The role of Lactobacillus plantarum in oral health: a review of current studies

ABSTRACT

Background

Oral non-communicable diseases, particularly dental caries and periodontal disease, impose a significant global health burden. The underlying microbial dysbiosis is a prominent factor, driving interest in strategies that promote a balanced oral microbiome. Lactobacillus plantarum, a gram-positive lactic acid bacterium known for its adaptability, has gained attention for its potential to enhance oral health. Recent studies have explored the use of probiotic L. plantarum in managing dental caries, periodontal disease, and apical periodontitis. However, a comprehensive review on its effects in this context is still lacking.

Aims

This narrative review evaluates current literature on L. plantarum’s role in promoting oral health and highlights areas for future research.

Content

In general, the utilization of L. plantarum in managing non-communicable biofilm-dependent oral diseases is promising, but additional investigations are warranted. Key areas for future study include: exploring its mechanisms of action, identifying optimal strains or strain combinations of L. plantarum, determining effective delivery methods and dosages, developing commercial antibacterial agents from L. plantarum, and addressing safety considerations related to its use in oral care.

Introduction

Oral disorders, a significant and pervasive challenge to global public health, have been globally recognized as the primary contributor to all level 3 burden of disease condition based on the comprehensive assessment conducted by The Global Burden of Diseases, Injuries and Risk Factors Study 2017 (GBD2017) [1]. Dental caries, in both deciduous and permanent teeth, and periodontal disease as non-communicable oral disease have affected around 2.8 billion and 796.1 million individuals, respectively, in 2017. Of particular concern is the prevalence of untreated dental caries, which has emerged as a widespread global health issue among human populations. The age-standardized prevalence of untreated dental caries was found to be 29.4% for permanent teeth and 7.8% for primary teeth [1,2].

The dental biofilm stands as a crucial biological determinant shared in the pathogenesis of both caries and periodontal disease [3]. Notably, recent advancements in the understanding of the etiological underpinnings of these diseases have shifted the paradigm towards the concept of microbial dysbiosis, as opposed to the traditional view of infection attributed to individual bacterium [4–6]. These evolving perspectives have catalyzed the development of innovative strategies designed to combat dental caries and periodontal disease, with a primary focus on nurturing a balanced and flourishing oral microbiome. These approaches emphasize the ecological perspective, such as the use of probiotics, in order to rectify the perturbed plaque ecology and promote the establishment and persistence of a symbiotic oral microbiome, ultimately contributing to long-term disease control [7].

Probiotics, defined as ‘live microorganisms which, when administered in adequate amounts, confer a health benefit on the host’ [8]. The overarching goal of probiotics is to prevent or mitigate severe dysbiosis with the aim of establishing a harmonized microbiome that confers beneficial effects upon the host [9,10]. These effects are increasingly acknowledged as capable of positively modulating various facets of human health, also including oral health [11–14].

Lactobacillus plantarum is a gram-positive lactic acid bacteria species with probiotic properties [15,16], it exhibits a high degree of heterogeneity, a characteristic underscored by its intricate functional genome and phenotypic variability. All these attributes contribute significantly to its ecological adaptability and metabolic versatility across diverse environmental niches [15–17]. Of particular significance is the aciduric property of L. plantarum, which can reduce the membrane fluidity through the activation of adaptive modifications in the fatty acid composition of its plasma membrane when exposed to low pH [18]. Furthermore, this aciduric adaptation involves the up-regulation of proton export facilitated by F0F1‐ATPase [18,19] and the modulation of amino acid metabolism [20].

L. plantarum, a probiotic, has demonstrated benefits to human health, especially in the gastrointestinal tract with the function of promoting intestinal integrity, modulating gut microbiome and enhancing mucosal as well as systemic immunity [21–24]. Given the well-established concept of a bidirectional axis connecting the oral cavity and the gastrointestinal tract [25], over the last decade there have been a growing number of studies aimed at deciphering the potential of probiotic L. plantarum in the realm of oral health, especially the dysbiosis-related oral disease.

Despite the existence of various narrative or systematic reviews examining the impact of various other probiotic Lactobacillus strains on oral health [11,12,26–28], there is a noticeable gap in relation to a dedicated review of the effects of L. plantarum. The present narrative review seeks to bridge this gap by offering a comprehensive synthesis of the extant evidence regarding the role of L. plantarum in oral health, as well as the underlying mechanisms. Furthermore, we aim to present a succinct overview of areas warranting further investigations, with the ultimate objective of facilitating the future utilization of L. plantarum within the realm of oral health.

Lactobacillus plantarum, a Novel Ecological Anti-Caries Candidate in Experimental and Clinical Settings

Dental caries, a polymicrobial biofilm-associated disease, is the consequence of dynamic interactions among microorganisms, the host and the host’s diet [29]. These well-established biofilms create a sophisticated micro-environment that enhances biofilm toxicity, impedes the penetration of antimicrobial agents and constrains the buffering capacity of saliva [29,30]. Biofilm resistance and drug tolerance challenge the traditional chemical caries prevention strategy [31]. Probiotic L. plantarum, as an ecological approach, has demonstrated its effectiveness in caries control in vitro, vivo and in clinical studies [32–46], as shown in Figure 1.

Figure 1.

An overview of L. plantarum in oral health.

In vivo and in vitro studies of L. plantarum’s capacities in caries control

Increasing endeavors have been made recently to provide laboratory evidence of utilization of L. plantarum in both planktonic and biofilm models. These experiments involved the use of various laboratory or clinically isolated strains (Table 1).

Table 1.

Experimental evidence of L. plantarum’s efficacy in caries control.

L. plantarum strain	Form	Study type	Origin of targeted pathogen	Model type	Sampling site	Targeted pathogen	Intervention duration (in vivo studies)	Anti-bacterial effect in Planktonic settings	Anti-biofilms effects	Other results
ST-III [33]	WBC	In vitro	Clinical isolate	Mono-species planktonic	Saliva	S. mutans	/	The ST-III had a strong inhibitory effect on the S. mutans with approximately 55.8%-80.0% inhibition rate.	The ST-III significantly reduced the number of S. mutans, Streptococcus spp and total bacteria in the mix biofilm cultures.	/
				Multi-species biofilm	Plaque	S. mutans, Streptococcus spp, Streptococcus sanguinis, Streptococcus sobrinus, Streptococcus salvarius, Porphorymonas gingivalis, Streptococcus oralis, & Actinomyces naeslundii
ATCC 14,917 [34]	WBC & CFS	In vitro	Clinical isolate	Planktonic & mono-species biofilm	Caries dentine	S. mutans ATCC 25,175	/	WBC and CFS both showed a significant inhibition zone against S. mutans. However, WBC exhibited larger inhibition zone than CFS (p<0.05).	1. The 14,917 CFS reduced around 81.0% adherence of S. mutans and 25.0% preformed biofilm. 2. The 14,917 changed the EPS matrix structure and quality.	1. After neutralizing the supernatant acidity, the antimicrobial effect was significantly reduced (p < 0.01).
										2. Catalase and trypsin treated supernatant didn’t significant influence the antimicrobial effect.
										3. L. plantarum stimulate hPBMCs to produce IFN-γ and reduced the IL-10 concentration.
										4. The virulence genes of S. mutans were down-regulated in planktonic and biofilms models.
FB-T9 [35]	WBC	In vitro & vivo	Laboratory strain	Planktonic and mono-species biofilm	/	S. mutans ATCC 25,175	70 days	The FB-T9 exhibited good bacteriostatic ability in a plate competition assay.	The FB-T9 significantly reduced the biomass and viability of S. mutans biofilms and induced structural damage of biofilm formation.	In a 70-day rat-based in vivo experiment:
							Three times a week			1. The FB-T9 significantly reduced the levels of S. mutans on the dental surfaces of rats by more than 2 orders of magnitude of the levels in the dental caries model group (p < 0.05).
										2. The FB-T9 significantly reduced the caries scores (modified Keyes scoring method) in both the prevention and treatment groups (p < 0.05).
CCFM 8724 [36]	WBC	In vivo	Laboratory strain & clinical isolate	Planktonic & duo-species biofilm	Caries dentine (C. albicans)	S. mutans ATCC 25175 & C. albicans SJ	40 days	/	/	1. The CCFM8724 in both the treatment and prevention groups could significantly decrease the population of S. mutans and C. albicans in the rats’ oral cavity (p < 0.001), the mineral loss of enamel (p < 0.05) and the scores of caries (p < 0.05).
							Three times a week
										2. The CCFM8724 exhibited better effects than chlorhexidine.
108 [37]	CFS	In vitro	Clinical isolate	Planktonic & duo-species biofilm	Not mentioned	S. mutans UA159 & C. albicans SC5314	/	The 108 CFS has a significant inhibition on the planktonic mode of growth of both S. mutans and C. albicans.	The 108 supernatants significantly inhibited the S. mutans and C. albicans mixed-species biofilm formation and reduced pre-formed mixed-species biofilms with poorly developed biofilm architecture.	The expression of S. mutans genes associated with glucosyltransferase activity and C. albicans hyphal specific genes (HWP1, ALS1 and ALS3) were down-regulated in the presence of the 108 CFS.
Ln4 [38]	WBC	In vitro	Laboratory strain	Mono-species biofilm	/	S. mutans KCTC 5124	/	/	1. The Ln4 showed higher antimicrobial activity than Lactobacillus rhamnosus GG (LGG).	/
									2. The Ln4-treatment exhibited a lower co-aggregation (58.9%), cell surface hydrophobicity (16.8%) and EPS production rate (73.3%) values, than those of LGG and the negative control.
									3. The Ln4 effectively inhibited biofilm formation of S. mutans KCTC 5124.
ATCC 8014, ATCC 14,917 [45]	WBC & CFS	In vitro	Laboratory strain	Planktonic & duo-species biofilm	/	S. mutans UA159 & C. albicans SC5314	/	L. plantarum demonstrated superior inhibition on the growth of C. albicans and S. mutans.	L. plantarum demonstrated superior disruption of virulent biofilm formation with reduced bacteria and EPS components, and formation of virulent microcolonies structures of C. albicans-S. mutans duo-species biofilms.	1. Genes of S. mutans and C. albicans involved in metabolic pathways were significantly down-regulated.
										2. Genes related to C. albicans resistance to antifungal medication (ERG4), fungal cell wall chitin remodeling (CHT2), and resistance to oxidative stress (CAT1) were significantly down-regulated.
										3. Lactobacillus genes plnD, plnG and plnN that contribute to antimicrobial peptide plantaricin production were significantly up-regulated.
										4. L. plantarum 14,917 possessed superior inhibition effect than L. rhamnosus ATCC 2836, L. plantarum ATCC 8014 and Lactobacillus salivarius ATCC 11741.
KCTC10887BP [39]	LTA	In vitro	Laboratory strain and clinical isolate	Mono-species biofilm	Not mentioned	S. mutans KCTC 3065, Ingbritt, OMZ-65, LM-7, KCOM1197 & KCOM1214	/	/	L. plantarum LTA inhibited the biofilm formation and aggregation of S. mutans without affecting the bacterial growth.	1. Only L. plantarum LTA showed a significant inhibition of S. mutans biofilm formation among Lactobacillus sakei, Lactobacillus delbrueckii and L. rhamnosus GG.
										2. Notably, L. plantarum LTA did not affect the established biofilm.
ATCC 10,012 [46]	CFS	In vitro	Laboratory strain	Planktonic & mono-species biofilm	/	S. mutans ATCC 25175 & S. sobrinus ATCC 33478	/	The 10012 CSC inhibited the growth of S. mutans and S. sobrinus.	The 10012 CSC significantly reduced biofilm formation by S. mutans and S. sobrinus.	The 10,012 CSC showed better inhibitory abilities than Lactobacillus johnsonii JCM 1022, L. rhamnosus ATCC 7469 and Lactobacillus kefiranofaciens DD2, DD5 and DD6.
K41 [40]	WBC	In vitro and vivo	Not mentioned	Planktonic and mono-species biofilm	/	S. mutans UA159	/	The K41 showed the highest inhibitory effect on growth of S. mutans and EPS production in vitro.	The K41 showed the highest inhibitory effect on the formation of exopolysaccharides (EPS) and biofilm (inhibitory rate: 98.4%) and reduce the network-like structure of biofilm in vitro.	1. The coaggregation and autoaggregation rates at 4 h of the K41 were 41.9% and 31.0 %, respectively in vitro.
										2. Rats treated with K41 had a significant reduction in the incidence and demineralization degree of dental caries.
LRCC 5193, 5194, 5195 and 5310 [41]	LTA	In vitro	Laboratory strain and clinical isolate	Mono-species biofilm	Plaque	S. mutans ATCC 25,175 (Lab strain), KCOM 1054, KCOM 1116 & KCOM 1223	/	/	1. The biofilm formations of four strains of S. mutans were effectively inhibited by 30μg/ml of LRCC 5310.	ex vivo: The LRCC 5310 LTA dramatically reduced the biofilm formation of clinical isolates of S. mutans on human dentin slices.
									2. CFUs from both Streptococcus gordonii and S. mutans biofilm were dose-dependently attenuated by LRCC 5310 Lp.LTA.
									3. LTA effect of other L. plantarum strains is not conclusive.
ATCC 8014, ATCC 14,917 [42]	WBC and plantaricin	In vitro	Clinical isolates	Planktonic and duo-species biofilm	Not mentioned	S. mutans UA159 and C. albicans SC5314	/	1. The 14,917 Inhibited the growth of S. mutans and C. albicans clinical isolates.	The 14,917 inhibited the biofilm formation with a compromised biofilm structure with a significantly smaller microbial and extracellular matrix and a less virulent microcolony structure.	1. The 14917 exhibited better inhibitory effects than L. salivarius 11,741 and L. plantarum 8014.
								2. The 14,917 reduced the growth of C. albicans and inhibited the switching from yeast to the hypha and pseudohypha form.		2. FurTre, one type of plantaricins, produced by L. plantarum inhibited the growth of S. mutans and C. albicans.
										3. The 14,917 had an inhibitory impact on the expression of S. mutans and C. albicans virulence genes, such as gtfB, gtfC, atpD, CHT2, ERG4 and HWP1 in biofilms setting.
ATCC 14,917 [43]	WBC	In vitro	Laboratory strain	Planktonic	/	S. mutans UA159 and C. albicans SC5314	/	1. A dose-dependent inhibition on C. albicans and S. mutans was observed with the increased dosages of L. plantarum.	/	The expression of C. albicans HWP1, ECE1 and ERG4 genes and S. mutans lacC and lacG genes were significantly downregulated with 108 CFU/mL of L. plantarum (p < 0.05).
								2. L. plantarum at 108 CFU/mL demonstrated the highest antibacterial and antifungal inhibitory effects.
ATCC 14917 [44]	CFS	In vitro	Laboratory strain	mono-species biofilm	/	S. mutans UA159	/	/	1. The antibiofilm agent, named 1-1-4-3 is a mixture of lactic acid (LA) and valine.	1. The CFS of L. plantarum showed the strongest antibiofilm activity among the tested CFSs of Lactobacillus casei ATCC 393, Lactobacillus gasseri ATCC 33,323, Lactobacillus fermentum ATCC 14,931 and L. salivarius ATCC 11741
									2. 1-1-4-3 showed the strongest antibiofilm effect among L. plantarum CFS, including reducing the generation of exopolysaccharides and making the biofilm looser and thinner.	2. The catalase treated CFS only show little change regarding anti-biofilm ability.
										3. After the pH was adjusted to 6.5, all tested CFSs lost their antibiofilm ability.

WBC, whole bacteria culture; CFS, cell-free supernatant; LTA, lipoteichoic Acids; EPS, exopolysaccharide.

In summary, L. plantarum has demonstrated a potent inhibitory effect on S. mutans by reducing bacterial counts and altering the quantity and structure of biofilms. Additionally, the interference with adhesive ability of cariogenic microorganisms to the tooth surface in the presence of L. plantarum has been reported by several studies [37,39,41].

Several investigations have undertaken comparative assessments between L. plantarum and other Lactobacilli strains, such as L. rhamnosus GG, L. sakei, L. delbrueckii and L. salivarius 11741, to assess their differential efficacy on cariogenic microorganisms or biofilms [38,39,42,44–46]. These comparative analyses have consistently indicated that L. plantarum, in conjunction with its biochemically antimicrobial compounds, exerts the most potent anti-caries effects. These effects encompass the inhibition of pathogenic microorganism proliferation and the prevention of biofilm formation. However, a limited number of studies have explored which specific L. plantarum strains possess the most robust impact [40–42,45], resulting in a lack of definitive conclusions.

It is important to note that the majority of these investigations were conducted using the mono-species cariogenic S. mutans model or simplified mixed species models that may not fully replicate the intricacies of the oral environment. Additionally, there has been a paucity of in vivo studies in this domain [35,36].

Clinical evidence of L. plantarum’s capacities in caries control

Available clinical information regarding the effectiveness of L. plantarum in controlling caries is quite limited, as outlined in Table 2. Gandhi et al. conducted a short-term (14 days) double-blind study involving 60 caries-active children aged 7–10, who were divided into three randomized groups, with one group applying a mucoadhesive patch containing a probiotic blend comprising L. plantarum (TSP-Lp1) and L. rhamnosus. The study concluded that this probiotic blend exhibited robust antibacterial properties, with a significant reduction in salivary levels of S. mutans and its favorable acceptance among patients [47]. Likewise, Lin et al. conducted a clinical trial involving 50 healthy adults who were randomly assigned to two groups. The intervention group received mixed probiotic lozenges containing L. salivarius subs. salicinius AP-32, Lactobacillu paracasei ET-66 and L. plantarum LPL2 for 4 weeks, and found that the administration of mixed probiotics led to a significant reduction in S. mutans burden and the inhibition of pathogen growth in saliva [48].

Table 2.

Clinical evidence of L. plantarum’s efficacy in oral health.

Study design/Arms	Participants	L. plantarum strain	N (n: n: n)	Delivery vehicle/Dose	Duration/Frequency	Measurements	Conclusion	Reference
RCT/3 arms including I: cinnamon patch, II: probiotic patch and III: control patch (placebo)	Caries-active children aged 7–10 with deft/DMFT score 3 and <5	L. plantarum (TSP-Lp1) and L. rhamnosus	60 (20: 20: 20)	Mucoadhesive patch/10 mg (5 × 1010 for each strain)	14 days/Two patches a day	1. Salivary S. mutans CFU/ml count 2. Patient compliance of the presence of adverse effects (taste, breath, teeth staining and nausea)	1. The probiotic incorporated patch caused a highly significant reduction in salivary S. mutans. 2. The probiotic patch had good patient acceptance.	Gandhi et al. [47]
RCT/2 arms. I: placebo, and II: viable probiotic lozenge	Healthy non-smoking adults aged 20–40	L. salivarius subs. salicinius AP-32, L. paracasei ET-66 and L. plantarum LPL28.	50 (25: 25)	Lozenge/1 g (109 CFU/g totally)	4 weeks/Three lozenges a day	1. Salivary microbiota change 2. Salivary IgA 3. Salivary S. mutans abundance 4. Self-reported oral and systemic health improvement	The mixed probiotic lozenge effectively: (1) reduced the number of S. mutans in oral cavity, (2) improved the oral microbial flora, (3) increased the performance of IgA antibodies in saliva, (4) decreased oral infections, and improved oral health, including reduced teeth bleeding while brush, (5) attenuated intestinal symptoms.	Lin et al. [48]
RCT/3 arms including I: fluoride, II: probiotic and III: control (placebo)	Healthy fixed orthodontic patients aged 12–30	L. plantarum (specific strain was not mentioned)	38 (12: 13: 13)	Mouthwash/108 CFU/each container	2 weeks/Two rinsing a day	Number of S. mutans present in dental plaque	The experimental probiotic mouthrinse in use did not show any advantage in terms of controlling S. mutans, compared to placebo.	Dadgar et al. [49]
RCT/2 arms including I: placebo, and II: heat-killed (HK) probiotic	Patients with periodontitis undergoing supportive periodontal therapy (SPT)	L. plantarum L-137	36 (17: 19)	Capsule/10 mg	12 weeks/One capsule a day	1. Plaque index (PI) 2. Gingival index (GI) 3. Bleeding on probing (BOP) 4. Probing depth (PD)	Daily HK L-137 intake can decrease the depth of periodontal pockets in patients undergoing supportive periodontal therapy.	Iwasaki K et al. [50]
Cross-over RCT/2 arms including I: placebo preparation, and II: home-based administration of probiotics	Systemically periodontally healthy patients rehabilitated with a single, implant-supported unit	L. plantarum and Lactobacillus brevis	12	Tablet/NA	6 weeks/One tablet a day	1. The number of sites with bleeding on probing (BoP+) 2. Modified plaque index (mPI)	The adjunctive use of probiotics did not significantly enhance the clinical outcomes of professionally administered plaque removal and photodynamic therapy for patients with peri-implant mucositis.	Mongardini C et al. [51]
RCT/2 arms including I: placebo, and II: probiotic gel and lozenges	Individuals with advanced periodontitis seeking periodontal treatment	L. plantarum and L. brevis	40 (20: 20)	Gel/6.0 × 109 CFU/ml of L. brevis and 6.0 × 109 CFU/ml of L. plantarum and lozenge/1.2 × 109 CFU/ml of each strain	3 months/One lozenges a day	1. The number of diseased sites (DS: PD > 4 mm + BOP) 2. The number of sites with gingival bleeding	The adjunctive use of probiotics in treating chronic periodontitis results in increased odds for healing of gingival bleeding but reduction of the odds for healing of diseased sites when compared with SRP + placebo; therefore, its use is unfounded.	Pudgar et al. [52]
RCT/2 arms including I: placebo, and II: probiotic tablets	Gingivitis non-smoking patients aged 18–55	L. plantarum CECT 7481, L. brevis CECT 7480 and Pediococcus. acidilactici CECT 8633	59 (30:29)	Tablet/1.00 × 103 CFU/ml of each strain	6 weeks/two tablets a day	1. Gingival index (GI) 2. Relative abundance of 6 periodontal pathogens	The use of probiotic tablets did not lead to significant changes in mean GI. The number of sites with severe inflammation was significantly reduced. The adjunctive use of this probiotic promoted a significant microbiological impact.	Montero et al. [53]

RCT, randomized controlled trial; N (n: n: n), number of the sample size (number of participants in arm I: number of participants in arm II: number of participants in arm III); deft, decayed, extracted due to caries and filled deciduous teeth; DMFT, decayed, missing due to caries and filled permanent teeth.

However, it is worth noting that another randomized, placebo-controlled clinical trial conducted by Dadgar et al., employing the mouthrinse as the delivery vehicle for L. plantarum, yielded a contradictory result. They observed that the L. plantarum probiotic mouthwash was ineffective in reduction of S. mutans levels in dental plaque. The authors acknowledged that variations in S. mutans carriage among different groups at baseline and the vehicle form of the mouthwash might have contributed to these unexpected results. This is particularly pertinent considering the limited duration that mouthwash remains in the oral cavity, which may impede the activation of probiotics [49].

In summary, the limited number of clinical studies and the divergent outcomes at present underscore the need for further research efforts. These efforts should particularly focus on determining the optimal L. plantarum strain, the most effective concentration, the appropriate duration of administration and the mode of delivery to maximize the potential of L. plantarum in caries management.

Mechanisms network of L. plantarum’s anti-caries abilities

The potential mechanisms underlying the anti-caries effects of L. plantarum have been summarized in Figure 2. Inter-species competition and co-aggregation with cariogenic microorganisms [32,38,40] directly impede the growth and establishment of cariogenic pathogens on teeth surface. As shown in the previous study, L. plantarum K41 exhibited an increased co-aggregation with S. mutans during the first 4 h and reached 33.6%–44.0% co-aggregation rate at 4 h [40].

Figure 2.

Network of L. plantarum‘s anti-caries mechanisms. LTA, lipoteichoic acid; SCFA, short chain fatty acid; EPS, exopolysaccharide.

The production of antimicrobial substances constitutes a pivotal facet of L. plantarum‘s anti-caries potential [34,35,37,39,41,42,44,45]. These antimicrobial substances encompass a spectrum of compounds, ranging from low-molecular-mass compounds such as lactic acid, short chain fatty acid and hydrogen peroxide, to high-molecular-mass compounds known as bacteriocins-peptides that are synthesized within ribosomes and possess antibacterial activity [54]. While lactic acid has been identified as one of the primary antibiofilm agents in caries setting [44], the role of hydrogen peroxide in the anti-caries properties of L. plantarum remains contentious. Some studies have suggested that hydrogen peroxide may not be the primary ingredient responsible for the anti-caries properties of L. plantarum, as the presence of catalase did not affect the anti-caries effect of L. plantarum [34,44]. Currently, the specific substances responsible for the highest anti-caries potency of L. plantarum strains have yet to be fully elucidated. Further research is warranted to explore the strain-specific chemical structures and regulatory effects on L. plantarum‘s anti-caries properties, with a particular focus on the role of environmental pH. Liang et al. and Wasfi et al. observed a decline or cessation of the antibacterial or antibiofilm properties upon neutralization of the supernatant acidity [34,44].

L. plantarum possesses the capacity to influence virulence factors of cariogenic microorganisms, including quorum sensing, biofilm formation and stress tolerance. This influence is evidenced by the suppression of key genes associated with quorum sensing, stress survival, biofilm formation and extracellular polysaccharide (EPS) production, such as gtfB, gtfC, gtfD and sacB in S. mutans [34,37,42,43,45,55]. Furthermore, L. plantarum can disrupt the virulence genes of Candida albicans, a cariogenic fungus that symbiotically interacts with S. mutans and exacerbates biofilm toxicity [56–58]. The HWP1, involving in hypha formation, ERG4, involving in resistance to antifungal medication, and ALS family genes of adhesins, were down-regulated in the presence of L. plantarum [37,42,43,59]. There exist inter-strain variations in this capacity. It is worth mentioning that there exists a divergence regarding the expression of atpD gene, associated with the acid stress tolerance, between planktonic and biofilm S. mutans. Unlike the down-regulation of atpD gene observed in biofilm S. mutans, several studies have documented the up-regulation of this gene in planktonic S. mutans [34,45,59]. These findings suggest that the suppressive effects of L. plantarum on S. mutans are not characterized by immediate eradication. Instead, they provide an opportunity for S. mutans to adapt to the significant decrease in pH caused by L. plantarum therapy. This observation aligns with the ecological approach to caries, which emphasizes modulation rather than elimination of endogenous cariogenic microorganisms.

Concerns have arisen regarding the colonization capacity of L. plantarum in the oral cavity, particularly under conditions of saliva flow and other harsh oral conditions. Such concerns have led experts to question the feasibility of using L. plantarum in this context. Although an in vitro study conducted by Jia et al. showed a low adhesive rate of L. plantarum AR113 on salivary-coated hydroxyapatite (7.0%) [60], this strain displayed favorable characteristics, including significant autoaggregation, reaching 38.8% within 5 h, and robust adhesion to epithelial cells with a highly uniform distribution across the cellular surface. Furthermore, the coaggregation capacity with S. mutans of L. plantarum has been certified by several previous in vitro studies [32,38,40]. And a study conducted by Zhang et al. revealed that L. plantarum possesses a remarkable ability to successfully establish colonization within the oral cavity of rats even within a short administration duration of 5 days [35].

The current understanding of the intricate anti-caries mechanisms of L. plantarum remains incomplete, particularly given the complex heterogeneity and various phenotypes of L. plantarum strains. Nevertheless, it is evident that the aforementioned mechanisms exhibit a significant degree of overlap and integration. They form a network-like connectivity rather than adhering to a strictly linear relationship. For instance, the Lipoteichoic acid (LTA), a Lactobacillus-derived molecule, has been recognized as an antimicrobial substance of L. plantarum against biofilm formation of cariogenic microorganisms directly [39,41], with ability to compete and interfere in the binding of S. mutans to teeth surface and suppress sucrose deposition [45]. Furthermore, LTA appears to have anti-inflammatory properties, including the attenuating the IL-8 production induced by Pam2CSK4, a synthetic bacterial lipopeptide [61]. Therefore, further investigations are warranted to elucidate these complex interactions fully.

L. plantarum, a promising adjunct for anti-periodontal disease with favorable attributes and experimental evidence

Periodontal disease is characterized as an irreversible chronic inflammatory disease involving connective tissue destruction, vascular proliferation and alveolar bone destruction induced by immune cells response [62]. The Polymicrobial Synergy and Dysbiosis (PSD) model has been proposed as a conceptual framework for this inflammatory disease [63,64]. In this model, the transformation of host immunity, driven by dysbiotic microbial communities with increased virulence, can further impair immune surveillance and promote an overall inflammatory response [65–67]. The interaction between inflammation and dysbiosis mutually reinforces one another eventually leading to significant changes in the microbial community, and its transition to a pathobiontic state. Prolonged and over-activated inflammation in response to microbial succession, characterized by the domination of proteolytic neutrophils and excessive recruitment of other immune cells, exaggerates tissue and bone degradation [67–70]. Despite ongoing ‘chicken and eggs’ debates on the causative relationship between inflammation and dysbiosis [71], the pursuit of a balanced microbiota emerges as a promising strategy to achieve host-microbe homeostasis and modulate the inflammatory and immune responses in host.

The potential anti-periodontal disease attributes of L. plantarum

Microbiota regulation and anti-microbial mechanisms

Like its anti-caries mechanisms, L. plantarum exhibits potential anti-periodontal disease properties through its anti-microbial and microbiota-regulating capacities. This includes enriching the microbiota diversity and suppressing pathogenic microorganisms [72–75]. While the modulation of microbiota by L. plantarum has been established in the gastrointestinal tract, its impact on the oral microbiome requires further investigation.

Anti-inflammatory and immunomodulatory properties

Broadly, L. plantarum’s cell-wall components and secreted products interact with the host and mediate the immune homeostasis by regulating cytokine secretion and M2 macrophage polarization (as shown in Figure 3). L. plantarum K8 lysates, for instance, reduced TNF-α production in THP-1 cells induced by lipopolysaccharides (LPS) by down-regulating the early signals of mitogen-activated protein kinase (MAPK) and nuclear factor-κB (NF-κB) followed by negative regulators in toll-like receptor (TLR)-mediated signaling in vitro [76]. In addition, the nanosized extracellular membrane vesicles (EMVs) of L. plantarum, constitutively releasing lipid bilayer-enclosed structures, could reduce pro-inflammatory cytokines levels, including IL-6, IL-1β, IL-2 and TNF-α on gut, by regulating the TLR4-MyD88-NF-κB pathway [77]. Notably, the down-regulation of myeloid differentiation primary response 88 (MyD88) gene expression in this study is of significance, as TLR-MyD88 signaling is pivotal in periodontitis-related osteolysis and MYD88 inhibitors that show preventive effect on jawbone loss in Porphyromonas gingivalis-driven periodontitis [78,79].

Figure 3.

Schematic overview of L. plantarum‘s anti-inflammatory, immunomodulatory and osteogenetic modulation. (a) L. plantarum and its bioactive components modulate the immune response through TLR4/NF-κB/MAPK pathways, resulting in the reduction of pro-inflammatory cytokines and the release of anti-inflammatory cytokines. (b) L. plantarum promotes osteogenesis by modulating osteoblast and osteoclast differentiation. (c) Extracellular membrane vesicles (EMVs) of L. plantarum induce M2 macrophages polarization with increased expression of M2-associated cell markers. Solid lines represent evidence from the periodontal domain; dotted lines represent evidence from other systems.

Furthermore, L. plantarum-derived EMVs induce M2b macrophage polarization in vitro, as observed by Kim et al. in 2020 [80]. This induction involves biased expression of M2 macrophage-associated cell-surface markers and cytokines (e.g. CLEC5A, SRA1, CD163) and inhibition of the expression of M1 macrophage-associated surface marker HLA-DRα. M2 macrophages, crucial for bone repair and ossification, play a vital role in maintaining a balanced ratio with M1 macrophages in the static periodontal environment [81,82]. An enhanced M2 ratio has been linked to preventing bone loss in periodontitis in vivo [83]. Additionally, the micro integral membrane protein (MIMP), a recently identified cell surface protein of L. plantarum, exhibits anti-inflammatory properties by modulating inflammatory cytokines. This includes a reduction in pro-inflammatory cytokines such as IFN-γ, IL-17 and IL-23, and an increase in anti-inflammatory cytokines such as IL-4 and IL-10 [84].

Mitigating bone loss through modulation of osteoblast and osteoclast differentiation

The current studies indicated the potential of L. plantarum to ameliorate bone loss through its influence on osteogenesis and anti-osteolysis pathways (Figure 3) [85–88]. L. plantarum promotes osteoblast differentiation via the Bone Morphogenetic Proteins (BMP) pathways [85]. Additionally, L. plantarum exerts a negative regulatory effect on osteoclastogenesis through Receptor Activator of Nuclear Factor-κB Ligand (RANKL) pathway [85,87]. This inhibition involves the down-regulation of the receptor activator of nuclear factor-κB (RANK) and nuclear factor-activated T cells c1 (Nfatc1) activation, resulting in down-regulated the osteoclast-associated genes, like tartrate-resistant acid phosphatase (TRAP) gene [85,87] in vitro. Of note is that TRAP activity is frequently employed as a reliable indication of osteoclast differentiation [89,90]. Moreover, one study suggested that L. plantarum can induce osteoprotegerin (OPG), a soluble RANKL decoy receptor that prevents osteoclast formation [88,91].

L. plantarum’s capacities as adjunct in periodontal disease management in vitro and clinically

Given the intricate interplay of the inflammatory and immune response in periodontal disease [67,68], the well-documented immunomodulatory and inflammation-modulating efficacy of L. plantarum in previous studies positions it as a promising adjunct immune-targeted therapy for managing periodontal disease. While L. plantarum has shown potential anti-periodontal disease characteristics in vitro or vivo in the context of other organs or systems, it is crucial to acknowledge that research specifically focused on the periodontal domain, especially underlying mechanism pathways, remains limited currently [55,72,73,92].

Despite limited evidence, available data from two in vitro studies confirm the anti-inflammatory properties of L. plantarum in the periodontal domain [55,72,92]. Kim. Y et al. [55] revealed that the lysates of L. plantarum attenuated P. gingivalis LPS-induced phosphorylation of MAPKs and activation of NF-κB in RAW 264.7 cells. Schmitter et al. [92] observed a reduction of inflammatory mediators, PGE2, IL-1, IL-6 and TNF-α, in LPS-stimulated primary monocytes and a decrease in IL-6 release in gingival fibroblasts following the administration of L. plantarum. Moreover, the bioactive metabolites 10-oxo-trans-11-oxadecenoic acid (KetoC) and 10-hydroxy-cis-12-octadecenoic acid (HYA), derived from L. plantarum, have shown the potential in promoting periodontal homeostasis. These metabolites enhance antioxidant activity through the up-regulation of NRF-2 and HO-1, reduce inflammation by decreasing the levels of pro-inflammatory cytokines TNF-α, IL-6 and IL-1β, and exert antimicrobial effects in vitro and in vivo [72].

The majority of clinical studies have examined the efficacy of L. plantarum as an adjunct therapy for periodontal disease, as presented in Table 2, but these results are inconsistent [48,50–53]. Lin et al. found that consumption of oral lozenges containing mixed probiotics, including L. plantarum LPL2, effectively reduced the occurrence of teeth bleeding during brushing [48]. Moreover, a double-blind, placebo-controlled RCT conducted by Iwasaki K et al. used heat-killed L. plantarum L-137 in capsules and observed that its administration, in addition to supportive periodontal therapy, and significantly reduced probing depth (p < 0.05) at sites with baseline probing depths of ≥4 mm after a 12-week intervention [50]. In contrast, a cross-over RCT conducted by Mongardini C et al. did not find significant improvements in the clinical outcome of mechanical-photodynamic therapy treating experimentally induced peri-implant mucositis with the adjunctive professional and home-based administration of probiotics containing L. plantarum and L. brevis [51]. Furthermore, the findings of Pudgar et al. indicated an unfavorable impact on periodontal disease, as there was an increased occurrence of residual diseased sites when probiotics containing L. brevis and L. plantarum strains were used as supplementary therapy alongside scaling and root planning [52].

L. plantarum, a potential solution for apical periodontitis needing further investigations

Apical periodontitis, an inflammatory disease, arises from bacterial infections originating from biofilms on the root canal wall [93]. The current limitations of intracanal antibacterial agents, including insufficient elimination efficacy, tissue damage and potential allergic reactions, prompt the exploration of probiotics such as L. plantarum as promising alternatives. Available evidence indicated that L. plantarum and its derivatives hold promise as novel tools for biofilm therapies within the root canal system [72,94–101]. Specifically, L. plantarum LTA has exhibited significant suppression of Enterococcus faecalis, a microorganism associated with persistent endodontic infections [102], in mono- or mixed-species biofilms, comparable to the routinely used calcium hydroxide [97,99–101]. However, it is crucial to emphasize that research on L. plantarum‘s role in addressing apical periodontitis is primarily confined to in vitro and in vivo studies. Further investigations are warranted to validate these potential therapeutic applications of L. plantarum in this specific context.

Discussion

Our narrative review provides a comprehensive evaluation of the existing literature on the role of L. plantarum in promoting oral health and sheds light on possible directions for further research. While the utilization of L. plantarum in the oral non-communicable biofilm-dependent disease is encouraging, additional research is needed.

Probiotics have been actively investigated as part of the ecological strategy to maintain oral health [103–106]. Given the established health benefits of Lactobacillus and Bifidobacterium in the gastrointestinal system, research on probiotics for oral health has concentrated on these probiotic core genera. Specifically, L. rhamnosus, L. paracasei, L. reuteri and L. acidophilus have undergone extensive investigations, showing promising results in managing both caries and periodontal disease [104–107]. However, research on L. plantarum in oral health, a versatile species with a long history of safe use, remains relatively insufficient [15,108]. L. plantarum is not only easily accessible, being widely isolated from various niches, including dairy products, vegetables, meat and silage [15,23], but also exhibits ecological adaptability, suitable for harsh oral environment. Moreover, it demonstrated a more potent anti-caries effect compared with other Lactobacillus strains, such as L. rhamnosus GG, L. sakei, L. delbrueckii and L. salivarius 11741 [38,39,42,44–46]. Therefore, a comprehensive review focusing on L. plantarum in oral health is essential.

In the field of caries management, the significant role of S. mutans and C. albicans, two pivotal cariogenic microorganisms, has been highlighted [109,110], particularly their combined influence in driving the development and potential severity of a dysbiotic/cariogenic oral microbiome [111]. Recent findings indicate a favorable efficacy of L. plantarum in controlling cariogenic microorganisms, especially S. mutans and C. albicans. Of note is that, while one study indicated increased numbers of commensal S. sanguinis [33] in multi-species biofilms when co-cultured with L. plantarum, a conflicting report suggested L. plantarum exerted a non-specific inhibitory effect on cariogenic (S. mutans) and health-associated (S. sanguinis) species in planktonic settings [112]. These contradictory findings may be due to the different L. plantarum strains used and the varying resistance properties of microorganisms in planktonic versus biofilm settings, highlighting the need for caution in the use of probiotics. The role of oral commensal Streptococci varies as early colonizers and accessory pathogens dynamically, through mechanisms such as competition, hydrogen peroxide and bacteriocins production, and potentiating pathogenicity [113–115]. Current investigations were conducted lacking a perspective of oral microenvironment and microbiota, which only focus on mono-species models or simplified mixed species models. Hence, it remains inconclusive whether the potential inhibitory effects of L. plantarum on oral commensal bacteria are beneficial or not. Recognizing the intricate and dynamic interactions within oral microorganisms [116,117] and the pivotal concept of microbiota transition in oral disease development, there is a growing emphasis on exploring the more representative and complex oral microbiota, instead of individual or a few microbes. For instance, ‘human-derived biofilm models’ [111,118] could be applied to better understand the effects of L. plantarum on oral pathogens and commensals.

Moreover, the underlying molecular mechanisms, by which L. plantarum and its bioactive compounds regulate bacteria-host homeostasis in the context of periodontal disease, remain poorly understood.

The growing attention towards probiotic L. plantarum in oral health has sparked inquiries regarding potential dangers. Concerns revolve around the potential for increased acid production within dental plaque and the occurrence of Lactobacillus bacteremia. It is intriguing that there is no significant difference regarding lactic acid levels and overall acid production in dental plaque suspensions in the presence or absence of L. plantarum 299 v in vitro [119]. Despite the strong acidogenic abilities of Lactobacillus, Marttinen et al. reported no change of plaque acidogenicity after consuming other probiotic Lactobacillus strains in clinical settings [120]. Moreover, another clinical study noted an increase in salivary pH levels following the consumption of Lactobacillus probiotics [121]. Although studies on the safety of L. plantarum, particularly regarding acid production, are limited, the observed unexpected change in acidogenicity may be explained by a reduction in cariogenic and acidogenic microorganisms. Additionally, the introduction of L. plantarum may promote the activity of other oral lactate-utilizing microorganisms, such as Veillonella, through lactate cross-feeding behavior [122]. Lactic acid produced by L. plantarum could serve as a carbon source for Veillonellae [123,124]. Although the opinions about the effects of oral Veillonellae species on oral health and disease are ambivalent, Veillonellae’s ability to convert lactic acid to weaker acids and reduce nitrate to nitrite [122,123,125] has been established. In addition, the type of carbohydrate chosen for fermentation impacts the lactic acid production of L. plantarum. Combining prebiotic galacto-oligosaccharide with L. plantarum has shown effective anti-cariogenic effects with a reduction in acidity in planktonic models, compared to L. plantarum alone [59]. Future investigations into the metabolic interaction between Veillonellae and L. plantarum, as well as exploring the combination of prebiotics and L. plantarum as anti-caries strategy within the context of oral microbiota, could be highly intriguing.

Lactobacillus bacteremia, while a rare condition, carries a high mortality rate. A review by Kullar R et al. on the topic of probiotics and Lactobacillus bacteremia suggests that the use of probiotics can generally be considered safe. However, it is crucial to note that further research is necessary to gain a comprehensive understanding of the potential implications and ensure the safety of probiotic L. plantarum usage [126].

Although L. plantarum has demonstrated encouraging beneficial effects on oral health both in vivo and in vitro, multiple considerations need to be addressed to maximize its clinical benefits, besides safety considerations. Utilizing probiotics in the form of multi-strain combinations has been reported to offer a broad spectrum of benefits and potential synergistic effects [127], and changes in the ratios of probiotics may influence the beneficial effects as well as mechanisms pathways [128]. Clinically, evidence supports both disease-specific and strain-specific probiotic chosen strategy [129]. The available studies regarding L. plantarum in oral health employed numerous distinct strains. Considering the strain-specific variation of L. plantarum, it is important to determine specific combinations and ratios of different L. plantarum strains, or combinations of L. plantarum with other probiotic genera, for more targeted applications in specific oral disease conditions. In addition, the limited duration of probiotics’ presence in the oral cavity may impede the activation of probiotics. Therefore, factors such as the delivery route, treatment duration, administration frequency and dosage for L. plantarum therapy should be carefully considered in clinical practice. Further investigations are essential to promote standardization of therapeutic probiotic application in oral health and maximize the benefits.

Funding Statement

This work was supported by grants from the Foundation of Science & Technology Department of Henan Province, China [No. 242102310376, No. 232102310320], Natural Science Foundation of Education Department of Henan Province, China [No. 21A320004], the Foundation of Science and Technology Department of Kaifeng City, Henan Province, China [No. 2203015], and the Foundation of Key Lab of Medical Molecular Cell Biology of Shanxi Province, Shanxi University, Taiyuan, China [No. MMCBOP-2023-03].

Disclosure statement

No potential conflict of interest was reported by the author(s)

Author contributions statement

Conceptualization, X.H. and Y.Z.; Supervision, Y.Z.; Writing-original draft, X.H. and J.B.; Writing-review and editing, X.H., J.B., M.Y., Y. Li., Y. Liu. and Y.Z. All authors have read and agreed to the published version of the manuscript.

Data Availability Statement

Data sharing is not applicable to this article as no new data were created or analyzed in this study.

Key messages

The review article presents comprehensive summaries of previous research on the role of L. plantarum in promoting oral health. The review aims to provide an overview of the state of L. plantarum applications in oral health, to highlight current research gaps and illuminate potential avenues for the further research.