed can be traced back to the studies of Louis Pasteur.
Dr Mushin managed to convince the entire microbiology class to consume milk that had been seeded with so-called “friendly” Escherichia coli. These bacteria were equipped with a bacteriocin armament that would enable them, from their proposed site of lodgement in the intestinal tract, to kill any vulnerable salmonellae that happened to pass close by. Dr Mushin’s proposal sounded logical and feasible. Bacteriocins, she explained, were proteinaceous antibiotics produced by bacteria which had a bacteriocidal mode of action against various other relatively closely-related bacteria that were potentially capable of competing with them for occupancy of the same ecological niche (i.e. they were anti-competitor molecules).
As the young John Tagg listened to Dr Mushin it occurred to him that perhaps a similar strategy could be applied in the human oral cavity to gain some relatively-specific protection against S. pyogenes infections.
That insight provided him with an irresistible challenge – he now knew what he wanted to do. First John needed to familiarise himself with the idiosyncrasies of streptococcal behaviour and his conviction was that, in order to prevent S. pyogenes from assaulting its human host, it would be important to try to strengthen the territorial defensive capabilities of the non-virulent streptococcal component of our indigenous microbiota. It occurred to him that over the course of their lengthy co-evolution with humans it was the indigenous oral streptococcal populations that would surely have developed the most effective and specifically-targeted bacteriocin weaponry to counter competition for their space by rapidly-multiplying virulent streptococci.
John Tagg next undertook PhD research at Monash University – the theme of those studies being an exploration of the relationship between S. pyogenes infections and the induction of the autoimmune manifestations of rheumatic fever. He set about screening many hundreds of oral streptococci for their bacteriocin-producing capability (i.e. bacteriocinogenicity) and included amongst these streptococci was a series of S. pyogenes isolates from the Fairfield Infectious Diseases Hospital in Melbourne. On September 1, 1969, John discovered that number 22 in this series produced bacteriocin-like inhibitory activity against some other S. pyogenes strains when tested in a deferred antagonism assay. The inhibitory agent, later given the name streptococcin A-FF22, was the first of the streptococcal bacteriocins to be isolated and characterised. Next it was time for John to undertake a post-doctoral apprenticeship, and from his reading of the current scientific literature, he knew where he wanted to continue his studies.
Next, it was time for John to undertake a post-doctoral apprenticeship, and from his reading of the current scientific literature, he knew where he wanted to continue his studies. Dr Lewis Wannamaker at the University of Minnesota was an influential leader in the field of streptococcal research and had played a major role in developing the original guidelines for the use of penicillin prophylaxis as a preventative against rheumatic fever recurrences. In 1972 Dr Wannamaker hosted a workshop on ‘Streptococci and Streptococcal Diseases’ at the University of Minnesota which was attended by many of the leading S. pyogenes researchers of that era. In his workshop summary, Dr Wannamaker remarked that “working with the streptococcus is like a love affair, which I guess explains why so many of us find it difficult to give up”. John Tagg could relate to this sentiment and wrote to him asking if they could work together, seeking a bacterial interference-based alternative to the use of penicillin for rheumatic fever prophylaxis
Three years of total streptococcal research immersion followed. Dr Wannamaker was generous in his support for John Tagg’s endeavours to find a harmless oral streptococcus capable of effectively engaging in bacteriocin-mediated warfare against S. pyogenes, while at the same time maintaining the view that what S. pyogenes really needed was greater scientific understanding – not extermination.
Before leaving Minnesota John Tagg wrote the first major review of the bacteriocins of gram-positive bacteria and upon purifying streptococcin A-FF22 demonstrated that it was closely similar to nisin, the best known and still the most widely applied of all the bacteriocins of gram-positive bacteria.
Rheumatic fever is a major public health concern in New Zealand, with a particularly high occurrence in the native Maori and Pacific Islander populations. In view of this John Tagg was excited in 1975 to obtain an academic position in the Microbiology Department at the University of Otago in Dunedin. His research agenda in New Zealand became firmly focused on finding a harmless oral streptococcal antagonist of S. pyogenes. He developed a procedure for the bacteriocin ‘fingerprinting’ of streptococci based on the deferred antagonism test in which a set of nine standard indicator bacteria are evaluated for their relative sensitivity to inhibitory substances released into an agar medium during the growth of a diametric streak culture of the test bacterium. It soon became clear that most (if not all) streptococci were probably capable of producing some sort of bacteriocin-like inhibitory activity. John Tagg then proposed the term BLIS as a ‘catchy’ preliminary descriptor for the molecular agents of these inter-bacterial inhibitory effects prior to the completion of more exhaustive tests designed to establish whether they were indeed bona fide bacteriocins. The pattern of inhibition of the nine standard BLIS indicator bacteria when converted to code format is referred to as the BLIS Production (P) type of the test bacterium. Over the next several decades John Tagg’s laboratory screened many thousands of streptococcal isolates for their BLIS activities and subsequently documented a remarkably heterogeneous array of proteinaceous inhibitory agents, ranging from post-translationally modified nisin-like peptides of the lantibiotic family to non-modified small peptides and relatively large proteins, some muralytic in their activity and others having an unusual circular conformation. Streptococci, especially those of the species uberis, mutans and salivarius appear to have been particularly inventive and acquisitive of unusual bacteriocin loci.
John Tagg’s second approach to identifying a naturally-occurring antagonist of S. pyogenes came in the form of a prospective study of 100 five-year-old Dunedin schoolchildren. The objective was to document changes occurring in the composition of the children’s oral microflora over the next six years and in particular to record if and when each child acquired S. pyogenes. Despite frequent outbreaks of S. pyogenes pharyngitis occurring in the school classrooms, not all similarly-exposed children experienced streptococcal infections. A particularly interesting observation was that many of the children who seldom acquired S. pyogenes had large populations of strong BLIS-producing S. salivarius on their tongues (i.e., the BLIS producers comprised at least 5% of the child’s total S. salivarius population).
This led to the hypothesis that the presence in the oral cavity of certain BLIS-producing S. salivarius may afford some protection against S. pyogenes infection. A follow-up study of 780 Dunedin school children identified two major types of BLIS-producing S. salivarius, the corresponding P-type patterns being 226 (11% of children positive) and 677 (9% positive). A further 20% of the children had S. salivarius of various other P-type designations, including some (approximately 1% of all tested subjects) having particularly strong (P-type 777) BLIS activity. The children harbouring populations of either P-type 677 or P-type 777 S. salivarius had a significantly reduced rate of acquisition of S. pyogenes during the 10-month study period. Strains of P-type 677 S. salivarius typically produce a 2315 Da bacteriocin of the lantibiotic class named salivaricin A (SalA). SalA differs from most other lantibiotics in that its inhibitory activity against S. pyogenes is bacteriostatic, rather than bacteriocidal. SalA inhibits the in vitro growth of all tested S. pyogenes, although the extent of inhibition of strains of serotype M4 (themselves producers of a SalA variant lantibiotic) is relatively reduced. SalA and its variants (SalA1, SalA2, SalA3 etc) function as cross-reactive signal peptides, capable of specifically up-regulating the production of all SalA lantibiotics. Perhaps even more significantly, this signal can effect inter-species communication, up-regulating production of SalA-like loci in strains of S. pyogenes, S. agalactiae and S. zooepidemicus. Specific SalA auto-inducing activity has been detected in the saliva of subjects following their colonisation with SalA-producing S. salivarius, showing that this lantibiotic activity is produced and is biologically active in vivo . In other studies, it has been demonstrated that anti-S. pyogenes inhibitory activity is also produced when SalA-positive S. salivarius are grown in saliva in an in vitro test system. Also, the dosing of children with SalA-producing S. salivarius stimulated clonal expansion of their pre-existing indigenous populations of SalA-producing S. salivarius. Moreover, when a SalA-producing S. salivarius population is present on the tongue, some other bacterial species on the tongue show increased levels of specific resistance to this bacteriocin.
The commercial outcome of these laboratory discoveries was the launching of the Dunedin-based company Blis Technologies Ltd in August 2000 and two years later the first oral probiotic product, BLIS K12™ ThroatGuard, appeared on the shelves of New Zealand pharmacies. A wide variety of BLIS K12™ products in powder, lozenge, chewing gum and ice cream formulations have subsequently been developed and many are now marketed internationally. A more recently released S. salivarius oral probiotic (strain M18) expresses the megaplasmid-encoded bacteriocins salivaricins MPS, A2 and 9 as well as the chromosomally-encoded bacteriocin salivaricin M. Some inhibitory spectrum differences are evident for strain M18, including increased inhibitory activity against the dental caries-associated species Streptococcus mutans.