bs_bs_banner Minireview Lactic acid bacteria as probiotics for the nose? Ilke De Boeck,1 Irina Spacova,1 evidence for oral or topical probiotics for common Olivier M. Vanderveken2,3 and Sarah Lebeer1* URT diseases such as chronic rhinosinusitis (CRS) 1Department of Bioscience Engineering, University of needs further substantiation. Antwerp, Groenenborgerlaan 171, Antwerp, B-2020, Belgium. 2ENT, Head and Neck Surgery and Communication Introduction Disorders, Antwerp University Hospital, Edegem, Inflammatory upper respiratory tract (URT) diseases Belgium. such as rhinitis, and acute and chronic rhinosinusitis 3Faculty of Medicine and Health Sciences, Translational (CRS), impose a major burden on public health and Neurosciences, University of Antwerp, Antwerp, Belgium. account for significant healthcare costs (Meltzer, 2016; Hellings et al., 2017). Rhinitis is the most common URT disease defined as symptomatic inflammation of the lin- Summary ing of the nose that is caused by infectious agents, aller- Several studies have recently pointed towards an gens or other factors (e.g., drugs and hormones) increased occurrence and prevalence of several taxa (Bousquet et al., 2008). Allergic rhinitis (AR) represents of the lactic acid bacteria (LAB) in the microbiota of the most commonly encountered type of non-infectious the upper respiratory tract (URT) under healthy con- rhinitis, while the term rhinosinusitis is defined as inflam- ditions versus disease. These include several spe- mation of the nose and paranasal sinuses, characterized cies of the Lactobacillales such as Lacticaseibacillus by two or more symptoms, one of which should be either casei, Lactococcus lactis and Dolosigranulum nasal obstruction or nasal discharge (Fokkens et al., pigrum. In addition to physiological studies on their 2020). When the latter condition lasts for more than potential beneficial functions and their long history 12 weeks, it is defined as chronic rhinosinusitis (CRS) of safe use as probiotics in other human body sites, (Fokkens et al., 2020). These disorders have in common LAB are thus increasingly to be explored as alterna- that inflammation, and sometimes also a disruption of tive or complementary treatment for URT diseases. the nasal epithelial barrier, underlie the pathology. In This review highlights the importance of lactic acid addition, a disbalance of the microbial communities or bacteria in the respiratory tract and their potential as dysbiosis inhabiting the airways, the ‘airway microbiota’, topical probiotics for this body site. We focus on the has been suggested as a key factor in the pathology of potential probiotic properties and adaptation factors these URT diseases. that are needed for a bacterial strain to optimally exert its beneficial activity in the respiratory tract. Dysbiosis in URT diseases Furthermore, we discuss a range of in silico, in vitro and in vivo models needed to obtain better insights Recent research shows that a balanced airway micro- into the efficacy and adaptation factors specifically biota plays an important gatekeeper role for respiratory for URT probiotics. Such knowledge will facilitate health, as reviewed by (Man et al., 2017), although it is optimal strain selection in order to conduct rigorous yet very difficult to determine what defines a balanced clinical studies with the most suitable probiotic microbiota. It is generally seen as the counterpart of dys- strains. Despite convincing evidence from micro- biosis. Such an imbalance in the composition and meta- biome association and in vitro studies, the clinical bolic activity of our microbiota can appear in several manners, for example as a loss of beneficial microorgan- Received 20 October, 2020; revised 4 January, 2021; accepted 7 isms, or an excessive growth of potential pathobionts January, 2021. (Wilkins et al., 2019). The identification of beneficial ver- *For correspondence. E-mail [email protected]; Tel. +32 sus potential pathobionts is not always straightforward. 2 653 285. Microbial Biotechnology (2021) 0(0), 1–11 Bacterial genera that are commonly abundant in the doi:10.1111/1751-7915.13759 URT of healthy individuals, without clear symptoms, ª 2021 The Authors. Microbial Biotechnology published by John Wiley & Sons Ltd and Society for Applied Microbiology. This is an open access article under the terms of the Creative Commons Attribution-NonCommercial License, which permits use, distribution and reproduction in any medium, provided the original work is properly cited and is not used for commercial purposes. 2 I. De Boeck et al. belong to Staphylococcus, Corynebacterium, Propioni- recently that we start to explore the potential for other bacterium, Dolosigranulum and Streptococcus species applications. Yet, the definition of probiotics, as formu- (Man et al., 2017; Kumpitsch et al., 2019). These taxa lated by an expert panel of the International Scientific can thus be seen to contain potential beneficial strains. Association on Probiotics and Prebiotics (ISAPP) is not Pathobionts such as Staphylococcus aureus, Streptococ- limited to gut applications. Probiotics are ‘live microor- cus pneumoniae, Haemophilus influenzae and Moraxella ganisms that, when administered in adequate amounts, catarrhalis appear to be more prevalent or abundant in confer a health benefit on the host’ (Hill et al., 2014). URT diseases (Van Eldere et al., 2014; Duell et al., Most probiotics studied so far are lactic acid bacteria 2016; Mahdavinia et al., 2016; van den Broek et al., (LAB) (order Lactobacillales), with some of the most 2019). In addition to these classic URT pathogens, other promising probiotic strains belonging to the Lactobacil- emerging pathogens, such as Corynebacterium tubercu- laceae family, recently reclassified (Zheng et al., 2020). lostearicum and Stenotrophomonas, have been sug- Lactobacilli are an interesting choice as probiotics, since gested based on microbiome data (Abreu et al., 2012; they have a long history of safe use for over 100 years Chalermwatanachai et al., 2018; Koeller et al., 2018). by people of all ages on a daily basis in dairy products, Nevertheless, it remains highly challenging to investigate fermented foods and food supplements (Salvetti and whether these changes and disruptions in the micro- O’Toole, 2017). Yet, their potential as URT probiotics is biome are either a causality or a consequence. not yet widely considered. Although various treatment options yet exist for CRS and AR, there is a lack of broadly applicable and effec- Lactic acid bacteria have a habitat in the respiratory tract tive treatment approaches (Hellings et al., 2017; Meng et al., 2019). Current options include mainly nasal irriga- In the recent decade, members of LAB, including Lacti- tions with saline solutions, systemic and/or topical corti- caseibacillus, Dolosigranulum and Lactococcus species, costeroid treatment, antihistamines (in AR) (Meng et al., have been described as part of the normal URT micro- 2019), antibiotic treatments (often macrolides because biota of healthy adults and/or children (Bogaert et al., they also have anti-inflammatory actions) and functional 2011; Laufer et al., 2011; Jensen et al., 2013; Ling endoscopic sinus surgery or FESS (in CRS) (Fokkens et al., 2013; Stearns et al., 2015). Lactobacilli are for et al., 2020). The latter surgery has the aim to clear the instance detected in the nasopharynx of Chinese (Ling diseased mucosa, eliminate the infection, relieve the et al., 2013; Gan et al., 2019), Canadian (Stearns et al., obstruction and restore the sinus ventilation (Piromchai 2015), and Belgian individuals (De Boeck et al., 2020) et al., 2013). However, patients do not always respond and the tonsillar crypts of children and adults (Jensen to the current treatment options and patients often et al., 2013). The pilot study by Abreu and colleagues relapse, even after the surgery. For example, CRS was one of the first that reported that certain LAB taxa, patients often receive multiple antibiotic treatments, lead- including Latilactobacillus sakei, was decreased in CRS ing to several disadvantages, such as microbiota disrup- patients, pointing towards a potential benefit for sinus tion and multidrug-resistant bacteria (Szaleniec et al., health. Furthermore, they developed a murine model of 2019). Also for otitis media (OM), the most common sinus infection, where they demonstrated that L. sakei URT infection in children, antibiotic prescription rates are ATCC15521 can protect the sinus mucosa from C. tu- high despite clinical guidelines limiting their use to strict berculostearicum-induced pathogenesis after nasal inoc- indications (reviewed in van den Broek et al., 2019). ulation, using goblet cell hyperplasia and mucin There is thus a clear need for alternative or complemen- hypersecretion as outcome parameters (Abreu et al., tary treatment options for these highly prevalent URT 2012). These results were obtained in a not yet widely diseases. In this review, we will describe the current applied murine model with only small sample sizes knowledge on the potential of lactic acid bacteria as topi- (n = 3) and have to the best of our knowledge not yet cal probiotics for the URT, with a focus on the probiotic been confirmed in larger sample sizes. In our recent properties and adaptation factors that are needed for a microbiome comparison study between healthy controls bacterial strain to exert its beneficial activity in the URT. and CRS patients, various genera of the Lactobacil- In addition, future perspectives and challenges for URT laceae