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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 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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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). 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.

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.

 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

 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. 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 sinusitisHistory 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 [910]. 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 [1920]. 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 [212223]. 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 [2627], 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. 

 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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 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 Lactobacillus sakei Credit: BacMap Genome Atlas

 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.

Scientists hope these harmless viruses will cure patients who have been infected by bacteria that is resistant to antibiotics, causing chronic ear, nose and throat infections as well as life-threatening illnesses such as sepsis. The first human trial of a phage therapy began at the Queen Elizabeth Hospital in Adelaide last week, when a female patient with chronic sinusitis started using a nasal rinse swimming with phages  that target golden staph.

Excerpts from an article discussing phage therapy, including that it is being tested on people with chronic sinusitis at AmpliPhi Biosciences in Virginia. From The Scientist: Viral Soldiers

Researchers on the hunt for more-effective therapies that preserve a healthy microbiome are taking a closer look at the many different viruses that attack bacteria. Bacteriophages (literally, “bacteria eaters”) punch holes through the microbes’ outer covering and inject their own genetic material, hijacking the host’s cellular machinery to make viral copies, then burst open the cell with proteins known as lysins, releasing dozens or hundreds of new phages. The cycle continues until there are no bacteria left to slay. Phages are picky eaters that only attack specific types of bacteria, so they’re unlikely to harm the normal microbiome or any human cells. And because phages have coevolved with their bacterial victims for millennia, it’s unlikely that an arms race will lead to resistance. This simple biology has led to renewed interest in the surprisingly long-standing practice of phage therapy: infecting patients with viruses to kill their bacterial foes.

While most research is still in the preclinical phase, a handful of trials are underway, and a growing number of companies are investing in the treatment strategy. Phage therapy is receiving as much attention now as it did in the pre-antibiotic era, when it flourished in spite of the dearth of clinical tests or regulatory oversight at the time. “Bacteriophage therapy will have its day again,” pathologist Catherine Loc-Carrillo of the University of Utah told The Scientist last year. “It sort of had one, before antibiotics came along, but it wasn’t well understood then.”

These days, centers like the Eliava Institute of Bacteriophages, Microbiology and Virology in the Republic of Georgia offer commercial phage preparations for specific indications, such as MRSA and gastrointestinal infections caused by E. coli and Shigella species. Researchers at the Eliava Institute also mix phages into custom cocktails for many infections. ...Years of research at the Eliava Institute have led to a carefully curated library with hundreds of vials of such isolates, from which the scientists prepare their custom combination therapies.

Mzia Kutateladze, the institute’s current director, says she receives a growing number of requests for treatment, including from patients in the U.S. and Western Europe. “They send us clinical materials, either cultures or swabs, before they arrive,” she says. “We first test our commercial products. If they don’t work, we identify phages in the library, prepare and test a final customized product before it’s used in the patients.” Patients can then travel to the clinic for treatment, or the Eliava Institute will send the phages to patients to use on their own.

Kutter suspects that success stories from the Eliava Institute and others will ease acceptance of phage therapy into the modern pharmacopeia. Indeed, retrospective analyses of phage therapies published by these groups are helping researchers understand which particular infections are likely to respond to the treatments. Fueled by these data and a prominent mention in a 2014 National Institute of Allergy and Infectious Diseases (NIAID) report on the agency’s antibacterial resistance program, companies around the world are preparing for a second coming of phage therapy.

But many questions remain....Another open question is how therapeutic viruses interact with the human immune system, and whether they might cause side effects. At the Ludwik Hirszfeld Institute of Immunology and Experimental Therapy at the Polish Academy of Sciences—where patients receive phage therapy on compassionate-use grounds after they’ve failed to respond to other treatments—researcher Andrzej Górski is sifting through years of clinical data to find answers. In a retrospective analysis of immune responses in 153 people treated with phages between 2008 and 2010, Górski and his colleagues reported that the therapies were well-tolerated in 80 percent of patients.10 Only a small number had to stop treatment because they experienced adverse reactions such as nausea or pain in response to gut treatments, or local reactions to topical phage applications, Górski said at a first-of-its-kind NIAID workshop on phage therapies that convened in Rockville, Maryland, last July.

Despite the challenges still facing phage therapy, numerous companies are now looking to bring the treatments to mainstream clinics.....A handful of US companies also aim to bring phage preparations to clinical trials. In 2009, the Maryland-based firm Intralytix published the results of its Phase 1 trial for a phage therapy that targets venous leg ulcers in diabetic patients. None of the 40 or so patients who received the phage cocktail had any adverse reactions to the treatment, but the company has not said whether a Phase 2 trial is planned.13 Meanwhile, Richmond, Virginia–based AmpliPhi Biosciences announced in November it was enrolling nine patients to test the safety of a natural phage cocktail intended to treat chronic sinus infections caused by S. aureus.

This study is interesting in that it found that there are already bacteriophages in the normal sinus microbiome, what they refer to as virus-like particles (VLPs). From PLOS ONE: Enumerating Virus-Like Particles and Bacterial Populations in the Sinuses of Chronic Rhinosinusitis Patients Using Flow Cytometry

There is increasing evidence to suggest that the sinus microbiome plays a role in the pathogenesis of chronic rhinosinusitis (CRS). However, the concentration of these microorganisms within the sinuses is still unknown. We show that flow cytometry can be used to enumerate bacteria and virus-like particles (VLPs) in sinus flush samples of CRS patients....We found high concentrations of bacteria and VLPs in these samples.....Our finding, that large numbers of VLP are frequently present in sinuses, indicates that phage therapy may represent a minimally disruptive intervention towards the nasal microbiome. 

An alternative treatment is phage therapy which utilises specific bacteriophages (phage) that infect and kill pathogenic bacteria [16]....Our results showed that the sinus, at least in patients requiring sinus surgery, is an active microbiological environment. We speculate that most VLPs detected are likely to be bacteriophages as they are the most commonly found in association with their hosts, bacteria, which we find to be present in abundance in sinuses. The proposal that phages can be used to treat bacterial infections of the sinus [17] can now be viewed in the light of this data showing that phages appear to be present in sinuses in large numbers.

 Bacteriophages   Credit:R. Duda/Univ. of Pittsburgh; P Serwer/ Univ. of Texas Health Science Center at San Antonio

Phages on the surface of an Escherichia coli cell inject genetic material into the bacterium.Credit:Eye of Science/Science Source

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  It's now 3 years being free of chronic sinusitis and off all antibiotics! Three amazing years since I started using easy do-it-yourself sinusitis treatments containing the probiotic (beneficial bacteria) Lactobacillus sakei. My sinuses feel great! And yes, it still feels miraculous.

After reading the original ground-breaking research on sinusitis done by Abreu et al (2012), it led to finding and trying L. sakei as a sinusitis treatment. Of course, there is an entire community of microbes that live in healthy sinuses (the sinus microbiome), but L. sakei seems to be a key one for sinus health.

I just updated the post The One Probiotic That Treats Sinusitis (originally posted January 2015) using my family's experiences (lots of self-experimentation!) and all the information that people have sent me. The post has a list of brands and products with L. sakei, as well as information about some other promising bacteria. Thank you so much!

Thank you all who have written to me  - whether publicly or privately. Please keep writing and tell me what has worked or hasn't worked for you as a sinusitis treatment. If you find another bacteria or microbe or product that works for you - please let me know. It all adds to the sinusitis treatment knowledge base. I will keep posting updates. 

(NOTE: I wrote our background story - Sinusitis Treatment Story back in December 2013, and there is also a  Sinusitis Treatment Summary page with the various treatment methods. One can also click on SINUSITIS under CATEGORIES to see more posts, such as "Probiotics and Sinusitis" - a discussion by one of the original sinusitis researchers about what she thinks is going on in sinus microbiomes and what is needed.)  

New research that found that microbial communities vary between the sinuses in a person with chronic sinusitis. This is a result that many sinusitis sufferers already suspect based on their sinusitis symptoms. The researchers also found that bacterial communities in the sinuses vary between people with chronic sinusitis. It is frustrating though for me to read study after study where the researchers focus on describing the types of bacteria found in chronic sinusitis sufferers (and then just saying that the sinus microbiomes or community of microbes vary from person to person) rather than studies comparing the sinus microbiomes (bacteria and other microbes, such as fungi) between healthy individuals and sinusitis sufferers.

Since research finds that sinusitis sufferers have altered sinus microbiomes, then what would be really helpful now is finding more beneficial or keystone species (besides Lactobacillus sakei) that are needed for healthy sinus microbiomes. This would be an important step towards then adding (perhaps using a nasal spray) these missing microbes to the sinus microbiome. From Frontiers in Microbiology:

Bacterial communities vary between sinuses in chronic rhinosinusitis patients

ABSTRACT: Chronic rhinosinusitis (CRS) is a common and potentially debilitating disease characterized by inflammation of the sinus mucosa for longer than 12 weeks. Bacterial colonization of the sinuses and its role in the pathogenesis of this disease is an ongoing area of research. Recent advances in culture-independent molecular techniques for bacterial identification have the potential to provide a more accurate and complete assessment of the sinus microbiome, however there is little concordance in results between studies, possibly due to differences in the sampling location and techniques. This study aimed to determine whether the microbial communities from one sinus could be considered representative of all sinuses, and examine differences between two commonly used methods for sample collection, swabs and tissue biopsies. High-throughput DNA sequencing of the bacterial 16S rRNA gene was applied to both swab and tissue samples from multiple sinuses of 19 patients undergoing surgery for treatment of CRS. Results from swabs and tissue biopsies showed a high degree of similarity, indicating that swabbing is sufficient to recover the microbial community from the sinuses. Microbial communities from different sinuses within individual patients differed to varying degrees, demonstrating that it is possible for distinct microbiomes to exist simultaneously in different sinuses of the same patient. The sequencing results correlated well with culture-based pathogen identification conducted in parallel, although the culturing missed many species detected by sequencing. This finding has implications for future research into the sinus microbiome, which should take this heterogeneity into account by sampling patients from more than one sinus. It may also be of clinical importance, as determination of antibiotic sensitivities using culture of a swab from a single sinus could miss relevant pathogens that are localized to another sinus.

CRS can be a debilitating condition that is recalcitrant to treatment. Bacterial colonization of the sinuses is likely to play an important role in the pathogenesis and perpetuation of the disease; however different studies have yielded contrasting results with respect to which bacterial taxa are characteristic of the disease (ref). We observed bacterial communities dominated by different taxa in CRS patients; for example some have sinuses colonized primarily with Haemophilus, while others are dominated by Corynebacterium and Staphylococcus, or Pseudomonas. Some patients’ sinuses contain anaerobic bacteria such as Anaerococcus, Finegoldia, and Peptoniphilus, while these were absent from others. Indeed, our results have shown, for the first time, that it is possible for a patient to simultaneously have different bacterial communities in different sinuses, pointing to distinct, localized microbiomes within the same patient. Understanding this variation in the sinus microbiome could prove critical to the appropriate selection of treatments for CRS in the future.

The weighted unifrac distances between samples within patients (Figure 1) demonstrate that at least some CRS patients have substantial variation of bacterial communities between sinuses, although it is significantly smaller than the variation observed between different individuals. While this variation was related to abundance rather than the presence or absence of dominant community members, some of these variations were large: for example Corynebacterium sequences dominating the right sinuses of patient 003 (60.7 and 41.7% of all sequences), while the left sinuses had much smaller abundances (9.8 and 6.2%) and were dominated by the anaerobic bacteria Anaerococcus, Finegoldia  and Peptinophillus.