Even as late as 2019, infectious diseases such as lower respiratory tract infections, diarrheal diseases, and tuberculosis were still in the top 10 global causes of death and/or disability-adjusted life years (DALYs; Global Health Observatory, 2021). Previous outbreaks of severe acute respiratory syndrome (SARS), Middle East respiratory syndrome (MERS), and the current COVID-19 pandemic have demonstrated that zoonotic diseases are on the rise (Skowron et al., 2022). Moreover, the incidence and burden of lower respiratory tract infections are predicted to increase in our aging population, which can have detrimental effects on healthcare systems if the situation remains unchanged (Feddema et al., 2021). In 2018, the global financial burden of infectious disease epidemics was estimated to be around US$60 billion annually, and the costs of the ongoing COVID-19 pandemic have been estimated to reach US$16 trillion (Cutler and Summers, 2020; Wellcome, 2021).

Currently, as several years have passed since the start of the pandemic, the world is still suffering the consequences. Despite innovation barriers such as a lack of knowledge about the newly emerging virus (Janse et al., 2021), various vaccines have been developed with sufficient short-term efficacy and effectiveness (Noor, 2021; Whitaker et al., 2022). However, at the moment, the long-term efficacy is still unknown and to date, curative medications have been developed but are not readily available yet (Couzin-Frankel, 2021; Kane and Kounang, 2022). Additionally, according to the WHO, the pandemic has caused disruptions in running immunization programs which may result in a rise of vaccine-preventable diseases in young children (World Health Organization, 2020). Furthermore, a new problem has surfaced in recent decades, which is that antibiotic interventions that have been developed to combat infectious diseases are becoming less effective due to antimicrobial resistance (Peri et al., 2019). Therefore, there is an urgent need for new types of interventional and prophylactic modalities to lower the burden of infectious diseases.

Maintaining and potentially restoring the microbiota of humans is considered a vital aspect of the resilience of humans and animals, protecting against a host of infectious and inflammatory diseases (Larsen and van de Burgwal, 2021). Probiotics, defined as “live microorganisms which when administered in adequate amounts confer a health benefit on the host” (World Health Organization, 2002, p. 8), have demonstrated potential as a clinical modality for several infectious diseases, possibly including COVID-19 (Lei et al., 2017; Infusino et al., 2020). Research suggests that probiotics can be used for infectious diseases because of their beneficial effects on the microbiota of the host, which in turn may result in various other health benefits (Valdez et al., 2014; Reid, 2017; Liu et al., 2018; Infusino et al., 2020). The most important target for probiotics is, to date, the gut microbiota, as it contributes greatly to the development of the immune system and comprises the largest immune organ of the human body (Ubeda and Pamer, 2012). Nevertheless, promising results have also been obtained for, e.g., the lung microbiota in which probiotics exert their effect through the gut-lung axis (Dumas et al., 2018; de Oliveira et al., 2021).

Some of the effects that probiotics can have by altering the human gut microbiota include increased antiviral activity after vaccination (Yeh et al., 2018; Infusino et al., 2020), and prevention and/or treatment of respiratory tract and urogenital infections through inhibition of bacteria adhesion and increasing mucosal barrier functioning (Reid, 2017; Liu et al., 2018; Stavropoulou and Bezirtzoglou, 2020; Lv et al., 2021; Theodosiou et al., 2021). The importance of the gut microbiota is also highlighted in the case of COVID-19, as this virus does not only affect the respiratory tract but has also been associated with a decrease in gut microbiota diversity due to the interactions between the respiratory and digestive tract termed the gut-lung axis (de Oliveira et al., 2021). While research on the relation between COVID-19 and the gut microbiota is still in its infancy, it has been suggested that the use of probiotics may improve the recovery of hospitalized COVID-19 patients compared to patients that do not use probiotics (Zhang L. et al., 2021). However, many clinical trials are still ongoing, making it difficult to fully assess the benefits of probiotics for COVID-19 (Kurian et al., 2021).

Altogether, probiotics may serve as a promising intervention targeting infectious diseases. Besides its potential clinical efficacy, research has also shown that probiotics for oral consumption are safe (van den Nieuwboer et al., 2014, 2015a,b; Larsen et al., 2017). Consequently, probiotics may become interventional modalities with a relatively high benefit to burden ratio. Concerns on the efficacy still remain due to conflicting results between clinical studies (Suez et al., 2019). These conflicting results may be caused by several research barriers. The effects of probiotics can vary not only between strains but also within strains, for example, because of different dosages or characteristics of the user (Suez et al., 2019). Moreover, probiotic species can exert their effects through different mechanisms; lactic acid bacteria, for example, can affect the gut microbiota through fermentation, communication via vesicles, as well as the production of antibiotics (Suissa et al., 2022). On top of that, probiotic efficacy has been shown to be impacted by carrier matrices (Flach et al., 2018). Hence, no general statements should be made regarding the efficacy of probiotics due to the aforementioned effects (Flach et al., 2018; Lebeer et al., 2018). Nevertheless, despite these barriers, the field of probiotics is growing very rapidly. Overall, the current state of the art still remains unclear, and in turn, it is unknown what the most beneficial applications of probiotics are regarding not only COVID-19 but other infectious diseases as well.

An effective strategy to understand the state of the art is to investigate what, if any, intellectual property and clinical trials have been applied for. According to Feddema and Claassen (2018), patents can be used as an early indicator of developments in the market as well as new technologies, while clinical trials provide insight into the development of the medical field. This is further clarified by Janse et al. (2020), stating that patents can be used to measure the amount of early-stage research and provide information on long-term developments in the field of research as they offer protection of intellectual property for 20 years. Clinical trials can be used to measure late-stage research because they are an essential step that needs to be completed before a new product can enter the market, providing information on short-term developments through a cross-sectional overview of active clinical trials at a given point in time (Janse et al., 2020). In this line, this review aims to create a broad and complete overview of the state of the art of probiotics and infectious diseases through the analysis of relevant patents and clinical trials of the past 20 years.

To gain insight into innovation efforts using probiotics as a means to prevent, treat, or alleviate symptoms of infectious diseases, both patent and clinical trial databases were studied. As patent applications are executed to protect the intellectual property of new inventions, they are a measure of output of early-stage, applied research (Janse et al., 2020). Clinical trials are a measure of output of late-stage research, as they are executed near the end of the research and development process before market entry (Ramezanpour et al., 2015; Janse et al., 2020). Taken together, they provide an overview of the development of the research field.

This study presents an overview of the state of the art regarding patents and clinical trials for probiotics targeted toward infectious diseases. The research landscape consisted of 789 patents and 602 clinical trials mainly targeted toward infectious diseases with digestive tract, urogenital, and respiratory symptoms. The rapid increase in cumulative patents and clinical trials that was observed from the year 1999 to the year 2021 strongly suggests that probiotics as clinical modalities for infectious diseases have gained considerable interest, mainly in Asia and North America, from industrial and academic parties.

It was found that over the past 20 years, the cumulative increase in the number of patents describing probiotic applications for infectious diseases differed slightly from the increase in the number of clinical trials. The cumulative number of patents seems to reach the beginning of a plateau, whereas the cumulative number of clinical trials seems to be increasing up to the year 2021 without reaching a plateau. According to Fernald et al. (2013), the cumulative number of patents over time can be compared to the so-called technology saturation curve (S-curve) originally described by Ernst (1997). This S-curve demonstrates technological change within an industry in four stages: Emerging, Growth, Maturity, and Saturation (Weenen et al., 2013). Based on the data we collected, it may be suggested that the probiotics industry as reflected by the cumulative number of patents has currently entered the maturity stage. However, this has yet to be confirmed by data from future years and may be subject to change due to delays caused by the COVID-19 pandemic and the 18-month patent application process.

Regarding clinical trials, the cumulative number over the past 20 years showed a less pronounced growth without seeming to reach a plateau, suggesting that based on the S-curve, the maturity stage has not yet been reached. This “lag time” between patents and clinical trials may have multiple causes. Firstly, van de Burgwal et al. (2018) state that patent application is normally an earlier step in the research process than clinical trial execution. Secondly, the patent application process is relatively less difficult and expensive than the execution of a clinical trial; new probiotic products may be abandoned during early-stage development due to strict regulations on probiotics research (van den Nieuwboer et al., 2016; Binda et al., 2020). This in turn could cause a gap between the number of patents that are applied for and the number of clinical trials that are executed.

Infectious diseases with digestive tract symptoms showed the highest growth for patents as well as clinical trials, making these the most popular indications overall. The high focus on digestive tract symptoms is not surprising, as the digestive tract is the place where probiotics can directly interact with the gut microbiota of the host as well as pathogens (Cazorla et al., 2018; Lv et al., 2021; Taverniti et al., 2021). Moreover, these findings are in agreement with a previous study by van den Nieuwboer et al. (2016). In this study, unmet needs and research priorities according to key opinion leaders (KOLs) in the field of probiotics showed that for people of all ages, conditions relating to the digestive tract such as antibiotic-associated diarrhea had a high priority (van den Nieuwboer et al., 2016).

The second and third highest numbers of patents and clinical trials were found for infectious diseases with urogenital and respiratory symptoms, respectively. Susceptibility to these types of diseases has been linked to the microbiome composition of young children and older adults (Horwitz et al., 2015; Unger and Bogaert, 2017). The study on unmet needs and research priorities according to KOLs (van den Nieuwboer et al., 2016) showed that there was a medium research priority for respiratory infections in infants and children, and a low research priority in adults. Overall, this medium to low prioritization appears to be in line with the percentages of patents and clinical trials that were found. The only exception is the high number of clinical trials studying the effects of probiotics on COVID-19 (n = 33) that have been executed in the last 2 years, which is not surprising considering that the COVID-19 pandemic only started after publication of the research by van den Nieuwboer et al. (2016). Regarding the research priority of infectious diseases with urogenital symptoms, it is difficult to compare the findings of this study with those of van den Nieuwboer et al. (2016) because these are not specifically articulated, either due to low prioritization or the use of alternative terminations.

Use of termination and specification was further investigated, showing that over half of the data entries included in this review did not specify the strain of the probiotic that was used. Data were sampled by randomly selecting 2–5 records of patents and clinical trials, respectively, for each of the top 24 most frequently studied infectious diseases. The number of patents and clinical trials that were sampled for each infectious disease depended on the number of results included in the final dataset to increase the accuracy of the sample, totaling approximately 10% of the data. Out of the 80 sampled patents, ~49% (n = 39) specified one or multiple probiotic strains and out of 62 patents, ~39% (n = 24) specified a probiotic strain or product with traceable composition. The lack of specification can be considered a barrier in the research process, as the effects of a probiotic can differ vastly between strains (Hill et al., 2014; Suissa et al., 2022), making it unclear which probiotic strain or strains are responsible for the reported health effects disclosed in patents and clinical trials, and negatively impacting the replicability of probiotic research.

The clinical trials included in this review were mainly sponsored/executed by academic institutions, whereas patents were mainly applied for by industrial parties. The contributions of the three main applicant/sponsor groups (industry, academia, and government) were compared for each indication type following methods described in previous research (van de Burgwal et al., 2016). For all nine categories of infectious diseases, similar divisions were found between the three groups of patent applicants and clinical trials sponsors. This is in accordance with the notion that clinical trials provide insight into research trends with academic parties being more focused on fundamental research, whereas patents can be considered a reflection of the market with industrial parties that are more focused on applied research and commercialization (Feddema and Claassen, 2018; Janse et al., 2020).

The International Probiotics Association (IPA) reported that in 2019, China ranked highest in sales of probiotic supplements and yoghurts, followed by the United States and Europe (International Probiotics Association, 2019). Analogous to these sales estimates, it was found that Asia and North America were the most popular locations for clinical trials and patent applications. According to Neevel et al. (2020), the location of patent applications is closely related to expected profit, as the costs of patent filing and maintenance are very high. Lower-income countries were less frequently reported as the patent application and clinical trial locations. Reid et al. (2018) have stated that many people in these countries do not have access to probiotic products. However, the IPA highlights that these particular people may benefit the most from probiotics as low hygiene and lack of clean water cause a surge in infectious disease prevalence (International Probiotics Association, 2015).

When interpreting the findings of this study, several limitations need to be considered. Firstly, due to the patenting process taking up to 18 months from application to publication (European Patent Office, 2021), no definite conclusions can be made about the most recent data. In a similar light, it seems most likely that the COVID-19 pandemic has affected the data that was collected in this study. However, as the pandemic is still ongoing its true effects cannot be determined yet. To ensure high-quality results, our research methodology was validated by research experts in the fields of patents, clinical trials, infectious diseases, and (medical) microbiology. To allow for a thorough investigation of the state of the art, the choice was made to focus on a broad scope of indications for probiotics only, leaving pre- and postbiotics out of the picture.

For further research, it may be beneficial to investigate details such as the strain and dosage of probiotics that were indicated in the relevant patents and clinical trials, as well as the mechanisms of action of the respective probiotics. Additionally, alternative interventions that target the gut microbiota should not be disregarded, like fecal microbiota transplants (FMT), which can be considered probiotics “in extremo” and can be, among others, helpful to restore dysbiosis caused by C. difficile infections (Ser et al., 2021). Interestingly, the effects of FMT after antibiotics are impaired by the use of a multistrain probiotic (Suez et al., 2018), which demonstrates again the need for more research into strain specific effects (Hill et al., 2014).

To conclude, the increasing amount of research as reflected by the numbers of patents and clinical trials of the past 20 years suggests the acknowledgement of the potential of probiotics as applications for the management of infectious diseases. The current state of the art coincides with reported research priorities, expected sales and market growth (van den Nieuwboer et al., 2016; International Probiotics Association, 2019). However, evidence suggests that research and development at the intersection of probiotic products and infectious diseases are slowing down. This may be due to the natural progression of the technology life cycle or external factors such as regulations on probiotics research. Either way, in light of the COVID-19 pandemic and any future infectious disease outbreaks caused by our changing society (Hersh et al., 2012; Zhang D. et al., 2021; Skowron et al., 2022), it is important to stimulate the progression of the state of the art of clinical modalities targeting infectious diseases. As highlighted before (Larsen and van de Burgwal, 2021), such progression should consider the effect of changes to microbial communities across ecosystems.

CW: analysis and writing with guidance of LB and OL. LB: reviewing and editing. OL: conceptualization and reviewing and editing. All authors contributed to the article and approved the submitted version.

The contribution of LB is financed by the project Preparedness for Emerging Infectious Diseases [with project number VI.Veni.201S.044 of the research program Veni SGW which is financed by the Dutch Research Council (NWO)]. The contribution of CW is financed by Yakult Nederland B.V.

LB is a consultant for several commercial parties in the field of probiotics and life sciences; none of her advising practices are related to or in conflict with the content of this research. OL is Senior Manager Science at Yakult Nederland B.V.

The remaining author declares that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest.

All claims expressed in this article are solely those of the authors and do not necessarily represent those of their affiliated organizations, or those of the publisher, the editors and the reviewers. Any product that may be evaluated in this article, or claim that may be made by its manufacturer, is not guaranteed or endorsed by the publisher.