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Category: sinusitis

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Published on 14 Comments on Do Probiotic Supplements Stick Around In the Gut?

People assume that taking probiotics results in the beneficial probiotic bacteria colonizing and living in the gut (or sinuses when using L. sakei). It is common to hear the phrase "take probiotics to repopulate the gut" or "improve the gut microbes". The human gut microbiota (human gut microbiome) refers to all the microbes that reside inside the gut (hundreds of species). Probiotics are live bacteria, that when taken or administered, result in a health benefit. But what does the evidence say?

First, it is important to realize that currently supplements and foods contain only a small variety of probiotic species, with some Lactobacillus and Bifidobacterium species among the most common. But they are not the most common bacteria found in the gut. And very important bacteria such as Faecalibacterium prausnitzii (a reduction of which is associated with a number of diseases) are not available at all in supplements. One problem is the F. prausnitzii are "oxygen sensitive" and they die within minutes upon exposure to air, a big problem when trying to produce supplements.

The evidence from the last 4 years  of L. sakei use for sinusitis treatment is that for some reason, the L. sakei is not sticking around long-term and permanently colonizing in the sinuses. My family's experiences and the experience of other people contacting me is that every time a person becomes sick with a cold or sore throat, it once again results in sinusitis, and then another treatment with a L. sakei product is needed to treat the sinusitis, even though less is needed over time. And of course this has been a surprise and a big disappointment. [See Dec. 2020 update below.]

The same appears to be true for probiotics (whether added to a food or in a supplement) that are taken for other reasons, including intestinal health. Study after study, and a review article, finds that the beneficial bacteria do not colonize in the gut even if there are health benefits from the probiotics. That is, there may be definite health benefits from the bacteria, but within days of stopping the probiotic (whether in a food or a supplement) it is no longer found in the gut. Researchers know this because they can see what bacteria are in the gut by analyzing (using modern genetic sequencing tests) what is in the fecal matter (the stool).

However, the one exception to all of the above is a fecal microbiota transplant (FMT) - which is transfer of fecal matter from one person to another. There the transplanted microbes of the donor do colonize the recipient's gut, referred to as "engraftment of microbes". Some researchers found that viruses in the fecal matter helped with the engraftment. So it looks like more than just some bacterial strains are involved. Another thing to remember is that study after study finds that dietary changes result in microbial changes in the gut, and these changes can occur very quickly.

[Dec. 2020 update: A few recent studies are now suggesting that if a person takes or uses a bacterial species that naturally occurs in the body and is depleted, than it may stick around for a while - this is colonization, even if only short-term. We also find this occurring with L. sakei - while we may need to use it now and then, this is occurring less frequently over time, and we need to use a much smaller amount when needed. Colonization! Overall, there has been major improvement of our sinuses over time - and yes, they feel great.]

From Gut Microbiota News Watch: Learning what happens between a probiotic input and a health output

What scientists know is that probiotics in healthy individuals are associated with a number of benefits. Meta-analyses of randomized, controlled trials show that probiotics help prevent upper respiratory tract infections, urinary tract infections, allergy, and cardiovascular disease risk in adults. But between the input and the output, what happens? A common assumption is that probiotics work by influencing the gut microbe community, leading to an increase in the diversity of bacterial species in the gut ecosystem and measurable excretion in the stool.

But this theory doesn’t seem to be true, according to a recently published systematic review by Kristensen and colleagues in Genome Medicine. Authors of the review analyzed seven studies and found no evidence that probiotics have the ability to change fecal microbiota composition. So even though individuals in the different studies were ingesting live bacterial species, the bacteria didn’t stick around to increase the diversity of the gut fecal microbiota.

“Do probiotics alter the fecal composition of healthy adults? The answer seems to be no,” says Dr. Mary Ellen Sanders, Executive Science Officer for the International Scientific Association for Probiotics and Prebiotics (ISAPP)....Dr. Dan Merenstein, Research Division Director and Associate Professor of Family Medicine at Georgetown University Medical Center in Washington, DC (USA), agrees. “Initially when probiotics were studied, some people expected to see permanent colonization. We now realize that is unlikely to occur,” he says. “This study shows that the probiotics tested to date do not result in overarching bacterial community structure changes in healthy subjects. But clinical effects are clearly demonstrated for probiotics, and likely some are mediated by microbiome changes.”

At issue, then, is not what probiotics do for healthy individuals, but exactly how they work: the so-called ‘mechanism’. Sanders, who described some alternative mechanisms in her BMC Medicine commentary about the Kristensen review, points out a logical error in news stories worldwide that covered the article: the assumption that if probiotics fail to change the microbiota composition, they fail to have any health effects. Sanders emphasizes that probiotics might work in many possible ways. “Probiotics may act through changing the function of the resident microbes, not their composition. They may interact with host immune cells,” she says. “They may inhibit opportunistic pathogens that are not dominant members of the microbiota. They may promote microbiota stability… .” 

Published on Leave a comment on Missing Bacteria In Chronic Sinusitis

What exactly are the differences between people with chronic sinusitis and those who are healthy and don't get sinusitis? I've written many times about the Abreu et al 2012 study that found that not only do chronic sinusitis sufferers lack L. sakei, they have too much of Corynebacterium tuberculostearicum (normally a harmless skin bacteria), and they also don't have the bacteria diversity in their sinuses that healthy people without sinusitis have.

In other words, the sinus microbiome (microbial community) is out of whack (dysbiosis). A number of studies found that there is a depletion of some bacterial species, and an increase in "abundance" of other species in those with chronic sinusitis.

Now a new analysis of 11 recent studies comparing people with chronic sinusitis to healthy people adds some additional information. Once again a conclusion was that those with sinusitis had "dysbiosis" (microbial communities out of whack) in their sinus microbiomes when compared to healthy people. And that an increased "abundance" of members of the genus Corynebacterium in the sinuses was associated with chronic sinusitis (studies so far point to C. tuberculostearicum and C. accolens). Nothing new there...

But what was new was that they found that bacteria of the genus Burkholderia and Propionibacterium seem to be "gatekeepers", whose presence may be important in maintaining a stable and healthy bacterial community in the sinuses. And that in chronic sinusitis the bacterial network of healthy communities is "fragmented". In other words, when a person is healthy, the community of microbes in the sinuses may provide a protective effect, and if the gatekeepers are removed (e.g., during illnesses or after taking antibiotics), then a "cycle of dysbiosis and inflammation" may begin.

PLEASE NOTE: Genus is a taxonomic category ranking used in biological classification that is below a family and above a species level. For example, Lactobacillus is the genus and sakei is the species. Also, the researchers discussed "gatekeepers" as being important for sinus health, while Susan Lynch discusses the importance of "keystone species" for sinus health.

OK... so which species of Burkholderia and Propionibacterium bacteria are found in the healthy microbiome? Unfortunately that was not answered in this study. And of course this needs to be tested further to see if the addition of the missing species of Burkholderia and Propionibacterium bacteria to the sinus microbiome will treat chronic sinusitis. Or perhaps other bacteria such as L. sakei and someother still unknown bacteria also need to be added to the mix.

Both Burkholderia and Propionibacterium have many species, but I have not seen any in probiotics. Species of Propionibacteria can be found all over the body and are generally nonpathogenic. However, P. acnes can cause the common skin condition acne as well as other infections.

One species - Propionibacterium freudenreichii (or P. shermanii)  - is found in Swiss type cheeses such as Emmental, Jarlsberg, and Leerdammer. Propionibacteria species are commonly found in milk and dairy products, though they have also been extracted from soil. There are many Burkholderia species, with a number of them causing illness (e.g., B. mallei and B. pseudomallei), but also beneficial species, such as those involved with plant growth and health. Burkholderia species are found all over, in the soil, in plants, soil, water (including marine water), rhizosphere, animals and humans. At this point it is unclear to me which are the species found in healthy sinuses.

But it is clear that while L. sakei works to treat chronic sinusitis in many people, the fact that L. sakei typically has to be used after each illness (cold, sore throat, etc,) means that the sinus microbiome may still be missing microbial species or that there is still some sort of "imbalance" (even though the person may feel totally healthy). The researchers noted that a variety of fungi and viruses are also part of a normal sinus microbiome, but they weren't discussed in the article. As you can see, much is still unknown. Stay tuned..,..

This was a very technical article - thus not easy to read. Keep in mind that the information about the conclusions about the bacteria species in the sinuses was from studies that used modern genetic sequencing data (16S rRNA sequence data) to determine what bacteria are in the sinuses. (These are called "culture independent technologies" and much, much better than using cultures in determining species of bacteria.) This way they could analyze differences in "sinonasal bacterial community composition" and see differences between healthy people and persons with CRS (chronic rhinosinusitis).

Excerpts from Environmental Microbiology: Bacterial community collapse: a meta-analysis of the sinonasal microbiota in chronic rhinosinusitis

Chronic rhinosinusitis (CRS) is a common, debilitating condition characterized by long-term inflammation of the nasal cavity and paranasal sinuses. The role of the sinonasal bacteria in CRS is unclear. We conducted a meta-analysis combining and reanalysing published bacterial 16S rRNA sequence data to explore differences in sinonasal bacterial community composition and predicted function between healthy and CRS affected subjects. The results identify the most abundant bacteria across all subjects as Staphylococcus, Propionibacterium, Corynebacterium, Streptococcus and an unclassified lineage of Actinobacteria.

The meta-analysis results suggest that the bacterial community associated with CRS patients is dysbiotic and ecological networks fostering healthy communities are fragmented. Increased dispersion of bacterial communities, significantly lower bacterial diversity, and increased abundance of members of the genus Corynebacterium are associated with CRS. Increased relative abundance and diversity of other members belonging to the phylum Actinobacteria and members from the genera Propionibacterium differentiated healthy sinuses from those that were chronically inflamed. Removal of Burkholderia and Propionibacterium phylotypes from the healthy community dataset was correlated with a significant increase in network fragmentation. This meta-analysis highlights the potential importance of the genera Burkholderia and Propionibacterium as gatekeepers, whose presence may be important in maintaining a stable sinonasal bacterial community.

The high density and diversity of host-associated microbial communities present in different body sites supports a near infinite number of potential host to microbe, and microbe to microbe interactions. A stable network of microbial interactions, established through processes such as niche competition, nutrient cycling, immune evasion, and biofilm formation help maintain homeostasis during health (Walter and Ley, 2011; Grice et al., 2009). Taxa that hold together the bacterial community by interacting with different parts of the network can be considered “gatekeepers” (sensu Freeman, 1980; Widder et al., 2014). During health, a consortium of microbes may provide a protective effect, and a breakdown in these networks due to the removal of gatekeepers may begin a self-perpetuating cycle of dysbiosis and inflammation (Vujkovic-Cvijin et al., 2013; Widder et al., 2014; Byrd and Segre, 2016).

The genus-level phylotype Corynebacterium was again associated with CRS bacterial communities, and Burkholderia was associated with healthy subjects.

In contrast to the variety of Actinobacteria and Betaproteobacteria phylotypes differentiating the healthy sinonasal bacterial communities, only one phylotype (Corynebacterium) was consistently associated with those individuals that were chronically inflamed. The significance of specific members of the genus Corynebacterium in CRS microbial communities is supported by findings in two previous studies (Abreu et al., 2012; Aurora et al., 2013). The relative abundance of C. tuberculostearicum and C. accolens was significantly higher in subjects with CRS in two recent 16S rRNA studies (Abreu et al., 2012 and Aurora et al., 2013, respectively). 

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Published on 12 Comments on Is Garlic The Source Of Beneficial Lactobacillus Sakei in Kimchi?

As you may have noticed, I write about the beneficial bacteria Lactobacillus sakei a lot. This is because it has turned out to be a great treatment for both chronic and acute sinusitis for my family and others (see post The One Probiotic That Treats Sinusitis). We originally found it in kimchi (it occurs in the kimchi during normal fermentation), but not all kimchi brands. Kimchi is a mix of vegetables (including typically cabbage) and seasonings, which is then fermented for days or weeks before it is eaten.

Why is L. sakei found in some kimchi, but not all? Which vegetable or spice is needed or important for encouraging L. sakei growth? It turns out it is not the cabbage - which is why L. sakei is not normally found in sauerkraut.

A recent study looking at several kimchi samples found that garlic seems to be important for the development of various Lactobacillus bacteria, of which L. sakei is one. The results mean that raw garlic has very low levels of L. sakei, and it multiplies during kimchi fermentation. Note that as fermentation progresses, the bacterial species composition in the kimchi changes (this is called ecological succession).

Korean studies (here and here) have consistently found L. sakei in many brands of kimchi (especially from about day 14 to about 2 or 2 1/2 months of fermentation), but not all kimchi brands or recipes. L.sakei, of which there are many strains, is so beneficial because it "outcompetes other spoilage- or disease-causing microorganisms" and so prevents them from growing (see post).

Excerpts are from the blog site Microbial Menagerie: MICROBES AT WORK IN YOUR KIMCHI

Cabbage is chopped up into large pieces and soaked in salt water allowing the water to draw out from the cabbage. Other seasonings such as spices, herbs and aromatics are prepared. Ginger, onion, garlic, and chili pepper are commonly used. The seasonings and cabbage are mixed together. Now the kimchi is ready to ferment. The mixture is packed down in a glass container and covered with the brining liquid if needed. The kimchi sits at room temperature for 1-2 days for fermentation to take place....Kimchi does not use a starter culture, but is still able to ferment. Then where do the fermentation microbes come from?

Phylogenetic analysis based on 16S rRNA sequencing indicates that the kimchi microbiome is dominated by lactic acid bacteria (LAB) of the genus Leuconostoc, Lactobacillus, and Weissella. Kimchi relies on the native microbes of the ingredients. That is, the microbes naturally found on the ingredients. Because of this, there may be wide variations in the taste and texture of the final kimchi product depending on the source of the ingredients. In fact, a research group from Chung-Ang University acquired the same ingredients from different markets and sampled the bacterial communities within each of the ingredients. The group found a wide variability in the same ingredient when it was bought from different markets. Surprisingly, the cabbage was not the primary source of LAB. Instead, Lactic acid bacteria was found in high abundance in the garlic samples. 

Note that Lactobacillus sakei is an example of a lactic acid bacteria. More study details from  the Journal of Food Science: Source Tracking and Succession of Kimchi Lactic Acid Bacteria during Fermentation.

This study aimed at evaluating raw materials as potential lactic acid bacteria (LAB) sources for kimchi fermentation and investigating LAB successions during fermentation. The bacterial abundances and communities of five different sets of raw materials were investigated using plate-counting and pyrosequencing. LAB were found to be highly abundant in all garlic samples, suggesting that garlic may be a major LAB source for kimchi fermentation. LAB were observed in three and two out of five ginger and leek samples, respectively, indicating that they can also be potential important LAB sources. LAB were identified in only one cabbage sample with low abundance, suggesting that cabbage may not be an important LAB source.

Bacterial successions during fermentation in the five kimchi samples were investigated by community analysis using pyrosequencing. LAB communities in initial kimchi were similar to the combined LAB communities of individual raw materials, suggesting that kimchi LAB were derived from their raw materials. LAB community analyses showed that species in the genera Leuconostoc, Lactobacillus, and Weissella were key players in kimchi fermentation, but their successions during fermentation varied with the species, indicating that members of the key genera may have different acid tolerance or growth competitiveness depending on their respective species.

Although W. koreensis, Leu. mesenteroides, and Lb. sakei were not detected in the raw materials of kimchi samples D and E (indicating their very low abundances in raw materials), they were found to be predominant during the late fermentation period. Several previous studies have also reported that W. koreensis, Leu. mesenteroides, and L. sakei are the predominant kimchi LAB during fermentation (Jeong and others 2013a, 2013b; Jung and others 2011, 2012, 2013a, 2014). 

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Published on 8 Comments on Antibiotic Use Increases Risk of Developing Chronic Sinusitis

Image result for antibiotics Yes, of course this makes sense!.... Many rounds of antibiotics have an effect not just in one area of the body, but kill off both good and bad bacteria in many areas of the human body. The researchers in this study found that taking antibiotics for a reason OTHER THAN SINUSITIS was associated with an increased risk of developing chronic sinusitis (as compared to those people not receiving antibiotics).

Use of antibiotics more than doubles the odds of developing chronic sinusitis without nasal polyps. And this effect lasted for at least 2 years.

Other research has already associated antibiotic use with "decreased microbial diversity" in our microbiome  and with "opportunistic infections" such as Candida albicans and Clostridium difficile. Diseases such as Crohn's disease and diabetes are also linked to antibiotic use. In other words, when there is a disturbance in the microbiome (e.g.from antibiotics) and the community of microbes becomes "out of whack", then pathogenic bacteria are "enriched" (increase) and can dominate.

This study lumped together chronic sinusitis without nasal polyps (CRSsNP) and chronic sinusitis with nasal polyps (CRSwNP), but when the 2 groups are separated out, then antibiotic use was mainly associated with chronic sinusitis without polyps. It appeared that antibiotic exposure did not significantly impact the odds of developing chronic sinusitis with nasal polyps.

The researchers write: "This effect was primarily driven by the CRSsNP subgroup, which also supports the evolving concept of CRSwNP (chronic sinusitis with nasal polyps) as a disease of primary inflammation rather than infection. Despite this, we elected to analyze the CRS (chronic rhinosinusitis) group as a whole because the precise relationship between CRS with and without nasal polyps remains incompletely understood, and it is possible that a proportion of the CRSsNP patients could go on to develop nasal polyps over time."

Which makes me wonder, will giving beneficial bacteria (such as Lactobacillus sakei) to those who have chronic sinusitis with nasal polyps show the same improvement in symptoms as those people without nasal polyps? Or do 2 treatments have to occur at once: something to lower the inflammation (which may be the reason for the nasal polyps) and also beneficial microbes to treat the bacterial imbalance of sinusitis? We just don't know yet. Note that CRS = chronic rhinosinusitis (commonly called chronic sinusitis). Research by A.Z. Maxfield et al from The Laryngoscope :

General antibiotic exposure is associated with increased risk of developing chronic rhinosinusitis 

Antibiotic use and chronic rhinosinusitis (CRS) have been independently associated with microbiome diversity depletion and opportunistic infections. This study was undertaken to investigate whether antibiotic use may be an unrecognized risk factor for developing CRS. Case-control study of 1,162 patients referred to a tertiary sinus center for a range of sinonasal disorders.

Patients diagnosed with CRS according to established consensus criteria (n = 410) were assigned to the case group (273 without nasal polyps [CRSsNP], 137 with nasal polyps [CRSwNP]). Patients with all other diagnoses (n = 752) were assigned to the control group. Chronic rhinosinusitis disease severity was determined using a validated quality of life (QOL) instrument. The class, diagnosis, and timing of previous nonsinusitis-related antibiotic exposures were recorded.

Antibiotic use significantly increased the odds of developing CRSsNP  as compared to nonusers. Antibiotic exposure was significantly associated with worse CRS QOL {Quality of Life} scores over at least the subsequent 2 years. These findings were confirmed by the administrative data review. Use of antibiotics more than doubles the odds of developing CRSsNP and is associated with a worse QOL for at least 2 years following exposure. These findings expose an unrecognized and concerning consequence of general antibiotic use.

Antibiotic use and chronic rhinosinusitis (CRS) have been independently associated with microbiome diversity depletion and opportunistic infections. This study was undertaken to investigate whether antibiotic use may be an unrecognized risk factor for developing CRS.....Antibiotics have also been associated with significant adverse side effects. It has long been recognized that antibiotic use may lead to increased susceptibility to secondary mucosal infections from pathogens including Candida albicans and Clostridium difficile.  Recent studies on the concept of mucosal microbial dysbiosis have suggested that these infections arise as a result of antibiotic induced depletion of the diverse commensal microbial assemblage, which enables the proliferation of pathogenic species.

Chronic rhinosinusitis (CRS) is defined....as having greater than 12 weeks of sinonasal symptoms, along with at least one objective measure of infection or inflammation by nasal endoscopy or radiographic imaging....However the distinct lack of long-term disease resolution following antimicrobial therapy and in some cases surgery, suggests that additional factors are likely involved. Through these studies, CRS with nasal polyps (CRSwNP) has been recognized as an inflammatory subtype characterized by eosinophilic inflammation and a T-helper cell type 2 immunologic profile. Although CRSwNP lacks the features of a classic infectious process, the precise role of bacteria and their byproducts in the promotion of nasal polyp-related inflammation remains unclear.

Recent findings from culture independent investigations of the sinonasal microbiome have offered new insights into the pathogenesis of CRS. These studies have suggested that a decreased microbial diversity exists in CRS patients as compared to healthy controls with a selective enrichment of pathogenic species. Furthermore, some studies have shown that antibiotic exposure may be a risk factor associated with this loss of biodiversity,  echoing the findings seen in postantibiotic C. difficile infections.  Although systemic antibiotics have long been a mainstay of therapy for CRS, these findings lead inexorably to the paradoxical hypothesis that antibiotic exposure may, in fact, promote its onset.

We performed a....case control study of 1,574 patients referred to the Massachusetts Eye and Ear Infirmary Sinus Center in 2014 with symptoms of presumed sinonasal disease.... Inclusion criteria included all antibotic naive patients, and all antibiotic exposed patients for whom antibiotic use was for nonsinonasal-related infections. Among the antibiotic exposed group, only patients who used antibiotics for nonsinonasal-related infections prior to the onset of symptoms of CRS (within the case group) were enrolled in the study.....The case group was further substratified into CRS patients without nasal polyps (CRSsNP, n =273) and with nasal polyps (CRSwNP, n =137) based on the presence of nasal polyps on sinonasal endoscopy.

Among the case patients, 56.34% reported a previous nonsinus-related antibiotic exposure as compared to 42.02% of control patients. Antibiotic use significantly increased the odds of developing both CRSsNP and any form of CRS as compared to nonusers. This odds ratio was similar even when excluding patients who were treated for upper aerodigestive infections. In contrast, antibiotic exposure did not significantly impact the odds of developing CRSwNP. The percent of patients with any form of CRS and CRSsNP only, which was attributable to a previous exposure to antibiotics, was 24.69%  and 33.70%, respectively. In both the case and control groups, the most common class of antibiotic patients received was a penicillin (52.63% vs. 45.77%), and the most common reported reason for antibiotic prescription was the diagnosis of pharyngitis(18.06% vs. 16.67%).

Among the CRS patients (i.e., case group), the use of antibiotics was significantly associated with worse QOL scores as compared to antibiotic-naıve CRS patients. The effect on QOL was enduring because patients who used antibiotics at least 2 years prior to the development of CRS (36.81%) had similar disease severity scores as compared to those with more recent exposures. There was no significant difference in QOL score among patients using different antibiotic classes and among patients with different underlying reasons for antibiotic use.

The human microbiome project has provided new insights into the distribution and abundance of bacterial species in both health and disease. Opportunistic pathogens, as defined by the pathosystems resource integration center, were found nearly ubiquitously in the nares of healthy subjects, albeit at relatively low abundance. Additional studies of the normal nasal cavity found an inverse correlation between the prevalence of Firmicutes such as S. aureus and benign commensal organisms, suggesting a homestatic antagonism between potential pathogens and the remainder of the healthy microbial assemblage. Extrapolation of this concept would therefore predict that events resulting in a perturbation or loss of the commensal microbial community would enable proliferation of pathogenic species, resulting in the disease phenotype. This prediction has borne out in several studies of the sinonasal microbiome in patients with CRS. Feazel et al. found a decreased number of bacterial types and an overabundance of S. aureus among CRS patients as compared to controls. Antibiotic exposure was one of the most significant clinical factors driving this effect. Similar findings were published by Choi et al. and Abreu et al.... Although literature regarding the sinonasal microbiome in health and disease remains nascent, it has provided some limited clues that antibiotics may lead to a reduction of sinonasal microbial biodiversity, which in turn may be a significant feature of CRS.

Our results demonstrate that exposure to antibiotics is a significant risk factor for the development of CRS and accounts for approximately 25% of the disease burden in our study population. These findings harmonize with the predictions of the nascent literature on the sinonasal microbiome. This effect was primarily driven by the CRSsNP subgroup, which also supports the evolving concept of CRSwNP as a disease of primary inflammation rather than infection. Despite this, we elected to analyze the CRS group as a whole because the precise relationship between CRS with and without nasal polyps remains incompletely understood, and it is possible that a proportion of the CRSsNP patients could go on to develop nasal polyps over time.....

One unexpected outcome of our study was that a large percentage of exposures preceeded the onset of the diagnosis of sinusitis by more than 2 years. This indicates that, regardless of the mechanism, the sequelae of antibiotic use may endure much longer then previously thought....The impact of antibiotics on promoting bacterial resistance, and the development of mucosal infections from pathogens such as C. difficile and C. albicans, has been well established. This study demonstrates that antibiotics also significantly increase the risk of developing CRS, an effect that is driven primarily by CRS patients who do not have nasal polyps. Furthermore, premorbid antibiotic use could account for approximately 25% of our patients who developed CRS, and exposure conferred a worse disease-specific quality of life.

Published on Leave a comment on Does Saline Nasal Irrigation Treat Sinusitis Symptoms?

A recent study compared saline nasal irrigation vs steam inhalation vs doing both saline irrigation and steam inhalation vs doing neither (the control group) for chronic or recurring sinusitis symptoms. In the study, people with a history of chronic or recurring sinusitis symptoms were randomly assigned to one of the 4 groups, and then studied 3 months and 6 months later. The results were: a modest (slight improvement) in the saline irrigation group in symptom and quality-of-life scores, but no improvement for the steam inhalation group. However, the researchers noted that the control group also had slight improvements at 3 and 6 months. Most of the improvement in the saline irrigation group was in the group that also did steam inhalation - thus perhaps some benefit to combining both.

In addition, patients in the nasal irrigation group reported fewer headaches, fewer of them used over-the-counter medications, and said they were less likely to consult with a physician about their nasal problems in the future when compared with patients in the steam inhalation group.

Most people with chronic or recurring sinusitis will probably agree with the findings. Yes, effects are modest with saline irrigation, but it definitely does improve nasal stuffiness (experiences of family members and readers). But it does NOT treat the sinusitis. The sinus microbial community continues to stay out of whack (dysbiosis). Which explains the researchers' finding that saline irrigation and steam inhalation did not result in differences in antibiotic use or physician visits after 6 months.

From Science Daily: Nasal irrigation may prevent chronic sinus ailments

Advising patient with chronic sinus congestion to use nasal irrigation -- a popular nonpharmacologic treatment -- improved their symptoms, but steam inhalation did not, according to a randomized controlled trial published in CMAJ(Canadian Medical Association Journal). More than 25 million people in the United States and about 2.5 million Canadians suffer from chronic rhinosinusitis, or sinus infection, and experience compromised quality of life. To alleviate symptoms, steam inhalation and nasal irrigation are widely suggested as an alternative to common treatment with antibiotics, which are often not effective and contribute to antibiotic resistance.

Researchers from the United Kingdom conducted a randomized controlled trial on the effectiveness of advice from primary care physicians to use nasal irrigation and/or steam inhalation for chronic sinusitis. The study involved 871 patients from 72 primary care practices in England who were randomly assigned to 1 of 4 advice strategies: usual care, daily nasal and saline irrigation supported by a demonstration video, daily steam inhalation, or combined treatment with both interventions.

Patients who were instructed to use nasal irrigation showed improvement at 3 and 6 months, as measured by the Rhinosinusitis Disability Index. Steam inhalation did not appear to alleviate symptoms of sinusitis.

"We found potentially important changes in other outcomes; in particular, fewer participants in the nasal irrigation group than in the no-irrigation group had headaches, used over-the-counter medications and intended to consult a doctor in future episodes," write the authors. "Although there was no significant difference in either physician visits or antibiotic use, as might be expected over only a 6-month follow-up period, our findings concerning consultations are important in the longer term, given antibiotic use increases the risk of antimicrobial resistance."

The Abstract (summary) of the study, which is from the Canadian Medical Association Journal (CMAJ): Effectiveness of steam inhalation and nasal irrigation for chronic or recurrent sinus symptoms in primary care: a pragmatic randomized controlled trial

ABSTRACT  Background: Systematic reviews support nasal saline irrigation for chronic or recurrent sinus symptoms, but trials have been small and few in primary care settings. Steam inhalation has also been proposed, but supporting evidence is lacking. We investigated whether brief pragmatic interventions to encourage use of nasal irrigation or steam inhalation would be effective in relieving sinus symptoms.

Methods: We conducted a pragmatic randomized controlled trial involving adults (age 18–65 yr) from 72 primary care practices in the United Kingdom who had a history of chronic or recurrent sinusitis and reported a “moderate to severe” impact of sinus symptoms on their quality of life. Participants were recruited between Feb. 11, 2009, and June 30, 2014, and randomly assigned to 1 of 4 advice strategies: usual care, daily nasal saline irrigation supported by a demonstration video, daily steam inhalation, or combined treatment with both interventions. The primary outcome measure was the Rhinosinusitis Disability Index (RSDI). Patients were followed up at 3 and 6 months. We imputed missing data using multiple imputation methods.

Results: Of the 961 patients who consented, 871 returned baseline questionnaires (210 usual care, 219 nasal irrigation, 232 steam inhalation and 210 combined treatment). A total of 671 (77.0%) of the 871 participants reported RSDI scores at 3 months. Patients’ RSDI scores improved more with nasal irrigation than without nasal irrigation by 3 months (crude change −7.42 v. −5.23; estimated adjusted mean difference between groups −2.51, 95% confidence interval −4.65 to −0.37). By 6 months, significantly more patients maintained a 10-point clinically important improvement in the RSDI score with nasal irrigation (44.1% v. 36.6%); fewer used over-the-counter medications (59.4% v. 68.0%) or intended to consult a doctor in future episodes. Steam inhalation reduced headache but had no significant effect on other outcomes. The proportion of participants who had adverse effects was the same in both intervention groups.

Interpretation: Advice to use steam inhalation for chronic or recurrent sinus symptoms in primary care was not effective. A similar strategy to use nasal irrigation was less effective than prior evidence suggested, but it provided some symptomatic benefit.

Published on Leave a comment on New Antibiotic Or Future Probiotic?

 Some people have nasal bacteria - Staphylococcus lugdunensis, that kills other disease causing bacteria such as Staphylococcus aureus (including strains of MRSA) and Enterococcus. This is because S. lugdunensis produces a molecule (lugdunin) that acts as an antibiotic. It is thought that 10% of people naturally carry S. lugdunensis in their nasal passages. Will this lead to a new class of antibiotics or to probiotics of the future? Could it help in treating sinusitis? Stay tuned... From Science News:

The nose knows how to fight staph

The human nose harbors not only a deadly enemy — Staphylococcus aureus — but also its natural foe. Scientists have now isolated a compound from that foe that might combat MRSA, the methicillin-resistant strain of S. aureus....Investigating the intense interspecies competition in the nose — where microbes fight for space and access to scant sugars and amino acids — might offer a fertile alternative to searching for new drug candidates in soil microbes.

Despite being a relatively nutrient-poor environment, the human nose is home to more than 50 species of bacteria. One of these is S. aureus, a dominant cause of hospital-acquired infections such as MRSA, as well as infections of the blood and heart. But there’s a huge variability in the nasal microbe scene between individuals: while S. aureus is present in the nasal passages of roughly 30 percent of people, the other 70 percent don’t have any sign of it.

Trying to explain this difference led Peschel and colleagues to study “the ecology of the nose.” They suspected that other nasal inhabitants, well-tuned to compete in that harsh niche, might be blocking S. aureus from colonizing the nose in those who don’t carry it. From nasal secretion samples, the team isolated 90 strains of different Staphylococcus species. Of these, one bacterium, S. lugdunensis, killed S. aureus when the two were grown together in a dish. Introducing a variety of mutations into S. lugdunensis produced a strain that didn’t kill. The missing gene, the team showed, normally produced an antibiotic, which the researchers named lugdunin; it represents the first example of a new class of antibiotic.

Lugdunin was able to fend off MRSA as well as a strain of Enterococcus resistant to the antibiotic vancomycin. Neither bacteria developed resistance. The team also pitted S. lugdunensis against S. aureus in test tube and mouse studies, with S. lugdunensis besting S. aureus. Only 5.9 percent of 187 hospital patients had S. aureus in their noses if they also carried S. lugdunensis, the team found, while S. aureus was present in 34.7 percent of those without S. lugdunensis. Peschel and colleagues also reported the results July 28 in Nature.

Lugdunin cleared up a staph skin infection in mice, but it’s unclear how the compound works. Researchers could not rule out that it damages the cell membrane, which could limit its use in humans to a topical antibiotic. Peschel and coauthor Bernhard Krismer also suggest that the bacterium itself might be a good probiotic, applied nasally, to fend off staph infections in vulnerable hospital patients.  (The original study and accompanying Commentary)

 A compound secreted by the nose-dwelling bacterium Staphylococcus lugdunensis may fight antibiotic-resistant strains of bacteria such as MRSA (pink). CREDIT: NIAID, NIH/WIKIMEDIA COMMONS

Published on Leave a comment on Microbial Community Differences Between Healthy Children and Those Who Get Sinusitis

An interesting study that compared bacterial communities between healthy children and those that have a history of acute sinusitis (but not chronic sinusitis). The study specifically looked at the nasopharyngeal (NP)  microbiome (community of microbes) over the course of one year in the 2 groups of children, who were between the ages of 4 and 7. Nasopharyngeal pertains to the nose or nasal cavity and pharynx. They used modern methods of genetic analysis to test for bacterial species - and found a total of 951 species among the 47 children, of which 308 species had some "depletion" among those children with a history of sinusitis, and one species was increased in "abundance".

NP samples from children with a prior history of acute sinusitis were characterized by significant depletion of bacterial species, including those in the Akkermansia, Faecalibacterium prausnitzii, Clostridium, Lactobacillus, Prevotella, and Streptococcus species. But there was a siignificant increase "in relative abundance" in the bacterial species Moraxella nonliquefaciens. Once again, a study shows bacterial communities to be "out of whack" in those who've had sinusitis - this time in children. And the diminished diversity was linked to more frequent upper respiratory illnesses. The researchers mention the "possibility that the manipulation of the airway microbiota" could help prevent childhood respiratory diseases. Research by C.A. Santee et al from the Microbiome journal at BioMed Central:

Nasopharyngeal microbiota composition of children is related to the frequency of upper respiratory infection and acute sinusitis

Upper respiratory infections (URI) and their complications are a major healthcare burden for pediatric populations. Although the microbiology of the nasopharynx is an important determinant of the complications of URI, little is known of the nasopharyngeal (NP) microbiota of children, the factors that affect its composition, and its precise relationship with URI.

Healthy children (n = 47) aged 49–84 months from a prospective cohort study based in Wisconsin, USA, were examined. Demographic and clinical data and NP swab samples were obtained from participants upon entry to the study. All NP samples were profiled for bacterial microbiota using a phylogenetic microarray, and these data were related to demographic characteristics and upper respiratory health outcomes. The composition of the NP bacterial community of children was significantly related prior to the history of acute sinusitis. History of acute sinusitis was associated with significant depletion in relative abundance of taxa including Faecalibacterium prausnitzii and Akkermansia spp. and enrichment of Moraxella nonliquefaciens. Enrichment of M. nonliquefaciens was also a characteristic of baseline NP samples of children who subsequently developed acute sinusitis over the 1-year study period. Time to develop URI was significantly positively correlated with NP diversity, and children who experienced more frequent URIs exhibited significantly diminished NP microbiota diversity (P ≤ 0.05). 

These preliminary data suggest that previous history of acute sinusitis influences the composition of the NP microbiota, characterized by a depletion in relative abundance of specific taxa. Diminished diversity was associated with more frequent URIs. 

....These observations indicate that the composition of the pediatric upper airway represents a critical factor that may either potentiate or protect against infection by respiratory pathogens. They also indicate that the interplay between the bacterial microbiota and respiratory pathogens associated with upper airway infection is important to consider.Both bacteria and viruses can influence each other’s pathogenicity [8] and a number of interactions between specific viruses and bacterial species have been reported in the airways [9, 10]. For example, human rhinovirus infection was found to significantly increase the binding of Staphylococcus aureus, S. pneumoniae, or H. influenzae to primary human nasal epithelial cells [11]....

A total of 951 taxa were identified in baseline NP microbiota of participants (n = 47) in our cohort. These bacterial communities were variably composed of members of the Rickenellaceae, Lachnospiraceae, Verrucomicrobiaceae, Pseudomonadaceae, and Moraxellaceae as well as multiple unclassified members of the phylum Proteobacteria. .... Our study used independent NP samples collected from individual participants over a 12-month study period that spanned all four seasons. Season of sample collection also demonstrated a relationship with bacterial beta-diversity.

Compared with children who had no history of acute sinusitis (n = 33), those with a past history of acute sinusitis (n = 14) did not exhibit differences in α-diversity indices, suggesting that differences in microbiota characterizing these groups may be due to the enrichment or depletion of a subset of taxa within these bacterial communities. A total of 309 taxa (representing 101 genera) exhibited significant differences in relative abundance between children with and without a history of acute sinusitis. NP samples from children with a prior history of acute sinusitis were characterized by significant depletion of 308 of the 309 taxa, including those represented by Akkermansia, Faecalibacterium prausnitzii, Clostridium, Lactobacillus, Prevotella, and Streptococcus species. The only taxon that exhibited a significant increase in relative abundance in these subjects was represented by Moraxella nonliquefaciens. 

Children who experienced at least one URI (n = 17) within 60 days of collection of the baseline sample had significantly lower phylogenetic diversity compared to those who had no URIs within that time frame (n = 23). Time to development of URI, defined as the number of days between the collection of the baseline sample and the first incidence of URI (a value of 365 days was assigned to those children who did not experience a URI during the year of monitoring), was also significantly correlated with phylogenetic diversity .... Hence, these data indicate that diminished diversity of the NP microbiota is a precursor to URI in these children.  

In addition to Moraxella, a Corynebacterium was enriched in relative abundance in the NP microbiota of children who experienced acute sinusitis subsequent to baseline sample collection during the study period. ... However, Abreu et al. previously found Corynebacterium tuberculostearicum to be significantly enriched in the maxillary sinuses of adults with chronic rhinosinusitis compared to healthy control subjects [17]. The authors subsequently confirmed the ability of C. tuberculostearicum to induce acute sinusitis in the context of an antimicrobial-depleted murine model of sinus infection. Moreover co-installation of Lactobacillus sakei (one of a number of taxa acutely depleted in relative abundance among chronic rhinosinusitis patients) protected animals against C. tuberculostearicum infection [17]. Our pediatric data exhibits similarity with these murine studies, in that six members of the Lactobacillus genus were among those taxa most significantly depleted in relative abundance in the NP bacterial communities of children who developed sinusitis during our study. Five of these same taxa were also depleted in relative abundance in the NP microbial communities of children with a prior history of sinusitis. 

In addition to Lactobacillus, many other bacterial taxa including Akkermansia, Faecalibacterium prausnitzii, Clostridium, Prevotella, and Streptococcus species were depleted in relative abundance among children with a prior history of acute sinusitis. Though traditionally associated with gut microbiota, anaerobic bacterial species can exist in biofilms in the upper respiratory tract [18] and Akkermansia  and Faecalibacterium have previously been detected in the nasopharynx of children [19, 20]. While its role in the airway is unknown, gastrointestinal Akkermansia muciniphilia metabolizes mucin and has been shown to activate immune homeostasis, increasing host expression of antimicrobial peptides such as RegIIIγand improving barrier function via an increase in 2-oleoylgylcercerol [21, 22, 23]. However, whether such mechanisms play a role at the airway mucosal surface remains to be determined. 

Mechanisms by which Lactobacillus and other bacterial species depleted in the NP microbiota of sinusitis patients may prevent the development of disease include competitive exclusion of pathogenic species. A previous murine study indicated that intra-nasal inoculation of mice with L. fermentum decreased S. pneumoniae burden throughout the respiratory tract and increased the number of activated macrophages in the lung and lymphocytes in the tracheal lamina propria [24]. Hence, it is plausible that the absence of NP genera with known competitive exclusion and immunomodulatory capabilities leads to pathogen expansion and associated clinical manifestations of upper airway infection. 

....We do show that a history of sinusitis, its pathophysiology or treatment, may shape the NP microbiota—which may inform future studies and their design. Additionally, though we recognize that the composition of the microbiota in the upper airways is likely highly influenced by antibiotic administration .... The pervasive effects of antimicrobials on the human microbiota are well-described [26, 27], and it is likely that lifetime antibiotic use plays an important role in shaping the baseline NP microbial community. 

The composition of the NP microbiota in healthy children between 49 and 84 months of age is associated with past and subsequent history of acute sinusitis and frequency of URI. Widespread bacterial taxon depletion and enrichment of M. liquefaciens and C. tuberculostearicum are associated with upper airway infection and the development of acute sinusitis. Collectively, these findings provide evidence of close connections between microbial colonization of the airways and susceptibility to upper respiratory illnesses in early childhood and raise the possibility that the manipulation of the airway microbiota could be applied to the prevention of childhood respiratory illnesses. 

Published on Leave a comment on Biofilms In Chronic Sinusitis

An interesting study (published in September 2015) looked at how prevalent biofilms are in the sinuses of people with chronic sinusitis (with or without nasal polyps) as compared to healthy people (without chronic sinusitis). Biofilms are communities of bacteria sticking to one another and coated with a protective slime. The researchers found that the most biofilms were found in people with chronic sinusitis who also had nasal polyps (97.1%) , followed by those with chronic sinusitis without nasal polyps (81.5%), and the least in the control group of healthy patients (56%). They felt that the biofilms contributed to or had a role in chronic sinusitis. But note that the majority of people in all groups had biofilms.

Unfortunately nowhere in the study was there an analysis of the bacteria making up the biofilms. Are the bacteria in the biofilms different in the healthy people versus those with chronic sinusitis? The general assumption is that biofilms are formed from pathogenic (bad) bacteria such as Staphylococcus aureus, but it is known that beneficial bacteria such as Lactobaccillus plantarum and Lactobacillus reuteri can also form biofilms. One study concluded that: "L. reuteri biofilms secreted factors that confer specific health benefits such as immunomodulation and pathogen inhibition." So what was in the biofilms of healthy people (without chronic sinusitis)? Were the biofilms in healthy sinuses made up of protective beneficial bacteria or pathogenic bacteria that were kept in check by other "beneficial" microbes (which can be bacteria, fungi, viruses, etc) in the sinus microbiome?

Biofilms are very hard to eradicate, even with antibiotics. The researchers mentioned that "To date many different modalities have been tested, from Manuka honey to ultrasound and surfactant, but none have been shown to be very efficient." However, they did not mention other bacteria (probiotics) as a treatment possibilty in eradicating biofilms in the sinuses. There has been research looking at using probiotics against biofilms elsewhere in the body (such as dental plaque on teeth).

If biofilms from pathogenic bacteria are so pervasive in chronic sinusitis (81.5% to 97.1%), then it appears that some bacteria such as Lactobacillus sakei somehow predominate over them. I am saying this based on the majority of people writing to me saying that L. sakei treated their chronic sinusitis, as well as the experiences of my own 4 family members (at least 3, perhaps all 4 of us probably had biofilms in our sinuses based on the 81.5% to 97.1% numbers in this research). Something to contemplate. From the journal Acta Oto-Laryngologica:

Bacterial biofilms in chronic rhinosinusitis; distribution and prevalence.

Biofilms were more prevalent in patients with CRSwNP [chronic rhinosinusitis with nasal polyps] compared to both CRSsNP [chronic rhinosinusitis without nasal polyps] and controls [healthy people], and also on the ethmoid bulla compared to the middle turbinate, supporting a biofilm-related pathogenesis of CRSwNP....This study comprised 27 patients with CRSsNP, 34 patients with CRSwNP, and 25 controls.

Chronic rhinosinusitis (CRS) is today understood as a multifaceted group of diseases. The most established differentiation is between CRS with nasal polyps (CRSwNP) and without nasal polyps (CRSsNP)....Patients with CRSwNP have the worst quality-of-life scores, and they have frequent recurrences of their symptoms after surgery.

The pathophysiology of nasal polyps is poorly understood. Bacterial infection, in the form of biofilms, is proposed as a major drive behind the inflammation in CRS. Bacterial biofilms is identified as the agent behind an ever increasing number of chronic infectious diseases, ranging from endocarditis to dental caries. Bacterial biofilms are communities of bacteria in their sessile form, and can be extremely difficult to eradicate with conventional antibiotic therapy.

The total number of patients in the CRS group was 61, 23 females and 38 males, and median age was 40 years....Bacterial biofilms were detected in 97.1% of patients with CRSwNP, 81.5% of patients with CRSsNP, and 56% of controls. Patients with CRSwNP had highly significantly increased prevalence of biofilms compared to controls....The prevalence of biofilms in different anatomical locations within the nasal cavity differed....Biofilms were detected in 79.6% of the samples from the ethmoid bulla, 70.9% of the samples from the uncinated process, and 62.0% of the samples from the middle turbinate.

In this study a significantly increased prevalence of biofilms were found in patients with CRSwNP compared to controls, but also compared to CRSsNP. Indeed only one of the patients with CRSwNP was biofilm negative. This indicates a role for biofilms in the pathogenesis of CRS, but specifically in CRSwNP.

The pathophysiological mechanisms underlying nasal polyps are still poorly understood. Biofilms are shown to be heterogeneous and can be composed of both bacteria and fungi. Staphylococcus Aureus feature prominently in most biofilms found in the sinonasal cavity, being isolated in 50% of the samples. and can possibly facilitate co-colonization with fungi....Bacteria in a biofilm are shown to have up to a 1000-fold increased resistance to antibiotics compared to planktonic bacteria. These features of biofilms make them notoriously hard to eradicate.... In the setting of CRS we have the opportunity of direct local treatment which gives us a greater range of potential treatment options. To date many different modalities have been tested, from Manuka honey to ultrasound and surfactant, but none have been shown to be very efficient....In regards to nasal polyps, further studies are needed to investigate why some patients with biofilms develop nasal polyps while others do not.

Biofilms thrive in moist areas without too much turbulence, conditions found deep in the middle meatus. This may also explain why there were a higher number of biofilm positive CRSwNP patients, as regular nasal polyps originate in the ethmoid....In the opinion of the authors the findings in this article suggest a role for biofilms in CRSwNP.

Bacterial biofilm in a person with chronic sinusitis Credit: Thiago Freire Pinto Bezerra et al,  Braz. j. otorhinolaryngol. (Impr.) vol.75 no.6 São Paulo Nov./Dec. 2009

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Published on 4 Comments on Researchers Discuss Probiotics For Sinusitis Treatment

A wonderful journal article from March 17, 2015 by E.K. Cope and S.V. Lynch (one of the original L. sakei - sinusitis researchers) in which they discuss various probiotic (beneficial bacteria) species that might have some benefit in treating chronic sinusitis, which they refer to as chronic rhinosinusitis (CRS). They discuss bacteria that have have been (somewhat) studied in humans or mice and could have potential in sinusitis treatment: Lactobacillus sakei, Lactobacillus rhamnosus, Lactobacillus casei, Lactobacillus plantarum, Lactobacillus johnsonii, and Staphylococcus epidermidis. [NOTE: So few studies (almost none) have been done with probiotics in CRS  that the odds are really good that other species of bacteria, or combinations of bacteria, will also prove to be beneficial.]

It seems that a nasal spray with a mixture of beneficial bacteria may ultimately work the best because the bacterial diversity of the sinus microbiome is depleted in persons with chronic sinusitis, and there is "enrichment of sinus pathogens" (bacteria that can cause disease). As I've mentioned in other posts, S.V. Lynch is involved in developing a nasal probiotic spray containing L. sakei and other Lactobacillus species to treat sinusitis, but it is unknown when that will be available.

The authors also made the point that probiotics (beneficial bacteria) may work several ways in the sinus microbiome (a community of microbes living in the sinuses). This "niche" with its own ecosystem or community of species can be altered, with some bacteria species wiped out, perhaps by illness and/or repeated courses of antibiotics. Therefore, think of the different microbial species in the sinus microbiome as having different functions: as a keystone (a species that has a very large effect on the community), pioneer (species that are the first to colonize the niche after a disruption), or dominant species found in a healthy state (species with a relatively high abundance in a niche).

They also discuss what are the main pathogens found in chronic sinusitis, but they also mention that bacteria that we think of as pathogenic (the bad bacteria) are also present in healthy persons - just at a lower level than in chronic sinusitis sufferers. Also, these diverse microbial communities can vary between healthy individuals - that is, the healthy microbial communities are a little different among people. Common pathogenic bacteria found in CRS are: Staphylococcus aureus, Pseudomonas aeruginosa, Corynebacterium tuberculostearicum (normally a harmless skin bacteria), and Streptococcus species. Remember, healthy sinuses have greater bacterial diversity than sinusitis sufferers, and CRS patients have "substantial microbiome dysbiosis" (microbial communities out-of-whack), with "microbiome community collapse" and "enrichment of specific sinus pathogens". In other words, the microbial sinus communities in CRS are in bad shape and need to get good bacteria in there.

For information on how some people are already successfully using probiotics such as L. sakei for sinusitis treatment, read The One Probiotic That Treats Sinusitis (products, brands, and methods).

When reading the following, remember that dysbiosis means "the microbial community is out of whack". Some excerpts from the Cope and Lynch article from Current Allergy and Asthma Reports:

Novel Microbiome-Based Therapeutics for Chronic Rhinosinusitis

The human microbiome, i.e. the collection of microbes that live on, in and interact with the human body, is extraordinarily diverse; microbiota have been detected in every tissue of the human body interrogated to date. Resident microbiota interact extensively with immune cells and epithelia at mucosal surfaces including the airways, and chronic inflammatory and allergic respiratory disorders are associated with dysbiosis of the airway microbiome. Chronic rhinosinusitis (CRS) is a heterogeneous disease with a large socioeconomic impact, and recent studies have shown that sinus inflammation is associated with decreased sinus bacterial diversity and the concomitant enrichment of specific sinus pathogens.

Similar to other chronic inflammatory diseases, including inflammatory bowel disease and asthma, evidence is emerging for the role of the sinus microbiome in defining upper airway health.....two trends in the literature are evident. First, all three studies that have examined the microbiota of healthy subjects demonstrate the presence of a diverse microbiome that includes bacterial groups classically considered as causative agents of respiratory disease, including Pseudomonas, Staphylococcus, and Streptococcus. Second, substantial sinonasal microbiome dysbiosis is associated with CRS. In one example, Abreu and colleagues demonstrated microbiome community collapse in the maxillary sinuses of CRS patients compared to healthy controls characterized by the outgrowth of Corynebacterium tuberculostearicum. In another study, nasal lavage specimens from CRS patients revealed microbiome collapse coincident with Staphylococcus enrichment.

Immune responses in individuals with CRS vary considerably across patients.... While the underlying processes contributing to a patient’s immune response are not well understood, there is evidence for microbial stimulation. Staphylococcus aureus exotoxins are associated with a Th2 inflammatory response characterized by eosinophilia and enterotoxin-specific IgE , and the Th2 cytokines IL-4 and IL-13 have been associated with S. aureus outgrowth in other inflammatory diseases. Another common sinus pathogen, Pseudomonas aeruginosa, can induce antimicrobial nitric oxide production by host recognition of bacterial quorum sensing molecules through stimulation of the bitter taste receptor T2R38. There is clearly heterogeneity across patients with CRS; thus, future therapeutic microbiome manipulation strategies must be targeted to the specific microbiome perturbation and immune dysfunction of the patient.

Since CRS is immunologically and microbiologically diverse, it is not surprising that current treatment strategies using corticosteroids alone or in combination with antibiotics are variably successful. Some patients recover completely without recurrence, although 10–25 % of patients require repeated treatment....Patients who do not respond to medical management are candidates for functional endoscopic sinus surgery (FESS). The goal of FESS is to remove polypoid tissue and open ostia to facilitate sinus drainage. While some patients rebuild their native, healthy microbial communities and epithelium following FESS, many patients require revision sinus surgeries. Importantly, these therapies only manage chronic airway diseases and, in many cases, do not address the underlying source of disease, e.g., dysregulated microbiota. Since it is clear that the microbiome plays a fundamental role in respiratory health, it is essential to begin to define the interaction between pathogens or pathobionts in the context of the healthy host microbiota.

As discussed above, the most common route of probiotic delivery (oral) takes advantage of the GI-respiratory axis. In the only clinical trial of probiotic use in chronic rhinosinusitis, Mukerji and colleagues reported that oral administration of L. rhamnosus R0011 improved patient-reported symptoms of rhinosinusitis in the short term (<4 weeks), but not the long term (8 weeks). These results suggest a potential role for GI microbiome manipulation to affect the sinus immune response; however, there has not been a follow-up study to further elucidate this role. Repeated dosing or inoculation with mixed species could improve these results.

Several variables should be considered when designing probiotics for potential treatment of sinus disease. The first consideration, the route of administration, will determine the mechanism of action of the probiotic. Oral probiotic supplements primarily affect the respiratory tract through translocation of microbial metabolites, cytokines, or immune cells to the airways via systemic circulation, while local delivery via sprays or nasal lavage will affect the sinonasal microbiota and local immune responses...This first variable, route of administration, will determine which probiotic species are used. A second consideration for probiotic development is whether to supplement with a single species or a mixed-species consortium. Single species or species mixtures can be selected based on how best to leverage the healthy microbiome. From an ecological perspective, the potential role of the probiotic(s) should be considered. For example, the specie(s) may function as keystone (a species that has a disproportionately large effect on the community), pioneer (species that are the first to colonize the niche after a disruption), or dominant species found in a healthy state (species with a relatively high abundance in a niche).

Animal models are powerful tools for exploring the relationship of the host-microbiome to health and disease.... In malnourished mice, nasal instillation of Lactobacillus casei can confer protection against pathogens by enhancing host innate immune response....Live L. casei had additional benefits of temporarily colonizing the respiratory mucosa to competitively exclude S. pneumonia. Intranasal administration of Lactobacillus plantarum DK119 protected mice from lethal loads of influenza A virus through modulating host immunity of alveolar dendritic cells and macrophages. Similarly, intranasal administration of L. rhamnosus GG protected mice from H1N1 influenza infection by activating lung natural killer cells..... They also show that this protection can be achieved through feeding a single species L. johnsonii, which was enriched in the cecum of mice fed house dust.... In a sinusitis model, Abreu and colleagues demonstrated that intranasal administration of Lactobacillus sakei, identified using 16S rRNA phylogenetic microarray analysis of healthy human sinuses, protects against C. tuberculostearicum-induced sinusitis. A similar murine study showed that Staphylococcus epidermidis can protect against S. aureus-induced sinusitis. Together, these studies show promise for microbiome based therapeutics in sinusitis. However, we must think critically about the species or community used for sinus protection, administration methods, as well as the timing for microbial intervention

Probiotic administration can influence the host-microbiome composition and function directly through production of antimicrobials, changing the pH, or through competitive colonization within a niche. Bacteriocins are antimicrobial peptides produced by bacteria with a wide range of activity, either narrow spectrum (active against similar species) or broad spectrum (active across genera). Lactic acid bacteria are well-established producers of bacteriocins. The protective species identified by Abreu and colleagues, L. sakei, is known to produce several bacteriocins with a wide range of characteristics and putative modes of action, although the best characterized bacteriocin from this species is sakacin. Sakacin has antimicrobial activity against Gram positive taxa, including Listeria spp. and Enterococcus spp., but not Gram-negative bacteria.

Other Lactobacillus species that are potential probiotics for the airways act through the production of alternative antimicrobial compounds. Lactobacillus reuteri produces the protein reuterin, which acts as an antimicrobial compound by inducing oxidative stress in competing bacteria. Reuterin production is increased in the presence of E. coli, suggesting that the effects of this protein are aimed at eliminating competing microbes, giving L. reuteri an advantage in adherence and colonization of host mucosa. Lactobacillus spp. also commonly produce acetic acid and lactic acid, thereby lowering the pH of their niche and inhibiting the growth of acid-intolerant taxa. Finally, probiotic species can compete for growth substrates or receptor binding sites. L. johnsonii competes with several known pathogens for adhesion receptors, which are either glycoproteins or glycolipids. One such receptor is gangliotetraosylceramide (asialo-GM1), a glycolipid that is abundant in pulmonary tissue.

Probiotic intervention for respiratory diseases is an area of active investigation, particularly in light of recent microbiome findings. While the field is still relatively nascent, the potential for probiotic manipulation of the sinus microbiome to treat or prevent CRS is great. However, our current understanding of the healthy sinus microbiome and, thus, how best to manipulate it in a disease state are not well defined. Whether to use mixed versus single species and strain inocula, specific species used, mode of delivery, inoculum concentration, and determining the frequency of supplementation are some of the factors that need to be addressed in optimizing probiotic effects. Most of the studies discussed in this article have focused on the gut microbiome and effects at distal sites because these interactions have formed the focus of the majority of stduies to date. However, the murine [mouse] studies discussed here suggest that local administration of probiotics to the sinuses can affect the dynamics of the sinus microbiome.

Lactobacillus sakei Credit: BacMap Genome Atlas

Published on Leave a comment on Phage Therapy May Help Sinusitis Sufferers

Some researchers are now testing to see if phage therapy  could be a possible treatment for some conditions, such as chronic sinusitis and wound infections. Phage therapy, which uses bacteriophages, was neglected for decades (except for Russia and the Republic of Georgia), but their use is again being studied as an alternative to antibiotics. A bacteriophage is a virus that lives within a bacterium, replicating itself, and eventually destroys the bacteria. The term is from "bacteria" and the Greek "phagein" which means to devour, so think of them as "bacteria eaters". Phages only attack specific types of bacteria (they are "bacterium specific"), so they’re unlikely to harm the normal microbiome (community of microbes) or any human cells.

I've been posting about the beneficial bacteria Lactobacillus sakei that treats chronic sinusitis, as well as some other probiotic (beneficial) bacteria that people have reported success with (see The One Probiotic That Treats Sinusitis). Most people contacting me or commenting have reported success with L. sakei products, but there is a group for whom L. sakei and other probiotics haven't helped. Why? And what can be done? Perhaps their sinuses are missing still unknown "keystone" species (very important microbial species for health). Or perhaps they have bacterial biofilms that even Lactobacillus species that are viewed as anti-biofilm cannot overcome. Perhaps phage therapy might help these people? 

Phage therapy is currently being tested by researchers in the treatment of chronic sinusitis in Australia. The video Antibiotic Resistance discusses phage therapy for sinusitis starting at 23:30. Looks promising.

And a write-up about the sinusitis phage therapy research from the Australian newspaper The Sydney Morning Herald: Medicine turns to bacteriophage therapy to beat superbugs

An arcane therapy for bacterial infections that dwelled behind the Iron Curtain for decades is making a comeback in Western medicine as a potential white knight against superbugs. Phage therapy involves infecting patients with viruses known as bacteriophages, which are the natural predators of bacteria, to kill the germs that antibiotics cannot.  ...continue reading "Phage Therapy May Help Sinusitis Sufferers"