The oral cavity provides a rich environment for the most diverse and stable microbiome in the human body [1]. The oral flora, like the intestinal microbiome, is an essential part of the human innate immune system. The microorganisms located there determine the balance between pathological and physiological states, which can have both local and systemic effects [2].

Depending on factors such as nutrition, age and saliva flow, pathogens can tip the balance of flora. The resulting microbial dysbiosis can lead to problems such as caries, gingivitis and periodontitis.

But it goes further. Studies have shown that the oral microbiome can also be directly associated with the development or deterioration of systemic infections, adverse pregnancy outcomes, cardiovascular diseases, diabetes mellitus and autoimmune diseases [1,3].

The largest group of microorganisms in the mouth are the bacteria which can attach themselves in so-called biofilms.  Plaque on teeth is a key example of this [4]. Bacteria within a biofilm are significantly more resistant to antibiotics, antibodies and antimicrobial peptides [5].

Oral bacteria can ferment sugars and carbohydrate-rich foods. This reduces the pH within the biofilm, and pathogenic bacteria such as Streptococcus mutans can gain the upper hand. These bacteria produce acids which can demineralise the tooth surface and thus lead on to caries [6,7].

Over time, the plaque layer can itself mineralise and become tartar.  As a result, gingivitis often arises, one of the most common diseases of the mouth [8].  Chronic gum inflammation can progress to periodontitis with the participation of gingivitis-inducing bacteria such as Porphyromonas gingivalis. In recent years, the relationship between periodontitis and systemic diseases has become increasingly clear. In particular, Porphyromonas gingivalis is found in atherosclerotic plaques [9].

The innate immune system provides numerous defence components to prevent the penetration of pathogens into the body via the oral cavity. These include the mucosal barrier, as well as individual proteins located in the body fluids, such as lysozyme and lactoferrin [10].

In view of the diversity of microorganisms, and the sensitive balance between these species, therapeutic intervention in the oral cavity poses a major challenge. 

Although we have many antibacterial substances, very few are able to dissolve a bacterial biofilm. Often, like dental plaque, this biofilm can only be physically removed.  It has already been shown that biofilms play a role in many diseases, from cancer [3], back pain [11,12], Alzheimer’s [13], asthma [9], to rheumatoid arthritis [9,14].

Lactoferrin, however, demonstrates a very efficient clearing of biofilms, even of multi-resistant bacteria, such as Pseudomonas aeruginosa and other oral pathogens [15].

A 2018 review examines the role of lactoferrin in the treatment of various oral and maxillofacial diseases [2]

Antibacterial effects

Lactoferrin showed very good effects against Streptococcus mutans, the main cause of caries, both during attachment, and in the formation of biofilms.

In the case of periodontitis, which is mainly initiated by the gram-negative bacteria Porphyrornonas gingivalis and Prevotella intermedia, lactoferrin was effective against both bacterial strains, albeit by slightly different mechanisms of action.

Antifungal effects

Candida albicans is the most common fungus in the oral cavity and can trigger various systemic and local disease events, such as oropharyngeal candidiasis and systemic candidaemia. Lactoferrin was very effective in inhibiting the growth of Candida albicans as well as less severe disease progression.

Antiviral effects

One of the most common viral infections of the oral mucosa occurs due to the Herpes virus. After the primary infection, it remains in the body and the infection can flare up again when provoked.  Lactoferrin can intervene here by inhibiting how the virus binds to the surface of the host cell, as well as it’s replication and cell-to-cell propagation.

Another common virus, the Epstein-Barr virus (EBV) often also affects the oro-facial region. Symptoms such as an inflamed throat, swollen lymph nodes and a rash can be found in the head and neck area.  If the host’s immune system is already weakened, serious complications such as viral meningitis, encephalitis or optic neuritis can also occur. Lactoferrin can prevent EBV from attaching and penetrating the host cell and effectively inhibit cell transmission.

The Coxsackie virus A16 (CA16) causes “hand, foot and mouth disease” (HFMD). Studies have shown Lactoferrin has an inhibitory effect in the first phase of the infection.  The same is the case for the human papilloma virus (HPV).

Further therapeutic applications of lactoferrin for oral health

  • Dry mouth
  • Bone regeneration in the vicinity of implants
  • Prevention of inflammation in the implant area

A double-blind, randomised intervention study in 2019 investigated the use of a toothpaste containing enzymes and proteins, including lactoferrin.  The composition reflected their natural presence in the saliva, with a view to improving the health of the gums [16].  Many components in saliva belong to the humoral part of the innate immune system, and it plays an important role in maintaining bacterial equilibrium in the oral cavity.  After 4 weeks, it was shown that both plaque formation and the gingival index were significantly reduced.

The oral cavity and its environment can be affected by various infections and pathologies. The authors of the aforementioned reviews recommend lactoferrin as a therapeutic agent in the field of oral health.  It has a wide range of applications without the development of side effects and/or resistance.

1   Sampaio-Maia B, Caldas IM, Pereira ML, Pérez-Mongiovi D, Araujo R. The Oral Microbiome in Health and Its Implication in Oral and Systemic Diseases. Advances in applied microbiology 2016; 97: 171–210.

2   Velliyagounder K, Bahdila D, Pawar S, Fine DH. Role of lactoferrin and lactoferrin-derived peptides in oral and maxillofacial diseases. Oral diseases 2019; 25: 652–669.

3   Hajishengallis G. Periodontitis: from microbial immune subversion to systemic inflammation. Nature reviews. Immunology 2015; 15: 30–44.

4   Mark Welch JL, Rossetti BJ, Rieken CW, Dewhirst FE, Borisy GG. Biogeography of a human oral microbiome at the micron scale. Proceedings of the National Academy of Sciences of the United States of America 2016; 113: E791-800.

5   Ochiai K, Kurita-Ochiai T, Kamino Y, Ikeda T. Effect of co-aggregation on the pathogenicity of oral bacteria. Journal of medical microbiology 1993; 39: 183–190.

6   Marsh PD, Lewis MAO, Rogers H, Williams D, Wilson M. Marsh and Martin’s Oral Microbiology – E-Book. 6th ed. Elsevier Health Sciences, London 2016.

7   Touger-Decker R, van Loveren C. Sugars and dental caries. The American journal of clinical nutrition 2003; 78: 881S-892S.

8   Moore LV, Moore WE, Cato EP, Smibert RM, Burmeister JA, Best AM, Ranney RR. Bacteriology of human gingivitis. Journal of dental research 1987; 66: 989–995.

9   Zhang Q, Illing R, Hui CK, Downey K, Carr D, Stearn M, Alshafi K, Menzies-Gow A, Zhong N, Fan Chung K. Bacteria in sputum of stable severe asthma and increased airway wall thickness. Respiratory research 2012; 13: 35.

10  Tlaskalová-Hogenová H, Stepánková R, Hudcovic T, Tucková L, Cukrowska B, Lodinová-Zádníková R, Kozáková H, Rossmann P, Bártová J, Sokol D, Funda DP, Borovská D, Reháková Z, Sinkora J, Hofman J, Drastich P, Kokesová A. Commensal bacteria (normal microflora), mucosal immunity and chronic inflammatory and autoimmune diseases. Immunology letters 2004; 93.

11  Teichtahl AJ, Urquhart DM, Wang Y, Wluka AE, Wijethilake P, O’Sullivan R, Cicuttini FM. Fat infiltration of paraspinal muscles is associated with low back pain, disability, and structural abnormalities in community-based adults. The spine journal : official journal of the North American Spine Society 2015; 15: 1593–1601.

12  Urquhart DM, Zheng Y, Cheng AC, Rosenfeld JV, Chan P, Liew S, Hussain SM, Cicuttini FM. Could low grade bacterial infection contribute to low back pain? A systematic review. BMC medicine 2015; 13: 13.

13  Olsen I, Singhrao SK. Can oral infection be a risk factor for Alzheimer’s disease? Journal of oral microbiology 2015; 7: 29143.

14  Tian H, Maddox IS, Ferguson LR, Shu Q. Influence of bovine lactoferrin on selected probiotic bacteria and intestinal pathogens. Biometals : an international journal on the role of metal ions in biology, biochemistry, and medicine 2010; 23.

15  Wakabayashi H, Yamauchi K, Kobayashi T, Yaeshima T, Iwatsuki K, Yoshie H. Inhibitory effects of lactoferrin on growth and biofilm formation of Porphyromonas gingivalis and Prevotella intermedia. Antimicrobial agents and chemotherapy 2009; 53: 3308–3316.

16  Daly S, Seong J, Newcombe R, Davies M, Nicholson J, Edwards M, West N. A randomised clinical trial to determine the effect of a toothpaste containing enzymes and proteins on gum health over 3 months. Journal of dentistry 2019; 80 Suppl 1: S26-S32.