People ask me: what's going on with research in the treatment of sinusitis with probiotics? Well, the answer is that things are moving along slowly - very slowly, but there are good signs. Earlier this year an interesting article by researcher Anders U. Cervin at the University of Queensland (Australia) was published that specifically talked about "topical probiotics" as a potential treatment for chronic sinusitis. By this he means that probiotics (beneficial bacteria) could be directly applied to the nasal passages in the nose, such as a nasal spray. And he discussed how the prevailing view nowadays, based on scientific evidence, is that in sinusitis there is an "imbalance of the sinus microbiome" - the community of microbes living in the sinuses. Yes!!!
Cervin mentioned all sorts of research showing beneficial effects of using different strains of probiotics for various illnesses, mentioned the Abreu et al study (which is the reason I focused on Lactobacillus sakei as a sinusitis treatment, and which works successfully for many people), but.... nowhere did he mention Lactobacillus sakei by name. What???
Cervin discusses how studies are needed to test nasal sprays for the treatment of sinusitis, and made a lot of good points. He looked at studies already done, wondered what bacterial strains might be beneficial, but obviously didn't read the Abreu et al study carefully to see that L. sakei might be a good candidate to test. And he didn't do an internet search to see what probiotics people are using already as a successful treatment for sinusitis (see post). He did mention that the only good trial using nasal spray probiotics in humans with sinusitis found no effect - because they tested the wrong Lactobacillus strains - they were honeybee strains [see post], and not ones found in humans.
Eh... So once again I'm heartened by the focus on the microbial community in sinusitis, and heartened that he said there it was time to get out of the laboratory and start testing probiotics as treatments on people. But I'm dismayed that the focus is so narrow that he's missing what is in front of him - what is already out there. He also missed that a "snot transplant" study is now going on in Europe, which is sure to have interesting results.
By the way, some of the questions the article raises are ones which, based on the experiences of myself and others over the past 5 years, we can already answer: living bacteria as a treatment are better than dead bacteria (using dead bacteria doesn't work), nasal treatments work but just swallowing a probiotic pill doesn't, Lactobacillus sakei works as a treatment for many, the L. sakei bacteria reduces inflammation in the nasal passages, the probiotic can be used in place of an antibiotic, and only treat when needed and not continuously (continuously treating can also result in an imbalance in the sinus microbiome). [See post The One Probiotic That Treats Sinusitis where these issues are discussed.]
Note that the medical term chronic rhinosinitis or CRS is used in the paper. Excerpts from Frontiers: The Potential for Topical Probiotic Treatment of Chronic Rhinosinusitis, a Personal Perspective
This review describes the rationale for topical probiotic intervention, the obstacles we are facing and a strategy for future research in the use of probiotics to modify CRS [chronic rhinosinusitis] symptoms and disease expression. Recent advances in molecular microbiology has revealed a plethora of microbial DNA in the nasal cavity and sinuses of healthy subjects as well as in chronic sinusitis (CRS) patients. An infection is today rather seen as an imbalance between the commensal microbiome and the bacterial pathogens, resulting in a reduction in commensal bacterial diversity, combined with an increase in the growth of microbes eliciting an inflammatory response. This will in turn lead to the clinical symptoms of sinusitis.
Probiotics (microorganisms that confer a health benefit) can be used either as a form of living antibiotics treatment, or as an immune-modulatory intervention. Topical probiotics, which is the focus of this review, have shown efficacy in a limited number of trials in otitis media and tonsillitis, but to date not in CRS. ... To gain more clinical experience without further delay, I recommend future research to focus on empirical clinical trials in well-defined CRS patient populations and study the underlying mechanisms in more detail once a clinical benefit has been established.
Chronic rhinosinusitis (CRS) is responsible for significant morbidity and health care costs across the globe. In spite of, the advancement of surgical methods and medical treatment little improvement has been seen in in the last 2 decades and it is estimated that 30% of CRS sufferers have symptoms not controlled by guideline therapy (Fokkens et al., 2012). Furthermore, I would argue that the present classifications system, based on ocular observation only, CRS with or without nasal polyps, is outdated and provides a very restricted view of the heterogeneous pathophysiology responsible for CRS symptoms. ...
It is in this context that we should consider the prospect of using probiotics (microorganisms that confer a health benefit) in the treatment of CRS. ... In this context however, I will focus on the potential of probiotic intervention to interfere with disease causing microorganisms.
I will briefly mention the role the commensal microbiome has in developing our immune system to a functioning defense system distinguishing self from non-self without causing undue tissue harm to the host. It seems that proper exposure to microbiota early in life is paramount to hone the immune system ... These data indicate that the first microbial exposure, when passing through the birth canal is paramount in developing the immune system. Inflammatory disorders have also been shown to be less common, in children who suck their thumb and bite their nails as well as in children whose parents clean their pacifier by sucking on it, an unintentional microbial transplant (Hesselmar et al., 2013; Lynch et al., 2016). These epidemiological studies show a link between early exposure to microorganisms and a lower incidence of inflammatory disorders later in life and it is referred to as “the hygiene hypothesis.” Findings suggests that a diverse microbiome in the gut is likely to be a key factor.
The microbiome of the airway has been less investigated, but it there have been suggestions that there is a healthy airway core microbiome (Erb-Downward et al., 2011), however most researchers still find it difficult to distinguish between healthy and diseased by analyzing the microbiome only (Psaltis and Wormald, 2017). The overall bacterial burden is similar in healthy subjects compared to CRS patients. Where a clear pathogen can be identified there seems to be a reduction in the overall bacterial diversity on the airway mucosal surface, suggesting that diversity is an indicator for a healthy microbiome (Ramakrishnan et al., 2013, 2016).
There is still no consensus on what constitutes a healthy microbiome in the sinuses, although certain phyla (the major lineages of the domain bacteria) have been identified in healthy controls and among those are; Firmicutes such as different strains of Lactobacillus, Actinobacteria, where you will find different strains of Propionibacterium, and Bacteroidetes (Abreu et al., 2012; Aurora et al., 2013; Ramakrishnan et al., 2013). To complicate matters further some species may act as commensal under certain circumstances, for example in low abundance or in concert with other microbes, where under different circumstance the same species may induce an inflammatory response. This seems to be the case with S. Aureus where in low abundance it may act as a commensal (Schwartz et al., 2016). Our own experiments confirm that certain strains of Propionibacterium, may act as a commensal, but under certain circumstances enhance the growth of pathogens (unpublished data).
What tools do commensal microbiome have available to outcompete pathogens? Lactobacilli, probably the most common probiotic, used as a food preservative in fermented food, produces lactic acid and thus lowers pH. It is well known that, for example; Pseudomonas does not thrive in an acid environment. ...
Unfortunately, there is a paucity of data regarding topical probiotic treatment of CRS, with only one placebo controlled trial available. There are several clinical trials however in otitis media as well as a trial in recurrent tonsillitis where topical bacterial interference has proven successful. There is also a small case series where MRSA carriers have been successfully treated with a combination of probiotic nasal spray and mouth wash. Table 1 outlines these trials. [Note: Table 1 makes clear how few trials have been done.]
What is evident when you study the clinical trials in detail is the lack of side effects, it seems that topical probiotics are safe, although the number of participants is still small, in total 460 patients reported in the studies above. Furthermore, except for the Martensson et al. study, the strains are all derived from humans, either oral or nasal microbiome and may already be present in the host.
The effects of a probiotic strain are specific rather than a general trait of a genus such as for example; Lactobacilli. This makes the whole process of identifying potential probiotic candidates much more complex and time consuming. Overall it seems that Streptococci strains are more successful than Lactobacilli strains. [Note: Streptococcus salivarius or BLIS K12 taken orally brought on sinusitis symptoms in some people, including myself.] Theoretically, Streptococci strains may be more prone to possible complications such as endocarditis, which is caused by low virulence Streptococci viridans, especially seen in patients with valve disorders or immune deficiency. I have not yet come across of a report suggesting that probiotic treatment have been responsible for such a course. However, it is important that all probiotic candidates are screened for antibiotic resistance and virulence genes.
Duration of treatment in past trials varies from 10 days up to 300 days and it is difficult to draw any conclusions on what constitute an effective treatment period. Although it seems that a duration of around 10 days is effective in several studies. Adherence of the probiotic strain to the mucosal surfaces may play a crucial role here, if this happens effectively, a shorter treatment duration may be all that is needed. One could however also speculate that a probiotic strain capable of changing pH or producing antibacterial substances could provide efficacy without adherence, if the probiotic is replenished regularly.
The Roos et al. case series on difficult to treat MRSA, is especially interesting as all patients had been carriers for over a year. This demonstrates that probiotic can be effective in spite of the target strain being resistant to multiple antibiotics. It shows promise for the future to target colonization of “superbugs” without the need for novel antibiotics.
What features of a probiotic strain confers positive effects? Is it possible to predict, engineer and enhance these properties in the future? For now, we are not able to answer these questions and the potential role of topical or systemic probiotics in the treatment of CRS is still in its early days. Such treatments could potentially reduce the use of antibiotics and serve as a new treatment alternative, that is both inexpensive and has an excellent safety profile. They could help to reduce antibiotic resistance in society as well as providing an alternative treatment in patients with multi-resistant bacterial colonization. ... To my knowledge successful transplant of nasal mucosal secretions has yet to be published. But it is an intriguing avenue to explore.
There are several choices to make when designing a probiotic study. I will discuss some of the aspects in the section below.
Living or Dead Bacteria? For antibacterial interference, it is likely that living bacteria with the capacity to produce antibacterial compounds would be more beneficial. Dead bacteria where the mechanism of action is limited to bacterial surface structures interacting with host immune receptors in a beneficial way, will not incur the risk of developing resistance or virulence genes. However, living probiotics have so far shown to be very safe and from that perspective limit use to dead bacteria is not necessary.
Single Strain or Multiple Strains? Although there is an example of a successful single strain intervention (Marchisio et al., 2016), the general impression is that multiple strains have the potential to provide synergistic effects. However, it requires further testing in the laboratory to make sure that the strains do not counteract each other while in the delivery device. Like mixing the wrong fish in the fish tank.
Prevention or Treatment? In adult CRS, we are of course focusing on treatment, but one could speculate that for example postoperatively provide patients with probiotic nasal washes to prevent a shift toward a gram-negative microbiome or to down-regulate an excess growth of S. Aureus. Attenuation of eosinophilic inflammation is another possibility and will be discussed below.
Probiotics as Single Treatment Modality or Adjuvant to Antibiotics? To facilitate the effect of probiotic supplement, a reduction of the load of bacterial pathogens by antibiotic treatment seems like the preferred route. One could start the probiotic supplement simultaneously with antibiotics and then continue after cessation of antibiotic treatment to prevent, with the probiotic, any potential for pathogen regrowth.
Local Treatment or Systemic Treatment? Using probiotics as living antibiotics, in other words bacterial interference, in form of a topical wash or spray, has in my personal opinion, the potential to be more effective rather than acting by proxy through the immune system. ...
There is now evidence that even in a person with no symptoms of sinusitis, pathogens are present on the mucosa, although in low abundance. In an experiment where healthy subjects where infected with rhinoviruses, a 5-fold increase was seen in the abundance of Haemophilus Influenza during the following days (Allen et al., 2014). This suggests that a bacterial complication to a viral rhinitis may not require any external source of Haemophilus, but rather created by an imbalance of the microbiome, prompted by rhinovirus exposure. It is not unlikely that a topical probiotic spray with the capacity for bacterial interference against the common respiratory bacterial pathogens will be able to reduce bacterial complications of the common cold or reduce the number of bacterial flare ups in CRS.
Improving Symptoms in Chronically Infected CRS Patients by Decolonization of Pathogens: Patients with previous multiple sinus surgery procedures tend to develop, or may already prior to surgery, have a high abundance of S. Aureus and / or a gram-negative microbiome. A probiotic nasal wash with commensals capable of interfering with for example Pseudomonas has the potential to reduce the abundance of the pathogens and subsequently improve patient symptoms and reduce remodeling of the upper airway mucosa. Of concern, is the presence of intra-cellular S. Aureus, which may or may not be the driver of symptoms, but would probably not be accessible to interaction by a probiotic topical spray (Tan et al., 2014).
Reduce Eosinophilic Inflammation in the Airway: Perhaps the most intriguing concept which, if successful, could have a big impact on asthma as well. This approach may include systemic probiotics influencing the gut-lung axis ... A recent review summarized the findings of preventing allergic rhinitis by systemic probiotics and showed that out of 23 studies comprising of 1991 patients, 17 studies showed benefit whereas 6 showed no benefit (Zajac et al., 2015). A more recent review revealed similar result but added that all 5 studies with Lactobacillus paracasei demonstrated clinically significant improvement suggesting that this is an important probiotic (Guvenc et al., 2016).