Characterization of lactic bacteria for biogenic amine formation

Characterization of lactic bacteria for biogenic amine formation J. Topić 1, L. Butinar 2, M. Bergant Marušič 1, D. Korte 1, B. Mozetič Vodopivec 2 1 Laboratory for Environmental and Life Sciences, University of Nova Gorica, Vipavska c. 13, 5000 Nova Gorica, Slovenia 2 Wine Research Centre, University of Nova Gorica, Glavni trg 8, 5271 Vipava, Slovenia Biogenic amines are compounds present in many different foods products and beverages (wine, beer, dairy products, fermented vegetables and soy products, fish, etc.). Their presence in foodstuff is a result of a microbial action during storage and ageing. The most important are histamine, tryptamine, β-phenylethylamine and tryptamine, which can induce undesirable physiological effects in humans. [1 4]. Monitoring of the content of biogenic amines in food is of public health concern in their relation to the food safety, food spoilage and food intolerance. Because microorganisms are used in food productions as starters and biopreservers, characterization of microorganisms for their ability to produce biogenic amines is equally important. Detection of biogenic amine producing lactic bacteria is important due to the public health concerns. Most methods that are used for screening involve measurement of the amino acid-decarboxylase activity, although methods using differential media and ph indicator have also been reported. Nowadays molecular methods are replacing culture methods. Culture independent methods which are based on PCR techniques are now regarded as most suitable methods for screening biogenic amine producing isolates [5]. 1. Introduction Biogenic amines are naturally occurring compounds that have been reported in variety of food, such as fish, meat, cheese, vegetables, and wines [6]. Even though they are considered endogenous to food of plant origin (fruit, vegetables), their occurrence in other food is a result of microbial action [1]. Biogenic amines are low-molecular weight basic polar or semi-polar nitrogenous compounds. Biogenic amines have aliphatic (cadaverine, putrescine, spermine, spermidine), aromatic (tyramine, phenylethylamine) or heterocyclic (histamine, pyrrolidine) structure [6]. Endogeneous biogenic amines play vital roles in regulation of cell growth and gene expression, protein synthesis, membrane division and stabilization, tissue repair, and modulation of intracellular signalling pathways and ion channels. Furthermore, agmatine, spermine, spermidine, putrescine, and cadaverine play an important role in the regulation of membrane-linked enzymes [7]. However, when such biogenic amines are formed by microorganisms they are considered exogenous and may have adverse effect on human health [7 9]. The most common biogenic amines found in food are histamine, tyramine, putrescine, cadaverine, 2-phenylethylamine, spermine, spermidine, tryptamine and agmatine [10] which are presented in Figure 1. Fig. 1 Chemical structures of biogenic amines commonly found in food and beverages. 99

Consumption of food with high concentrations of biogenic amines can cause migraines, headaches, gastric acid and intestinal problems, as well as allergic reactions. High concentrations of histamine, the most studied biogenic amine, represent a risk factor for food intoxication, whereas moderate concentrations could lead to food intolerance [11]. Excessive intake of tyramine could be considered as dangerous as it is connected to increase in blood pressure and possibility of hypertension. Secondary amines such as putrescine and cadaverine, have the possibility to produce carcinogenic nitrosamines when reacting with nitrites [12]. Furthermore, presence of putrescine, cadaverine and other biogenic amines may potentiate toxic effect of histamine through inhibition of metabolic enzymes diamine oxidase and hydroxylmethyl transferase [13 15]. Biogenic amines in food are produced from precursor amino acids bydecarboxylation of the α-carboxyl group resulting in formation of corresponding amine. The factors that affect the biogenic amine content in food and beverages are the availability of free amino acids, the presence of microorganisms with decarboxylase activity and the favourable conditions for the growth of these microorganisms [16]. The formation of main biogenic amines through enzyme decarboxylation of precursor amino acids is presented in Figure 2. Fig. 2 Formation of main biogenic amines through enzyme decarboxylation of precursor amino acids. Amino acid decarboxylation enzymes are present in numerous food and beverage producing microorganisms. Amino acid decarboxylation enzymes have been found in species of the genera Bacillus, Pseudomonas, Photobacterium, as well as in genera of the family Enterobacteriaceae (Citrobacter, Klebsiella, Escherichia, Proteus, Salmonella, and Shigella) and Micrococcaceae (Staphylococcus, Micrococus, and Kocuria). Furthermore, many lactic acid bacteria belonging to the genera Lactobacillus, Enterococcus, Carnobacterium, Pediococcus, Lactococcus, and Leuconostoc have the possibility to decarboxylate amino acids [13,17 19]. 2. Occurrence of biogenic amines in foods and beverages Biogenic amines produced by lactic acid bacteria can be found in many fermented food and beverages, like cheese, sausages, fermented vegetables and wine. Consumers demands for better and healthier food have resulted in renewed interest in studies on biogenic amines. Furthermore, the advances in technology and microbiology of fermented food and beverages, previously limited to indigenous microflora, resulted in more controlled technological processes through the use of selected starters [20]. 2.1 Biogenic amines in dairy products Dairy products are important part of human diet and the consumption of dairy products is high. Milk provides great medium for growth of numerous microorganisms due to its rich chemical composition. Dairy products have been associated with foodborne intoxications caused by the presence of toxins of microbiological origin such as bacterial ecotoxins, mold mycotoxins and biogenic amines. The problem of biogenic amines in dairy products has been gaining attention in the last decade. Their presence has been reported frequently and at high levels in various types of dairy products (e.g. ripened cheeses). Biogenic amines are produced not only by foodborne microbial contaminants, but also by the technological microorganisms used in the fermentations and/or ripening of dairy products including lactic acid bacteria. Tyramine is the most common biogenic amine found in dairy products and is the most frequently associated with dairy intoxication known as cheese reaction [9]. Concentrations of biogenic amines in dairy products vary, 100

depending on the type of cheese and milk. In well-established industrial cheeses such as parmesan, mozzarella, cheddar, blue-veined cheese, feta cheese, emmentaler, camembert, gouda and edam concentrations of biogenic amines varied from 0.0 mg/kg to more than 1500 mg/kg. The most frequently found biogenic amines were tyramine, histamine, cadaverine, and putrescine. The amount of tyramine and cadaverine detected in blue-veined cheese was 1585.4 mg/kg and 2101 mg/kg, respectively [9,21]. The occurrence of biogenic amines in fermented milks, stirred yogurt and kefir is also frequent.. Costa et al. (2015) detected tyramine in fermented cow milk in concentration 250 mg/kg [22]. 2.2 Biogenic amines in fish and fish products Fish and fish products are known to contain high levels of biogenic amines with histamine, cadaverine and putrescine being the most frequently found. Scombroid poisoning occurs when fish (fresh, canned or smoked) with high levels of histamine is ingested. First reports of this poisoning were with fish Scombroidea, e.g. tuna and mackerel. The reason for high levels of histamine lies in improper processing and storage that enable growth of biogenic amine producing microorganisms. The symptoms that are connected with scombroid poisoning are headache, dizziness, sweating, abdominal cramps, vomiting and diarrhea. The microorganisms behind with the decarboxylation of histidine into histamine are not lactic acid bacteria, but by enteric Gram-negative bacteria found in the intestine and cutis of the fish (Escherichia coli, Klebsiella species, Pseudomonas aeruginosa) [23 25]. 2.3 Biogenic amines in wine Histamine, putrescine and tyramine are the major biogenic amines produced by wine lactic acid bacteria that are found in wine. The reported concentrations of biogenic amines in wines vary from lower mg/l concentration range to about 50 mg/l depending on the quality of wine [26,27]. The variability in concentrations of biogenic amines originates from differences in the winemaking process, storage conditions, raw material quality and possible microbial contamination during winery operations [20,27]. Lactic acid bacteria strains are used in wine production in the process of malolactic fermentation, the conversion of malic acid to lactic acid by lactic acid bacteria. Malolactic fermentation is necessary step in the production for majority of red wines that occurs after alcoholic fermentations. We already know that concentration of biogenic amines is lower at the end of alcoholic fermentation and increases mainly during malolactic fermentation [20]. The main biogenic amine found in wine is histamine. For a long time only Pediococcus strains were condisdered as producers, however, strains of Oenococcus oeni have also been found to produce biogenic amines, namely histamine [20,28]. Characterization of lactic acid bacteria starters for biogenic amine production is important step for safe wine production, as O. oeni species are considered to be the most suitable and safe species to perform malolactic fermentation [20,27,29,30]. 3. Lactic acid bacteria Lactic acid bacteria are a heterogeneous group of Gram-positive organisms which produce lactic acid as a major product during fermentation of carbohydrates. They are non-sporeforming, non-motile, aerotolerant of rod and coccus shape [31]. Early taxonomy divided lactic acid bacteria in four main genera that are involved in food fermentations, Lactobacillus, Leuconostoc, Pediococcus, and Streptococcus [32]. Advances in the field resulted in the reclassification of the lactic acid bacteria in the following genera: Lactobacillus, Lactococcus, Leuconostoc, Pediococcus, Streptococcus, Aerococcus, Alloiococcus, Carnobacterium, Dolosigranulum, Oenococcus, Tetragencoccus, Vagococcus, Enterococcus and Weisella, with Lactobacillus being the largest genus, with more than 100 species known [33 35]. Lactic acid bacteria have been investigated as biopreservatives due to the production of antifungal metabolites such as organic acids, phenyllactic acid, reuterin, cyclic dipeptides, fatty acids, and proteinaceous comopounds [31]. Some of the antifungal metabolites produced by different lactic acid bacteria isolates are presented in Figure 3. 101

Fig. 3 Chemical structures of some antifungal compounds produced by lactic acid bacteria [36 43]. Lactic acid bacteria have a high potential as bio-preservatives, and they could replace chemical preservatives in food [31]. Although lactic acid bacteria present ideal candidates for commercial applications due to their GRAS (Generally Regarded As Safe) status and their QPS (Qualified Presumption of Safety) status in the European Union, some caution is needed as enzymatic activities of lactic acid bacteria could result in formation of toxic compounds such as biogenic amines, which should be avoided in food and beverages due to the possible detrimental effects on human health [5,31]. 4. Characterization of lactic acid bacteria for biogenic amine production In the last years, biogenic amine associated pathways have been described as strain dependent and not as species dependent [44]. Because of the high variability of microorganisms to decarboxylase amino acids, the detection of bacteria that have the possibility to transform precursor amino acid into biogenic amines is very important in order to estimate the risk of biogenic amines accumulation in food and beverages [45]. Numerous methods for detection of biogenic amines in lactic acid bacteria have been proposed. The most reliable procedure includes growing lactic acid bacteria in media that contains the precursor amino acids and subsequent high performance liquid chromatography (HPLC) analysis of supernatant. Even though HPLC method is precise; it is time-consuming and requires expensive equipment. Alternative strategies are being proposed which are less expensive and less time consuming [46]. The detection methods for characterization for biogenic amine producing bacteria can be divided into two main categories: amino acid decarboxylase microorganism detection like culture method and molecular methods. The second group consists of biogenic amine detection using thin layer chromatography (TLS) and high performance liquid chromatography (HPLC). For determination of biogenic amine contents in different food and beverages capillary electrophoresis, gas chromatography, biosensors and ELISA have also been implemented [6,47 50]. 4.1 Culture methods Qualitative detection screening of biogenic amine forming lactic acid bacteria is based on the use of differential medium containing a ph indicator such as bromocresol. Normally, the media consist of tryptone, yeast extract, sodium chloride, and/or glucose. To this media precursor amino acids are added. Positive results are indicated by the change of the medium colour to purple, which is a result of a ph shift. The ph change is a result of biogenic amine production, since they are more alkaline than corresponding amino acids [51]. Differential plating medium was used by Joosten and Northold (1989) to detect amine-producing capacity of two Lactobacillus strains in cheese [52]. Choudhory et al. (1990) used decarboxylase assay medium for the screening of two Leuconostoc oenos strains and one L. buchneri strain [53]. The medium used by Joosten and Northold (1989) was more complex than the medium used by Choudhory et al. (1990) as it contained also MgSO 4, MnSO 4, FeSO 4 and Tween 80. The more complex media with added metal was used to promote growth of lactobacilli. The optimal ph for this media was 5.0 and optimal glucose concentration 0.1%, as with higher concentrations of glucose homo-fermentative strains produced to much acid, counteracting the purple discoloration. Colonies of decarboxylating bacteria were detected by the presence of purple halo, while non-decarboxylating strains produced yellow halo. The characteristic colour change could 102

not be used for detection of tyrosine-decarboxylating strains. Due to the tyrosine s low solubility, the plates were not translucent. Nevertheless, tyrosine-decarboxylating lactobacilli were surrounded by the presence of clear halo, which resulted from disappearance of the tyrosine sediment [51,52]. The amine-forming capacity of strains was confirmed by using chromatographic methods [52]. Maijala et al. (1993) also used plating method for detection of tyramine and histamine producing bacteria [54]. Thirteen strain of lactic acid bacteria isolated from meat were investigated for amine production. In contrast to the methods proposed by Joosten and Norhold (1989) [52] and Coudhory et al. (1990) [53], the glucose and NaCl were omitted from the media. Glucose was omitted due to possible prevention of purple colour formation. The histamine and tyramine formation was confirmed using high performance liquid chromatography using dansyl chloride as derivatisation agent. Among the tested strains, none of the commonly used starters produced histamine and tyramine, and the only strain that was positive for biogenic amine formation was L. brevis, traditionally used for bakery products [54]. The same method was also used for qualitative screening of 78 lactic acid bacteria strains isolated from grape must or wine from different wine producing regions of Spain [55]. Bover-Cid and Holzapfel (1999) improved decarboxylase screening medium for lactic acid bacteria that enabled improved detection of biogenic amine positive strains. The glucose concentration used was 0.05% in order to avoid excessive acid production. Metal sulphates, Tween 80, and ammonium citrate were added in order to enhance the growth of lactic acid bacteria. Additionally, thiamine and pyridoxal-5-phosphate were added. Thiamine was used because some lactic acid bacteria require thiamine to grow, while pyridoxal-5-phosphate enhances amino acid decarboxylase activity as it acts as cofactor. The authors screened a total of 177 strains of lactic acid bacteria. 40% the lactic acid bacteria were able to produce tyramine. The confirmation of the production of biogenic amines by lactic acid bacteria was done using HPLC [51]. 4.2 Molecular methods Early detection of biogenic amine producing bacteria is important due to the possibility for food poisoning. Molecular methods for identification of biogenic amine forming bacteria present good alternative to culture methods. Among molecular methods, PCR and DNA hybridization have become important methods, because of their speed, sensitivity, simplicity and specific detection of the target genes. A big advantage of molecular methods is that they are culture independent and can detect potential biogenic amine risk formation in the food before the biogenic amines are produced. The main drawback of PCR method is the detection of non-viable cells [45]. 4.2.1 Histamine producing lactic acid bacteria Transformation of histidine in histamine occurs through decarboxylation with histidine decarboxylase (HDC; EC 4.1.1.22). The reaction is presented in Figure 2. Because the decarboxylation is done specifically with the enzyme histidine decarboxylase, it is possible to develop detection for the gene encoding histidine decarboxylase. There have been several primers designed for the detection of histamine-producing bacteria in Gram positive bacteria and Gram negative bacteria. Primers for Gram positive bacteria CL1, CL2, JV16HC, and JV17HC were designed by [56]. Histidine decarboxylase activity assay confirmed the presence of histamine-producing bacteria identified by PCR. Furthermore, DNA hybridization technique was also used for the identification of histamine-producing bacteria. DNA probes based on the amplified DNA fragment of histidine-decarboxylating strains were used for hybridisation [56]. Coton and Coton (2005) designed primer set HDC3/HDC4 to amplify the hdc gene from Gram-positive bacteria. The designed primers were used to detect histamine-producing bacteria in smoked salmon samples [57]. Constantini et al. (2006) designed two primers PHDC1/PHDC2 that were used for detection of histamine producing bacteria. In total, 133 lactic acid bacteria strains were tested, and only one L. hilgardii strain was positive for hdc gene [58]. 4.2.2 Tyramine producing lactic acid bacteria Transformation of tyrosine in tyramine occurs through decarboxylation with tyrosine decarboxylase (TDC; EC 4.1.1.25). Costantini et al. (2006) screened 133 lactic acid bacteria strains using two original sets of primers, P1/P2 and Pt3/Pt4, with similar results. Of the tested strains, four were positive. The both sets of primers gave the same results. All four of the strains belonged to L. brevis species [59]. Landete et al. (2007) tested 150 lactic acid bacteria strains for the presence of the tdc gene. 32 tested strains were positive for the tdc gene [60]. 4.2.3 Putrescine producing lactic acid bacteria Transformation of ornithine to putrescine is catalysed by the enzyme ornithine decarboxylase (ODC; EC 4.1.1.17). De Las Rivas et al. (2006) designed primer set PUT1-F and PUT1-R, which amplified a 624-bp DNA fragment of ornithine decarboxylase from Pseudomonas. Of all the tested bacterial strains, only strain of Lactobacillus sp. 30A was positive and O. oeni strain RM83 was positive for odc gene [61]. Marcobal et al. (2004) tested 42 O. oeni strains isolated from Spanish grape must and wine using primers 3 and 16, which were based on two conserved domains showed by the alignment of amino acid sequences of ODC proteins. None of the tested strains were positive for odc gene [29]. 103

4.2.4 Cadaverine producing lactic acid bacteria Cadaverine is formed by decarboxylation of amino acid lysine by lysine decarboxylase enzyme (LDC. EC 4.1.1.18). De Las Rivas et al (2006) identified two different groups of lysine decarboxylase from enterobacteria. They designed two sets of primers CAD1-F/CAD1-R and CAD2-F/CAD2-R. None of the lactic acid bacteria strains tested was positive for ldc gene [61]. 4.2.5 Multiplex PCR for detection of biogenic amine producing bacteria Detection of biogenic amine producing bacteria with PCR has become an invaluable tool in the characterization of lactic acid bacteria. The advances in PCR assay have resulted in development of methods that allow simultaneous detection of lactic acid bacteria producing histamine, tyramine and putrescine [57,61 63]. Since all of the targeted amines can be detected in one assay, multiplex PCR methods reduce analysis time and reagent consumption [45]. De Las Rivas et al (2005) developed multiplex PCR method for the simultaneous detection of histamine, tyramine and putrescine producing bacteria. They used the following sets of primers; JV16HC/JV17HC and 106/107 for hdc gene detection, P1-rev/P2-for for tdc gene detection and primers 3 and 16 for odc gene detection. Two Lactobacillus strains were tested. One tested positive for tdc gene, while the second was positive for hdc and odc gene [62]. Coton and Coton (2005) developed multiplex PCR assay for detection of histamine and tyramine producing lactic acid bacteria. The authors tested seven lactic acid bacteria strains; four tested positive for hdc gene, and one tested positive for tdc gene [57]. Marcobal et al. (2005) developed multiplex PCR method that simultaneously targeted three genes hdc, tdc, and odc. They tested in total 78 lactic acid bacteria strains. The primers that authors used were JV166HC/JV17HC for hdc, P1-rev/P2-for for tdc, and 3/16 for odc.[63]. Coton et al (2010) tested 810 lactic acid bacteria strains using multiplex PCR method. 17 strains were positive for hdc, 67 for tdc and 4 strains for the odc gene [64]. 4.3 Chromatographic methods Biogenic amine production by microorganism is frequently studied by using culture and molecular methods (See Chapter 5.1 and 5.2). The main drawback of these methods is that they are qualitative and they do not give information about concentration of biogenic amines. For this purpose chromatographic methods are used, especially high performance liquid chromatography (HPLC). HPLC methods are popular due to their specificity and sensitivity. Nevertheless, the analysis of biogenic amines by HPLC is complex, as derivatization step is normally needed in order to detect them using ultraviolet, visible, or fluorescence derivatization. Derivatization is essential as biogenic amines lack chromophore in their structure. Derivatization reaction occurs through amino group with various agents such as o-phthaldialdehyde, dansyl chloride, benzoyl chloride, dabsyl chloride, diethyl ethoxymethylenemalonate (DEEMM) [4,65]. Guerrini et al. (2002) tested 44 strain of O. oeni. They were grown in MRS broth under microaerophilic conditions and the supernatants were used for biogenic amine determinations. Biogenic amines were determined as dansyl derivatives using HPLC with fluorescence detector (FLD). 61% of the tested strains were able to produce at least one biogenic amine. All the positive strains were able to produce histamine in concentration ranging from 1.0 to 32.8 ppm [28]. (Morreno- Arribas et al. (2003) investigated 85 cultures of strains representing nine species of lactic acid bacteria. Of all tested strains, one strain was able to produce histamine in concentration 1.3 g/l. HPLC analysis was performed using o- phthaldialdehyde as derivatization agent using culture supernatants [55]. Coton et al. (2010) screened 810 lactic acid bacteria strains isolated from wine and cider using multiplex PCR and HPLC with dansyl chloride as derivatization agent. 158 strains were positive for biogenic amine formation [64]. Similarly, Sebastian et al. (2011) also used HPLC for analysis of culture supernatants of lactic acid bacteria. They used o-phthaldialdehyde and employed a pre-concentration step with solid-phase extraction (SPE). In total, 71 strains were able to produce biogenic amines. This corresponded to 59% of all lactic acid bacteria isolates tested in the study [66]. Henriquez-Aedo et al. (2016) isolated lactic acid bacteria from samples of spontaneous malolactic fermentation of Chilean red wines. All of the 65 isolated colonies showed aminogenic capacity. Supernatants of the cultures were analysed with HPLC-FLD. There was a clear difference between species as L. rhamnosus showed significantly higher biogenic amine capacity than O. oeni. Only L. rhamnosus isolates produced histamine [67]. 5. Concluding remarks Lactic acid bacteria are important bacteria used in food production as biopreservatives and starters. However, one of their side products are also biogenic amines known for their allergenic and toxic effects on human. That is why their capacity to produce biogenic amines has to be closely investigated and well described nowadays if we want to use them as starters or biopreservatives. Although culture methods and molecular methods provide an extremely valuable tool in such diagnostics, they lack quantitative information about the concentrations of biogenic amines formed. This can be overcome with the use of chromatographic techniques, namely HPLC coupled to different detection systems (DAD, FLD, MS/MS), offering better specificity and sensitivity for these analytes, but they all need additional step in the analytical protocol a derivatisation step. 104

Acknowledgments The Agrotur/Karst agrotourism project, which is implemented within the Cross-Border Cooperation Programme Italy Slovenia 2014-2020, funded by the European Regional Development Fund and national funds is acknowledged for financial support. The authors also acknowledge Slovenian Research Agency (ARRS) for the financial support (Grant number: ARRS-MR-LP- 2017/393). References [1] Shalaby AR. Significance of biogenic amines to food safety and human health. Food Research International 1996;29:675 690. [2] Landete JM, Ferrer S, Pardo I. Biogenic amine production by lactic acid bacteria, acetic bacteria and yeast isolated from wine. Food Control 2007;18:1569 1574. [3] Erim FB. Recent analytical approaches to the analysis of biogenic amines in food samples. Trends in Analytical Chemistry 2013;52:239 247. [4] Ordóñez JL, Troncoso AM, García-Parrilla MDC, et al. Recent trends in the determination of biogenic amines in fermented beverages A review. 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