**6. Anti-inflammatory substances produced by lactic acid bacteria**

Periodontitis and candidiasis are both inflammatory diseases; therefore, inflammation symptoms are desired to be cured by biogenics, but there are few candidates for that.

CLA is a general term for regioisomers and structural isomers of linoleic acid having a conjugated diene structure.

Diene structure means there are two double bonds with a single bond in between. Rumenic acid, for example, is one of the 28 isomers of CLAs and exists in the fat and dairy products of ruminants [71]. It is a trans fat; however, CLAs can also appear as cis-fats. CLAs are known to reduce the production level of IgE and a chemical mediator leukotriene in a rat inflammatory model [72]. However, the opposite effect of increasing serum C-reactive protein value and reducing serum adiponectin level in human by CLA supplementation was observed recently [73].

## **7. Understanding the property of biofilm**

Most bacteria and fungi have the potential to grow in a biofilm, in an environment with liquid flow and solid surfaces. Biofilm formation, which has been experimentally observed in single bacteria, is now known not only to cross species but also to cross the kingdom of microbes. In human bodies, such situations particularly exist in the resident microbiota. Microorganisms including oral pathogens have the potential to express pathogenic properties in biofilms, contrary to the planktonic type. In other words, the so-called biofilm phenotypes upregulate the production of EPS that block the stimuli or stress from outside the biofilm, such as antibiotics and disinfectants. The EPS also provides sticky intercellular binding material and extracellular energy storage compounds [74, 75] to promote interaction among contacting microbial cells [76], resulting in complex and dynamic interplay.

## **8. Disruption of the quorum-sensing signals**

Recently, a QS inhibitor (QSI) and QS signal quencher (QQ ) molecule attracted attention in regard to understanding biofilm infections. Biofilm formation is triggered and controlled by a cell-to-cell communication process in harmony with the bacterial population density known as quorum-sensing system, which is based on small molecules termed autoinducers [77]. Some reports revealed that bacteriocins produced by probiotic lactobacilli such as *L. acidophilus*, *L. plantarum*, and *L. reuteri* functioned as QSI or QQ molecules [78]. It may be possible to purify the effective ingredients of probiotic bacteria against oral pathogenic activity in biofilms for use in the biogenics process. Recently, some instance of QC disruption by cyclic dipeptides has been reported. *L. reuteri*, a human vaginal isolate, was

*Prebiotics and Probiotics - Potential Benefits in Nutrition and Health*

**5.3 Low-molecular-weight antimicrobial substances**

ness against the yeast forms of *Candida* [57].

bacteriocins produced by lactic acid bacteria against *S. mutans* and *P. gingivalis* are not yet known. Bacteriocin L23 produced by *Lactobacillus fermentum* L23 [44], plantaricin produced by *L. plantarum* [45], and pentocin TV35b produced by *L. pentosus* [46] appear to be effective against the yeast form of *Candida*. Bacteriocins effective for the hyphal forms of *Candida* have not yet been identified [47, 48].

Reuterin, an antibacterial substance (also known as 3-hydroxypropionaldehyde; molecular weight, 74 Da; composition formula, C3H6O2), is a product of glycerol fermentation, which has been seen in several probiotic bacteria. These probiotic bacteria include not only *L. reuteri* [49] but also *L. brevis*, *L. buchneri* [50], and *L. collinoides* [51]. Under anaerobic conditions *L. coryniformis* [52] also produces a low-molecular-weight antimicrobial substance that does not contain amino acids [53]. Reuterin was found to exert its antibacterial effects by causing oxidative stress within the bacterial cell [54]. In addition to reuterin, the low-molecular-weight substances of lactobacilli, reutericyclin [55] and diacetyl [56] also showed effective-

As the smallest peptides, diketopiperazines (DKPs, cyclic dipeptides) are known

**Origin Biological function References**

Antimicrobial activity [66]

Antifungal activity [68]

diketopiperazines are a group of cyclic organic compounds where two amino acids are connected by a peptide bond, forming a lactam, and it is the first peptide whose three-dimensional structure has been completely solved by Robert Corey in the 1930s [58]. Corey determined the structure of the cyclic anhydride of the dipeptide glycylglycine. Diketopiperazines are also biosynthesized from amino acids in diverse organisms including mammals and are considered to be secondary metabolites [59]. Although some protease enzymes, such as dipeptidyl peptidase, produce a dipeptide by cleavage from the protein terminus, it is known that the

Cyclo(Leu-Pro) *Lactobacillus casei* AST18 Antifungal activity [64] Cyclo(Phe-Pro) *L. plantarum* MiLAB393 Antifungal activity [65]

Cyclo(Phe-Pro) *L. reuteri* RC-14 Antimicrobial activity [67]

Cyclo(Leu-Leu) *L. plantarum* AF1 Antifungal activity [69]

*L. fermentum* ALAL020 Antimicrobial activity [70]

to possess several physiological activities, including an antimicrobial effect.

**140**

**Table 1.**

**Cyclic dipeptide**

Cyclo(Phe-4-OH-Pro)

Cyclo(Tyr-Pro)

Cyclo(Leu-Pro) Cyclo(Met-Pro) Cyclo(His-Pro)

Cyclo(4-OH-Pro-Leu)

Cyclo(Gly-Leu) *L. plantarum* VTT

Cyclo(Pro-Pro) *L. amylovorus* DSM

E-78076

19280

*Diketopiperazines (cyclic dipeptide) produced by probiotic bacteria.*

capable of producing the cyclic dipeptides cyclo(L-Phe-L-Pro) and cyclo(L-Tyr-L-Pro), inhibiting the staphylococcal quorum-sensing system driven by the AI named agr, to suppress the expression of toxic shock syndrome toxin-1 in *S. aureus* [79]. The report is useful for a better understanding of interspecies cell-to-cell communication between *Lactobacillus* and *Staphylococcus* and provides a hint to attenuate virulence factor production by bacterial pathogens. However, this idea requires further study before clinical application.
