Respiratory infections are the largest cause of childhood deaths [1,2] and an are important cause of morbidity and mortality among adults worldwide [3,4]. Respiratory infections take responsibility for approximately 4 million deaths per year globally [3]. Among them, lung infections are a common and potentially life-threatening illness, being a major medical burden accounting for more than 15% of the deaths of children younger than 5 years of age [2]. Risk factors for the incidence and severity of lung infections in infants and children mostly include the lack of immunization, malnutrition, chronic underlying diseases, HIV infection and smoke exposure/indoor air pollution [5]. The Global Burden of Disease Study indicated that the most important risk factors were malnutrition, air pollution or sub-optimal breastfeeding [6]. In 2015, although the improvement of living conditions, nutrition and vaccines, 700,000 children younger than 5 years of age still died from lung infections worldwide [6]. In particular, the COVID-19 pandemic has increased the emergency of taking action to protect against respiratory infections.

Transmission of lung infections is thought to occur by airborne droplets/pathogens or through direct contact with colonized/infected individuals. The epithelial mucosal surface of the lungs is constantly exposed to invasive pathogens that have the potential to threaten the defense of susceptible hosts [7]. After the epithelial mucosa is invaded by pathogens, the inflammatory response occurs subsequently to recruit additional defenses. However, when these pathogens have the capacity to overwhelm the host defense, invasion of pathogens results in infections of the respiratory tract [7,8,9].

NDOs are low molecular weight carbohydrates, usually containing 3 to 10 sugar moieties. Food products that naturally contain NDOs, such as cereals, fruits, vegetables, nuts, beans, and seafood, but also breast milk and the application of prebiotics in functional food are the main sources of NDO intake [16]. Many NDOs are not digested by humans due to the lack of enzymes required to hydrolyze the β-links formed among the monosaccharide units. The most famous physicochemical and physiological properties of NDOs are related to their ability to behave like dietary fibers and prebiotics, including the improvement of gut microbial composition and gastrointestinal homeostasis. Moreover, due to the decrease in intestinal pH caused by their fermentation, NDOs exhibit the ability to reduce the growth of pathogenic bacteria, increase the populations of bifidobacteria and lactobacilli, and increase the utilization of minerals in the gut [16]. In addition, NDOs are associated with a lower risk of (gastrointestinal, respiratory, and urogenital) infections and exert anti-inflammatory and immunomodulatory properties [16,17]. In this review, we mainly focused on several representative NDOs, including human milk oligosaccharides (HMOs), and galacto-oligosaccharides (GOS) and fructo-oligosaccharides (FOS) that mimic structures observed in mother milk.

Human milk is the golden standard for infant nutrition, as most health experts, including the American Academy of Pediatrics, recommend exclusive breastfeeding for the first six months of life [18]. The average macromolecular profile of one liter of breast milk contains 9–12 g of proteins, 32–36 g of fats, 67–78 g of lactose, and 5–20 g of HMOs [19]. HMOs are the first group of NDOs consumed by humans after birth. Breastfed infants have a lower incidence of respiratory diseases, including respiratory infections, during early life [20,21,22,23]. In addition to the well-known prebiotic properties of HMOs and corresponding immunomodulatory effects [16], approximately 1–5% of HMOs are absorbed by the intestine into the systemic circulation [24], directly interacting with pathogens, immune cells, and epithelial cells outside the intestine to exert anti-inflammatory and anti-infective effects [16]. Moreover, breastfeeding infants ingest mother milk several times per day, bathing the nasopharynx and mouth for several minutes at each feeding with a solution high in HMOs, which might inhibit local adherence of airway pathogenic bacteria [20]. Bovine milk-derived infant formula is commonly used as an alternative to human breast milk. However, the concentration of oligosaccharides in bovine milk (0.7–1.2 g/L) is much lower compared to human milk (12–24 g/L) [25,26]. HMOs are composed of the five monosaccharide building blocks D-glucose, D-galactose, N-acetylglucosamine, L-fucose, and sialic acid. Currently, around 200 oligosaccharide structures have been identified in human milk compared to ± 50 identified oligosaccharide structures in bovine milk [27]. More than 70% of the oligosaccharides in bovine milk are composed of sialylated oligosaccharides, in contrast, human milk contains predominantly neutral oligosaccharides, and sialylated oligosaccharides account for approximately 10–30% of total HMOs [24,26,27,28,29]. Despite recent modern analytical techniques, the identification and biosynthesis of HMOs remain a challenge for researchers. The composition and content of HMOs can vary considerably between mothers. It depends both on their blood group and on the duration/length of the lactation period. Many manufacturers are trying to emulate HMOs; however, due to the lack of industrial production methods, the essential ingredients are mostly absent from infant formulas [30].

Various strategies have been used to mimic the beneficial effects of HMOs, including GOS and FOS, which have been supplemented in dietary products and infant formula [31,32]. Commercial production of GOS has been achieved from lactose by the transgalactosylation reactions, using β-galactosidases (EC 3.2.1.23) as biocatalysts [17,33]. FOS can be produced from the controlled enzymatic hydrolysis of the polysaccharide inulin, which can be extracted from roots of chicory, artichoke, yacon, dahlia or agave [33,34]. The process involves transfructosylation reactions in which fructosyltransferases (β-fructofuranosidase, EC 3.2.1.26 or β-D-fructosyltransferase, EC 2.4.1.9) act as biocatalysts [33]. GOS/FOS in a 9:1 ratio is commonly used in infant formula to mimic the molecular size distribution and beneficial functions of HMOs in breast milk [35].

Both GOS and FOS exert many beneficial properties. For example, both can stimulate the growth of bifidobacteria and lactobacilli and support the development of the immune system. Moreover, both can inhibit the inflammatory responses and prevent epithelial barrier dysfunction in the intestine; in particular, GOS have the property of inhibiting the adhesion of pathogens to intestinal epithelial cells [16,32]. There is no doubt that GOS/FOS mixtures have similar properties, and even recently, a reduction in airway inflammation after oral administration of this mixture was demonstrated [36,37]. There are several studies investigating the supplementation of GOS and/or FOS in human respiratory infections mainly focusing on clinical parameters, observing a reduced frequency of respiratory infections and antibiotic prescriptions in infants, as well as a decreased duration and symptoms of cold or flu in university students [38,39,40]. These impressive observations encourage GOS and/or FOS to become attractive candidates in the prevention and clinical treatment of respiratory infections. Although not reported in respiratory infections, the effects of NDOs in some studies of inflammatory immune diseases are inconsistent; for example, a combination of probiotics and GOS showed no preventive effect on allergic diseases in infants [41]. In a study with mice, a mixture of FOS and inulin did not affect the immune response of delayed hypersensitivity in an influenza vaccination model [42]. In this focused review, we present a balanced overview of the role and mechanisms of NDOs in respiratory diseases (infections) (Figure 1).