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Bioactive Ingredients from Lactic Acid Bacteria for Functional Food Production and Their Health Effects

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06 October 2023

Posted:

09 October 2023

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Abstract
Lactic acid bacteria are traditionally applied in a variety of fermented food products and have the capability to produce a wide range of bioactive ingredients during fermentation including vitamins, bacteriocins, bioactive peptides and bioactive compounds. The bioactivity and health benefits associated with these ingredients have gained interest in applications in the functional dairy market and have relevance both as components produced in situ and as functional additives. This review provides a brief description of the regulations regarding the functional food market in the European Union as well as an overview of some of the functional dairy products currently available in the Irish and European markets. A better understanding of the production of these ingredients excreted by lactic acid bacteria can further drive the development and innovation of the continuously growing functional food market.
Keywords: 
Subject: Biology and Life Sciences  -   Food Science and Technology

1. Introduction

Lactic acid bacteria (LAB) are a diverse group of microorganisms that have an essential role in the food and pharmaceutical industries [1]. The bacteria in this group can generally be characterised as gram-positive, non-spore-forming with a cocci or rod shape with their main metabolic product being lactic acid. Organisms belonging to either of the genera Lactobacillus, Leuconostoc, Pediococcus and Streptococcus are considered LAB, but it has been suggested that also Aerococcus, Alloiococcus, Carnobacterium, Dolosigranulum, Enterococcus, Globicatella, Lactococcus, Oenicoccus, Tetragenococcus, Vagococcus and Weissella should be included [2,3].
Historically LAB has been cultured and applied in the transformation of raw food material into fermented products such as yoghurt, cheese, bread and a wide range of fermented meat and vegetables (Figure 1) [4]. The fermentation process aids in the conservation of food material, enhances the texture and flavour profiles of products and increases the health benefits that can be derived upon consumption [2]. Their traditional applications in food production have given LAB GRAS (Generally Regarded as Safe) status [5].
This review explores the diverse range of functional ingredients produced by lactic acid bacteria including vitamins, bacteriocins, bioactive peptides and bioactive compounds. Exopolysaccharides are another metabolite excreted by LAB and its production, purification and health benefits have previously been reviewed extensively, and will therefore not be discussed in this review [6]. Additionally, lactic acid itself is a viable food ingredient produced by LAB and has been discussed at length in several publications [7,8,9] and is therefore not the target of this review.

1.1. Food product regulations

The European Union (EU) has a common framework of regulations for food, that can be intricate and thorough to navigate. The objective of this framework is to guarantee that a level of food safety standards are met and that the marketing of products is not misleading or confusing for consumers with unsubstantiated claims, thereby safeguarding consumer interests [10]. The European Food Safety Authority (EFSA) provides this framework of scientific advice and risk assessments, and aids in the decision making. EFSA furthermore evaluates the scientific claims made by companies and determines the validity and substantiation of suggested health claims [11].
Introducing innovative products with novel food ingredients and health claims on the European market the products need to comply with The Nutrition and Health Claims Regulations (NHCR) (Regulation EC No. 1924/2006) [12]. To receive approval for sale in the EU, the product must therefore adhere to the regulations set forth by the (EFSA). Specifically, the following points must be met [13]:
  • The food/constituent is defined and characterised.
  • The claimed effect is based on a nutrient essentiality OR the claimed effect is defined and a beneficial physiological effect can be measured in vivo in humans.
  • The food/constituent is required for bodily function OR a cause-and-effect relationship between consumption and human health has been established.
  • The quantity of the food/constituent can be consumed as part of a balanced diet to obtain the claimed effect.
Additional guidance for the determination of benefits to human health can be found in documents describing the following health claims related to [14,15]:
  • Functions of the nervous system
  • Physical performance.
  • Bone, joints, skin and oral health.
  • Appetite ratings, weight management and blood glucose concentrations.
  • The immune system, the gastrointestinal tract and defence against pathogenic organisms.
This extensive framework aims to promote trust in the functional food market among consumers but can also be a challenge for food innovation in the food industry. The high standard of the NHCR regulations can be discouraging for producers of functional products, with “wording of claims” and “missing transparency being reported by the industry as the major challenges [10].
Health claims stating that microorganisms act as probiotics have not yet been authorised by the European Commission, however, some member states do allow the use of the term “probiotic effect” [14].

1.2. Current functional dairy products on the European market

The growth of the functional food market worldwide has been forecasted to continue its increase throughout the next decade with an expected global market increase from 177.4 USD billion in 2021 to 219.5 USD billion in 2026 [6]. With the increased focus on health and nutrition after the COVID-19 pandemic, consumers are actively seeking out products with added health benefits such as dairy products that can aid in the support of nutritional requirements or generally improved health [16]. Additionally, the dairy market is dynamic and undergoing constant development and innovation. The total amount of dairy products sold in Europe is steadily increasing according to MarketLine and will reach 155 billion euros in 2023 (Figure 2). This, in combination with the growing interest in functionality in foods among customers, renders dairy products an optimal choice for the enhancement of fortification.
The majority of food products on the European market with health claims deal with the addition of vitamins, minerals, protein and/or fibre [17]. Regarding microorganisms like LAB, NHCR regulations prevent the term probiotic from being applied as this claim has not yet been authorized by the European Commission, however, some member states do allow the use of the term “probiotic effect” [14].
Table 1 provides a summary of dairy products available within the Irish and European markets and includes kefir, yoghurt and drinking yoghurt, milk, butter and milk powders.
A current trend among consumers is the tailoring of functional products to specific needs and population groups, in which the fortified milk range by Avonmore (Tirlán) is a good example as it includes Avonmore Super Milk for improved nutrition and bone health, Avonmore Fibre Plus Milk for improved immune function and gut health and Avonmore Slimline Milk targeted population groups with higher iron requirements such as pregnant women (Table 1).
Milk powders with functionality are currently mostly aimed at infant and child nutrition but are starting to see their introduction in adult nutrition as well with the launch of Aerabo skim milk powders from Dairygold, which is being sold on the Chinese market. Like the Avonmore range of functional milk, the Dairygold line of functional milk powders also targets its application towards different groups: Aerabo Active Vitality targeted the middle-aged and senior population ([18], Aerabo Active Boost for improved immune support [19] and Aerabo Active Light for improved nutrition and wellbeing with a lower calorie content [20].
Table 1. summary of dairy products available in the Irish and European markets and includes kefir, yoghurt and drinking yoghurt, milk, butter and milk powders.
Table 1. summary of dairy products available in the Irish and European markets and includes kefir, yoghurt and drinking yoghurt, milk, butter and milk powders.
Product Product name Functional ingredient Health benefit Company Ref
Kefir Kefir Smoothie Probiotics
Calcium		 Gut health Müller [21]
Kefir Kefir Yoghurt Probiotics Gut health Glenillen Farm [22]
Kefir Spoonable Kefir Probiotics
Calcium		 Gut health Irish Yogurts, Clonakilty [23]
Kefir Kefir Drink Original Probiotics
Vitamin B12 and B2
Calcium		 Immune health
Gut health		 Biotiful Gut Health [24]
Kefir Kefir Yoghurt Original Probiotics
Vitamin B12 and B2
Calcium		 Digestion Immune health
Gut health		 Biotiful Gut Health [25]
Spreads Flora 100% natural ingredients Vitamin A
Omega 3 and 6		 Nutrition Flora [26]
Spreads Flora ProActiv Plant sterols Cholesterol-lowering Flora [27]
Spreads Benecol© Spread Plant sterols Cholesterol-lowering Raisio Lpc. [28]
Milk Avonmore Super Milk Vitamins Bone health
Nutrition		 Tirlán [29]
Milk Avonmore Fibre Plus Milk Vitamins
Fibre		 Gut health
Immune health
Nutrition		 Tirlán [30]
Milk Avonmore Slimline Milk Vitamins
Iron		 Nutrition
 Tirlán [31]
Milk powder Nido© Vitamins
Minerals		 Nutrition Nestlé [32]
Milk powder Baby&Me© Organic Vitamins
Minerals
Oligosaccharides		 Nutrition Arla [33]
Milk powder Aerabo Active Vitality Amino acids
Antioxidants
Glucosamine
Minerals
Vitamins		 Bone health
Nutrition
 Dairygold [18]
Milk powder Aerabo Active Boost Amino acids
Antioxidants
Beta carotene
Vitamins		 Immune support
Nutrition		 Dairygold [19]
Milk powder Aerabo Active Light Amino acids
Antioxidants
Beta carotene
Minerals
Vitamins		 Nutrition Dairygold [20]
Milk drink Goede Morgen! Vitamins Nutrition Friesland Campina [34]
Yoghurt Activia Probiotics Gut health Danone [35]
Yoghurt Danonino Minerals
Vitamins		 Nutrition Danone [36]
Yoghurt Benecol© Yoghurt Plant sterols Cholesterol-lowering Raisio Lpc [37]
Yoghurt Natural Yoghurt Probiotics Gut health Glenillen farm [38]
Yoghurt Greek style natural Probiotics Gut health Irish Yoghurts, Clonakilty [39]
Yoghurt
drink		 Actimel Probiotics
Vitamins		 Immune health Danone [40]
Yoghurt drink Benecol© Yoghurt Drink Plant sterols Cholesterol-lowering Raisio Lpc. [37]

2. Vitamins

Vitamins are organic compounds that constitute an essential part of the human diet. Humans are for the most part unable to synthesise vitamins themselves and rely on supplementation through a balanced diet. Certain LAB have the capability to synthesize some of these essential vitamins that humans are incapable of producing including folate (vitamin B9), cobalamin (vitamin B12), riboflavin (vitamin B2), menaquinone (vitamin K2) and thiamine (vitamin B1) [41,42].
The ingestion of vitamins is widely known to be associated with a range of health benefits (Figure 3).

2.1. Folate

Folate is essential for a wide range of biological functions including amino acid metabolism and DNA repair and is essential for cell division [43].
LAB, Bifidobacteria and PAB are all capable of producing folate while also being food-grade microorganisms (Table 2). Folate yields are however generally reported to be very low, even in genetically engineered strains [44,45,46]. Folate is therefore primarily produced synthetically as folic acid, but the human dihydrofolate reductase enzyme has an extremely low rate of folic acid conversion into bioactive vitamins and a high concentration of this synthetic form is therefore needed [47].
Table 2. Overview of folate-producing lactic acid bacteria.
Table 2. Overview of folate-producing lactic acid bacteria.
Microorganism(s) Fermentation Medium Yield Ref
L. acidophilus Flask MRS 37.2 µg/l [48]
L. amylovorus Flask MRS 81.2 µg/l [48]
L. amylovorus
S. thermophilus
L. delbrueckii subsp. bulgaricus 		Flask Milk 263 µg/l [48]
L. brevis Flask Supplemented whey permeate 131 µg/l [49]
L. casei Flask MRS 1.5 µg/l [48]
L. coryniformis Flask MRS 81 µg/l [50]
L. delbrueckii subsp. bulgaricus Flask MRS 54 µg/l [51]
L. delbrueckii subsp. bulgaricus
S. thermophilus 		Flask Non-fat milk 180 µg/l [52]
L. fermentum Flask MRS 6.9 µg/l [48]
L. fermentum Flask Supplemented whey permeate 84 µg/l [49]
L. helveticus Flask MRS 89 µg/l [51]
L. lactis Flask MRS 45 µg/l [51]
L. lactis subsp. cremoris 5 L batch bioreactor Skim milk powder 187 µg/l [53]
L. lactis subsp. lactis Flask M17 291 µg/l [51]
L. lactis subsp. lactis biovar diacetylactis Flask M17 100 µg/l [51]
L. paracasei subsp. paracasei Flask MRS 38.7 µg/l [48]
L. plantarum Flask MRS 57.2 µg/l [48]
L. plantarum Flask Supplemented whey permeate 397 µg/l [49]
L. plantarum Flask MRS 108 µg/l [50]
L. plantarum
P. freudenreichii 		1 L bioreactor Supplemented whey permeate 8399 µg/l [54]
L. reuteri Flask Supplemented whey permeate 125 µg/l [49]
L. sakei Flask MRS 107 µg/l [50]
S. thermophilus Flask M17 202 µg/l [51]
S. thermophilus 2 L batch bioreactor Modified M17 54.53 µg/l [55]

2.1.1. Production of folate

Hugenschmidt et. al. (2010), screened 151 LAB strains and 100 PAB strains for their ability to produce folate in a supplemented whey permeate media. Strains belonging to Lactobacillus showed the highest extracellular folate production, with L. plantarum SM39 being the highest producer with 3.97 ng/ml [49]. This strain was subsequently used in a follow-up study examining the production of folate and cobalamin in co-culture with P. freudenreichii, in a supplemented whey media. The addition of para-aminobenzoic acid (pABA) to the fermentation media increased the folate yield more than 10-fold [54]. This stimulating effect of pABA has also been observed in other studies on the strains S. thermophilus and L. lactis, where the production yield of folate was dependent on pABA in the media. This can be explained by pABA being one of the precursors of folate production. The level of pABA needed for optimal folate production is not fully described, with one study reporting that production yields did not increase with a concentration of pABA above 1 µM [56] while another reported this number to be above 100 µM [51].
Mousavi et. al. (2013) tested the effect of different carbon sources (glucose, maltose, sucrose, lactose) and nitrogen sources (meat extract, yeast extract, peptone/casein, peptone/meat, (NH4)2 SO4- and NH4NO32-) was tested to find optimal cultivation conditions for folate production of S. thermophilus. Here, it was concluded that lactose and yeast extract were the optimal carbon source and nitrogen source [55].
Another study further supplemented media with the prebiotics mannitol and sorbitol increased the yield of folate due to the stimulatory effect of prebiotics on cell growth. Folate molecules are highly sensitive to oxidation, and the reducing agents sodium thioglycolate, sodium ascorbate and cysteine hydrochloride have been added with a positive effect on the final yield of folate produced by a strain of L. lactis [41].
Two studies carried out fermentation of S. thermophilus in bioreactors and observed a high increase in folate production when pH was controlled, but where one study observed 7.3-9.3 as the optimal pH range [51], another determined pH 7 to be the optimal pH [56].
The production of folate in situ has been studied as well. Yoghurt is an example of a product well known for its potential of being a source of folate, although the concentrations of folate are however highly variable [42,52]. By fermenting milk with high folate-producing strains of the known yoghurt-producing species S. thermophilus and L. delbrueckii subsp. bulgaricus it was possible to increase folate content by 125% compared to commercial yoghurts [52]. Currently, commercial yoghurts can contribute to 10-20% of daily levels of folate but with both optimum strain selection and growth factors this number has great potential for future increase [51].

2.1.2. Health benefits of folate

Folate is an essential nutritional component, that cannot be synthesised by mammalian cells, and thus it must be supplemented through diet. Some population groups exhibit a higher risk of folate deficiency which is especially prevalent in the elderly population due to lower food consumption but also in pregnant women as higher levels of folate are required to assist in neural tube development [57]. Obtaining the right amount of folate is essential as excessive intake can lead to the accumulation of folic acid in the bloodstream and mask a potential cobalamin deficiency, as symptoms are comparable [58].
Low levels of folate in the diet during pregnancy have been associated with neural tube defects which can lead to severe consequences for the developing foetus including anencephaly (absence of major parts of the brain), spina bifida (spinal cord not formed properly), encephalocele (sacks containing brain tissue protrudes through the skull) and stillbirth [59]. Due to this, most countries are recommending folate supplementation of at least 400µg/day for pregnant women [59,60].
Folate can lower the levels of homocysteine, an amino acid that has been associated with neurodegeneration and Alzheimer’s disease [61,62]. Large studies in the UK and Sweden have indeed found an association between folate levels and cognitive function and Alzheimer’s disease [61,63]. A correlation between folate deficiency and depression and schizophrenia has also been described [64]. This was investigated in a study where patients suffering from depression and schizophrenia were supplemented with 15 mg of methyl folate per day for 6 months in addition to standard psychotropic treatment and a significant improvement of clinal and social recovery was observed [65].
The ability of folate to lower homocysteine levels can furthermore reduce the risk of cardiovascular diseases and studies have shown an inverse relationship between folate and cardiovascular disease [66,67]. Oral administration of folate has shown the ability to reduce homocysteine levels by 25% in subjects that are not folate deficient [68].
Folate levels might also modulate the risk of cancer, as a higher intake of folate has been associated with a lowered risk of colon cancer [69]. Balancing the intake of folate is also a necessity as it has been demonstrated how a modest supplementation of folate can reduce carcinogenesis while an excessive amount might increase the growth of tumours [69].

2.2. Cobalamin

Cobalamin is an important co-factor in the metabolism of amino acids, carbohydrates, fatty acids and nucleic acids [42]
Chemical production of cobalamin is far too expensive to be commercially viable and involves more than different 70 steps, so industrial preparation takes place through bacterial fermentation [70]. In industrial fermentations, species of P. freudenreichii, P. denitrificans and B. megaterium are highly used. Of these, only P. freudenreichii has GRAS status and is therefore the only of these microorganisms that can currently be utilised directly in food production (Table 3) [45,71].

2.2.1. Production of cobalamin

The production of cobalamin from different strains of Propionibacterium in a whey-based fermentation medium has also been optimized in several studies [77,78,79,80]. The production of cobalamin by P. shermanii was optimised by investigating optimal levels of whey and yeast extract in the growth medium. It was determined that with a given level of whey, a certain amount of yeast extract was needed, with 10% whey solids and 1.5% yeast extract resulting in maximum yield [77].
The addition of the amino acids betaine and choline as well as diammonium hydrogen phosphate ((NH4)2HPO4) to a whey-based media showed an increase in cobalamin production. It was determined that the addition higher than 0.5% w/v of either of the amino acids did not increase cobalamin production further. In addition, the effect of betaine was observed to be more stimulating than choline [79,80]. This stimulating effect of betaine concurs with studies on cobalamin production of P. denitrificans [73,81] and is explained by betaine acting as a methyl group donor for the highly complicated cobalamin structure that contains up to eight methyl groups [73].
PAB are microaerophilic and produce cobalamin in high yield only when the concentration of oxygen is kept low [70]. One step in the cobalamin synthesis does however require oxygen, and the fermentation process producing cobalamin from P. freudenreichii is therefore often divided into two stages, as the optimal yield is dependent on both an anaerobic and aerobic phase [82]. A periodic fermentation with P. freudenreichii was developed with a fluctuation of oxygen supply and a cyclic operation switching between anaerobic and aerobic conditions. This operation mode resulted in a low concentration of propionic acid together with a high level of cobalamin [83].
One of the challenges of producing cobalamin from Propionibacterium is the accumulation of metabolites such as propionic acid and acetic acid which harbours growth inhibitory effects [84]. In a study by Miyano et al (2000) three different strategies were applied to circumvent this in P. freudenreichii fermentations: periodic changing of DO concentration between 0 and 1 ppm, a cell recycle system and mixed culture with R. eutropha that are capable of assimilating propionic acid. From these three methods, the cell recycle system gave the highest cobalamin productivity, but the mixed cell system resulted in the highest cobalamin produced per unit volume of medium [76].

2.2.2. Health risks associated with cobalamin deficiency

Cobalamin deficiency can occur in the elderly population, children, pregnant women and people on a plant-based diet that excluded natural cobalamin-high foods such as meat and dairy [85]. This deficiency is usually caused either by a lack of cobalamin in the diet or by malabsorption. It is estimated that 6% of the UK population under 60 and 20% of the population over 60 years exhibit a cobalamin deficiency. [85]. The deficiency of cobalamin typically appears with symptoms such as fatigue and anaemia, but can also result in bone marrow suppression and risk of cardiomyopathy in more serious cases of deficiency [85]. Patients with a cobalamin deficiency can be ordinated oral treatments of the vitamins, while fortification of foods to make them more functional could be the solution in countries with high numbers of deficiencies in the population [86].
In addition to low folate levels inducing the risk of neural tube development, there is also evidence that low cobalamin levels might induce the same risk [87,88]. This area of research is however still lacking in data on both need and dosage, but the benefits of cobalamin supplementation outweigh any potential consequences [89].
As mentioned, the levels of homocysteine appear to be related to cardiovascular disease. A study that found a reduction of homocysteine levels by supplementation with 5 mg folate, found a small, but further decrease by also supplementing the diet with 0.4 mg/day cobalamin with 7% [90]. Most of the research on cardiovascular disease is however done on folate with or without the addition of cobalamin, making the information on the specific effect of cobalamin limited [91].
Cobalamin deficiency has also been linked to low bone mineral density, low bone mineral content, growth retardation and increased risk of bone fraction [92,93,94].

2.3. Riboflavin

Traditionally riboflavin has been produced chemically, but the biotechnological production through strains such as B. subtilis, A.gossypii, C. famata and L. lactis has gained more interest, with only L. lactic belonging to the group of LAB (Table 4) [95]. Although some strains of bacteria and yeast are considered good producers of riboflavin, the ascomycete fungi A. gossypii is considered the best as it can produce 40000 times more riboflavin than it needs for its growth [96].

2.3.1. Production of riboflavin

L. acidophilus and L. lactis have been applied in studies examining their riboflavin production [95,97]. L. lactis and L. acidophilus were grown on both milk and whey. Whey appeared to be a more optimal growth medium for riboflavin production, and L. acidophilus was the optimal producer of riboflavin with a final yield of 2.93 mg/L [103]. Although this yield is significantly lower than those that are possible to obtain with A. gossypii the interest in producing riboflavin from LAB is due to the potential of producing fermented foods with high levels of riboflavin produced in situ [104]. Mohedano et al (2019) investigated Five strains of L. plantarum as a probiotic by examining their ability to produce riboflavin as well as their capability to survive under digestive tract stresses. One strain of L plantarum 3.33 mg/L survived well under gastric stress conditions, alluding to its potential as a probiotic strain for functional foods [100].
High yields of 5.72 mg/L riboflavin have been obtained for another strain of L. plantarum by optimising its growth medium. Glucose and sucrose were evaluated as carbon sources at both 30°C and 37°C, and the highest yields of riboflavin were observed when growing in a sucrose-based medium at 30°C [102].

2.3.2. Health benefits of riboflavin

A balanced diet will in most cases supply the necessary amount of riboflavin in healthy humans. Nevertheless, different population groups can be at risk of insufficient riboflavin supply such as the elderly, children and pregnant women [105].
Riboflavin has been shown to exert an antioxidant effect in two ways: by prevention of lipid peroxidation and by the attenuation of reperfusion of oxidative injury [106]. The research conducted on this antioxidant activity in humans is however limited [107]. This antioxidant activity is attributed to the role riboflavin plays in the activity of several antioxidant enzymes such as superoxide dismutase, catalase and glutathione peroxidase [106].
Some studies have also shown that intake of adequate amounts of riboflavin could lead to a decreased risk of breast cancer [108], lung cancer [109], colorectal cancer [110], gastric cancer [111] and ovarian cancer [112], emphasizing its importance in a healthy lifestyle.
It has been hypothesized that riboflavin can have a neuroprotective effect on diseases such as Parkinson’s disease, migraine and multiple sclerosis [107]. A low level of riboflavin has been reported in patients with Parkinson’s disease. By adding a riboflavin supplement to the diet and eliminating red meat, it was possible to increase motor functions [113]. This same effect has however not been observed in other studies [114,115].
There are a few studies that have investigated the effect of riboflavin on multiple sclerosis. In one study on animal models, riboflavin had a suppressive effect on neurological disability [116] but the same effect was not observed in a human interventional study [117].
Migraine is a common neurological disorder, estimated to affect around 3% in early childhood and up to 23% of the adult population [118]. Adults with a migraine who were administered 400mg of riboflavin for 3 months or 6 months showed alleviation of migraine symptoms [119,120].

2.4. Menaquinone

There are two available forms of vitamin K: phylloquinone produced by plants and menaquinone primarily produced by bacteria [70]. It is an essential cofactor involved in the post-transitional carboxylation found in proteins related to blood clotting, cardiovascular disease and bone health [42]. B. subtilis is the most well-studied strain for menaquinone production, but some LAB is also capable of synthesising menaquinone (Table 5) [121].

2.4.1. Production of menaquinone

The potential of synthesis of menaquinone by LAB has been researched in a study that screened 21 strains. Of the screened species of LAB, five strains were selected due to their high production of menaquinone: three strains of L. lactis subsp. Cremoris, one strain of L. lactis subsp. lactis and one strain of L. lactis. All five of these strains were able to produce a meaningful amount of menaquinone when grown in non-fat dry milk [123].
P. freudenreichii has been investigated both for its ability to produce menaquinone and its precursor 1,4-Dihydroxy2-Naphthoic Acid (DHNA). When grown in a skim milk-based media in a 3L bioreactor, relatively high yields of menaquinone of 0.12 mM were obtained [124].

2.4.2. The role of menaquinone in cardiovascular disease and bone health

Menaquinone has long been recognised for its role in blood coagulation but has shown a potential to improve bone health and inhibit the growth of cancer [125,126].
Studies have shown that the intake of specifically vitamin K in the form of menaquinone is associated with reduced coronary calcification and a reduced risk of cardiovascular disease [127,128,129]. The effects of vitamin K in the form of phylloquinone and menaquinone over 10 years in 4807 Dutch men and women over the age of 55 were investigated [127]. Interestingly, this study found that the intake of menaquinone but not phylloquinone reduced the risk of coronary heart disease and coronary calcification [127]. This comparison of phylloquinone to menaquinone was also done in another study that found a similar effect of only menaquinone reducing the risk of coronary calcification [130].
Menaquinone can play an important role in bone health as three different menaquinone-dependent proteins have been isolated from bone [128]. The effect of menaquinone on bone mineral density in human intervention studies is inconclusive, with some showing a beneficial effect [131,132] while another study has concluded no beneficial effect [133]. One major limitation of the study by Emaus et al (2010) is however the short follow-up period, of 1 year with another study stating that effects might only become significant after 2 years of intervention [132]. In addition to improving bone mineral density, menaquinone has also shown indications of improving bone strength in a human intervention study [132].

3. Bacteriocins

Bacteriocins are antimicrobial peptides produced by certain bacteria that can kill or inhibit the growth of both gram-negative and gram-positive bacteria (Table 6) [134]. Several applications of bacteriocins have been reported in the literature including, control of microflora in fermentation products [135] and extension of shelf life [136]. Bacteriocins are proving worthy of commercial interest, due to their preservation qualities that can aid in fulfilling consumer demand for foods that are safe and long-lasting without the use of chemical preservatives [137,138].
Currently, the only commercially available bacteriocins are nisin produced by L. lactis and pediocin PA-1 produced by Pediococcus species [139]. These are both approved for safe use in food by the Food and Drug Administration (FDA) and the European Food Safety Authority (EFSA). In addition to nisin and pediocin, several other bacteriocins are highly studied, but not yet approved for safe use in foods including lactococcins, enterocins and aureocins [140].
Table 6. Overview of nisin and pediocin produced by LAB.
Table 6. Overview of nisin and pediocin produced by LAB.
Microorganism(s) Product Fermentation Medium Yield Ref
L. lactis Nisin Flask Skim milk-based media 75 IU/ml [141]
L. lactis Nisin Shake flask Whey based media 92.9 mg/L [142]
L. lactis Nisin Shake flask Whey based media 1167 AU/ml [143]
L. lactis Nisin Shake flask Whey based media 2618.7 IU/ml [144]
L. lactis Nisin Single batch – free cells Whey based media 32800 & 41000 BU/ml
(16400 & 20500 IU/ml)		 [145]
L. lactis Nisin Single batch – free cells MRS 160 AU/ml [146]
L. lactis Nisin Repeated cycle batch - ICT Whey based media 20480 IU/ml [147]
L. lactis Nisin Fed-batch Complex 4185 IU/ml [148]
L. lactis Nisin Fed-batch Whey 60.3 BU/ml [149]
L. lactis Nisin Fed-batch Whey + glucose 124 BU/ml [150]
L. lactis Nisin Fed-batch Whey + MRS nutrients 258.47 BU/ml [151]
L. lactis Nisin Fed-batch Defined 2594 · 106 IU/ml [152]
L. delbrueckii subsp. bulgaricus
S. thermophilus 		Nisin Continuous fermentation Skim milk-based media 4500 BU/ml [153]
L. lactis
K. marxianus 		Nisin Single batch – free cells Defined 98 mg/L (3920 IU) [154]
L. lactis
S. cerevisiae 		Nisin Shake flask Defined 150.3 mg/L [155]
L. lactis
P. acidilactici 		Nisin
Pediocin		 Shake flask Whey based media 74 BU/ml
195 BU/ml		 [156]
L. lactis
P. acidilactici 		Nisin
Pediocin		 Shake flask Whey based media 9 BU/ml
45 BU/ml		 [157]
L. lactis
P. acidilactici 		Nisin
Pediocin		 Shake flask MRS
Whey based media		 50 and 22.9 BU/ml
493.2 and 57.9 BU/ml		 [158]
L. lactis
P. acidilactici 		Nisin
Pediocin		 Single batch – free cells Whey based media 3000 AU/ml (18h)
1359 AU/ml (16h)		 [159]
P. acidilactici Pediocin Flask Whey based media 12800 AU/ml [160]
P. acidilactici Pediocin Flask MRS 12800 AU/ml [161]
P. acidilactici Pediocin Flask Whey based media 150000 AU/ml [162]
P. acidilactici Pediocin Shake flask Whey based media 189 BU/ml [163]
P. acidilactici Pediocin Shake flask MRS
Whey based media		 493.2 BU/ml
167.3 BU/ml		 [164]
P. acidilactici Pediocin Single batch – free cells TGE broth 40000 AU/ml [165]
P. acidilactici Pediocin Repeated cycle batch - ICT MRS
Whey based media		 4096 AU/ml ( 0.75h)
4096 AU/ml (2h)		 [166]
P. acidilactici Pediocin Fed-batch Defined 712 BU/ml [163]
P. acidilactici Pediocin Fed-batch Whey based media 517 BU/ml [164]
P. acidilactici
S. thermophilus
L. delbrueckii subsp. bulgaricus 		Pediocin Flask Skim milk-based media 6400 AU/ml [161]
P. acidilactici
P. pentosaceus 		Pediocin Flask Whey based media 3220 AU/ml
26100 AU/ml		 [167]
P. pentosaceus
L. plantarum 		Pediocin Flask Whey based media 51200 AU/ml [168]

3.1. Production of nisin

Nisin is commercially used in over 48 countries and has FDA and EFSA approval [139]. It was first isolated from milk in 1928 and gained approval as a safe food additive in 1969 by the Joint Food and Agriculture Organization/World Health Organization (FAO/WHO) [169]. Nisin is usually manufactured via fermentation of milk or whey using L. lactis. The fermentation broth is subsequently harvested, concentrated, separated and spray-dried [134]. To reach the optimal nisin production more complex media including MRS are usually required together with control over parameters such as pH and temperature [148].
Several studies have compared the nisin production yields from L. lactis grown on whey-based feedstocks with MRS media [149,158]. A selection of studies has reported that the production yields using MRS medium can reach yields of 50 and 55 AU/ml [149,158], whereas typical yields of 22 and 22,5 AU/ml are achieved using diluted whey medium
[149,158]. Malvido et. al (2019) supplemented a base whey media with MRS nutrients. Nutrients were supplemented in concentrations corresponding to MRS medium of 25%, 50%, 75%, 100% and 125% w/v. The addition of MRS nutrients increased the nisin yield from 22.67 bacteriocin units (BU) for diluted whey to 57.26 BU for whey supplemented with 100 v/w of MRS nutrients. There was an observed increase in yield with MRS nutrient addition, however only up until 100% where the yield stagnated [151].
It has been reported that to further optimise the production of nisin, it is necessary to provide additional protein in the form of e.g. peptone, tryptone or yeast extract [148].
To optimise nisin production, a fed-batch fermentation on a whey media with a feed composition of concentrated glucose (400g/L), concentrated whey and 4% yeast extract, and a feeding volume addition corresponding to the amount needed to restore initial total sugar concentration was studied. Nisin production was increased to 50.6 and 60.3 BU/ml when compared to yield obtained in batch cultures grown in whey of 22.5 BU/ml [158] and 50 BU/ml when compared to growth batch culture growth in MRS [149].
The production efficiency and costs of production in fed-batch fermentation of nisin were compared in supplemented and unsupplemented whey. They had a feed consisting of concentrated whey and concentrated glucose and a feed profile adding volumes to the fermentation to restore the initial total sugar composition. The cost of nisin in a fed-batch fermentation supplemented with MRS nutrients was 30% lower than the cost of nisin in fed-batch fermentation with unsupplemented media. Here, the highest yield obtained on a whey-based fed-batch fermentation with MRS nutrients was 258 BU/ml compared to 124.66 BU/ml in a whey-based fed-batch with no added nutrients [151].

3.2. Production of pediocin

Pediocin is a bacteriocin with a broad spectrum, meaning that it is capable of inhibiting several different species of gram-positive bacteria [170]. It is however particularly known for its ability to inhibit the growth of L. monocytogenes and S. aureus which are both common food pathogens [171]. Both P. acidilactici and P. pentosaceus are capable of pediocin production (Table 6) and are well-known from food fermentations, and are either naturally present or added as a starter culture in the fermentation of vegetables and sausages [170,172].
The influence of the different salts ammonium phosphate, calcium chloride, potassium dihydrogen phosphate and manganese(II)sulphate monohydrate on pediocin production was tested in a direct plate bioassay for rapid assessment. Manganese is an essential growth factor for lactic acid bacteria, and the addition of MgSO4 also resulted in a significantly increased pediocin yield. Each of ammonium phosphate, calcium chloride and potassium dihydrogen phosphate resulted in a suppression of pediocin production [146]. A whey and yeast extract-based media could therefore possibly be further optimized by the addition of manganese. The growth and pediocin production of pediococcus has also been tested in both a repeated batch and a fed-batch setup with whey and yeast extract as the batch media, with reports of increased yield [173,174,175].
Pediococcus species more readily metabolise glucose than other carbon sources [146,159]. Excessive glucose in the fermentation broth can however have an inhibitory effect, and its addition in a simple batch resulted in decreased pediocin, suggesting substrate inhibition. The addition of glucose in the feed of a fed-batch fermentation instead resulted in great improvements in the pediocin yields, showing at least a 2-fold increase of 517 BU/ml in a fed-batch compared to 167 BU/ml in a simple batch in one study [174]. Pediocin has furthermore been determined to be a pH-dependent metabolite, and that pH should be maintained at levels lower than 5 to achieve maximum production [157,174,176]. This is due to a requirement of low pH for the post-translational processing of pre-pediocin to active pediocin [165].

3.3. Mixed culture induction

The presence of other bacterial strains can enhance bacteriocin production either by the production or consumption of metabolites or by acting as a stress signal which in some cases increases bacteriocin production. Pediocin production by P. pentosaceus was increased by 250% in the presence of L. plantarum [168], while another study observed that the co-culturing of P. acidilactici with S. thermophilus and L. delbrueckii enhanced pediocin production in fermented milk [161].
S. cerevisiae improved nisin production in a study by Shimizu et. al. (1999) from L. lactis by 85% to a final yield of 150.3 mg/L. This was attributed to the lactic- and acetic acid assimilation by S. cerevisiae which normally acts as a limiting factor for nisin production [155]. A similar enhancement of 70% was observed when L. lactis was co-cultured with another yeast, K. marxianus, where it was also concluded that the increased nisin production was caused by lactic acid assimilation and the resulting control of pH levels. [154].

3.4. Health benefits of bacteriocins

Bacteriocins produced by LAB possess several health benefits. Their antimicrobial activity can be applied in the treatment of harmful bacteria, as they can selectively target pathogenic organisms, while not affecting commensal bacteria. This makes them a valuable alternative to antibiotics that are less target-specific [177].
The antimicrobial nature of bacteriocins makes them Additionally, research is suggesting that bacteriocins can have applications in the treatment of cancer as well as immunomodulatory effects (Figure 3).

3.4.1. Treatment of pathogens and alternatives to antibiotics

The anti-listerial effect of both purified pediocin and its producer strain P. acidilactici was investigated in vivo in mice infected with L. monocytogenes. The effect of oral administration of P. acidilactici did not result in a decrease of L. monocytogenes in the intestine, liver or spleen, while the administration of purified pediocin resulted in a 2-log decrease of L. monocytogenes. None of the treatments altered the composition of the gut microbiota, making purified pediocin a promising agent against L. monocytogenes [178]. In this study, however, administration of P. acidilactici was only given as a single dose and purified pediocin was administered over 3 days. Another study administered both a pediocin and non-pediocin strain of P. acidilactici and a nisin-producing strain of L. lactis for 16 days in mice infected with vancomycin-resistant enterococci (VRE). Results showed, that on day 6 none of the infected mice administered either pediocin-producing P. acidilactici or nisin-producing L. lactis had detectable levels of VRE [179].
S. aureus is one of the most common pathogens in the upper respiratory tract and nisin has been assessed for its ability to combat S. aureus infections in vivo in immunocompromised rats. Rats were provided nisin intranasally, and growth of S. aureus was inhibited [180]. These results suggest that nisin and pediocin can indeed be used to fight pathogens and could have importance against pathogens with resistance to antibiotics. Another advantage of bacteriocins over antibiotics is their specific activity that does not affect the commensal bacteria in the gut, as antibiotics do [181]. A study investigated the sensitivity of 21 common intestinal bacteria to pediocin and two types of nisin in vitro. Both types of nisin inhibition of all the gram-positive bacteria and only one of the gram-negative bacteria. Pediocin on the other hand did not inhibit any of the 21 intestinal bacteria assayed, which further strengthens its potential as a non-invasive alternative to pathogenic infections [181].

3.4.2. Anti-cancer treatment

There is research that suggests the cytotoxicity of bacteriocins against cancer cells [182].
Nisin has been reported to have cytotoxic and antitumour effects against head and neck squamous cell carcinoma in vivo in mice [183]. Mice were fed 200 mg/kg of nisin for three weeks which resulted in a significant reduction of tumour size compared to control. These effects of nisin were also tested in vitro and were found to be due to induced apoptosis, cell cycle arrest and reduction in cell proliferation [183]. This effect of nisin on head and neck squamous cell carcinoma was also observed in vivo in another study in mice [184]. Here, it was also found that when getting dosages of nisin, the tumour size would reduce and would prolong survival.
Nisin has also shown possible application as an adjunct together with the chemotherapeutic agent doxorubicin in the treatment of skin cancer [185]. Carcinogenic mice were treated with either nisin, doxorubicin or a combination of the two. The tumour size was reduced by 14% with nisin, 51% with doxorubicin and 66.82% when mice were treated with both agents, as compared to untreated groups.
Pediocin has also shown potential as an anti-cancer agent in vitro against various cell cancer lines such as colon, liver, cervical and mammary gland cancer cells [186,187].

3.4.3. Immunomodulatory role of bacteriocins

Host-defence peptides are ubiquitous and play an important role in the innate immune system. Despite being smaller and having a different structure, bacteriocins share similar physiochemical properties to host-defence peptides, which could indicate that they might have similar immunomodulatory properties [188,189]. This immunomodulatory ability has been demonstrated in vivo in mice [190] and turbot [191]. By feeding mice nisin in the commercial form Nisaplin an increase in the T-lymphocytes CD4 and CD8 and a decrease in B-lymphocyte levels was observed. Long-term administration resulted in a return to normal levels of B- and T-lymphocytes and an increase in the macrophage/monocyte population [190].
An in vitro study found that nisin could induce the stimulation of the chemokines monocyte chemoattractant protein- 1 (MCP-1), Gro-α and IL-8 while significantly reducing TNF-α in response to bacterial lipopolysaccharide in human peripheral blood mononuclear cells [189].
Lastly, a study has found that nisin was able to activate neutrophils and suggested that nisin might be capable of influencing multiple subsets of host immune cells [192].
The research conducted on nisin’s ability to alter the host immune response is limited, so further studies on the area are needed.

4. Bioactive peptides

Proteins that occur naturally in food can in addition to providing nutritional benefits, also contain sequences called bioactive peptides that can exert health various health benefits (Figure 3) [193]. When present in the parental protein these sequences are inactive but can be released in 3 ways: through hydrolysis by gastrointestinal enzymes, through the action of proteolytic enzymes derived from plants or microbes or by microbial fermentation with microbes exerting proteolytic activity [194]. The focus in this section will solely be on the bioactive peptides released by microbial fermentation. During the fermentation of milk, LAB is capable of hydrolysing milk proteins to make nitrogen sources like peptides and amino acids available [195].

4.1. Angiotensin-converting enzyme inhibitory peptides

Several members of the species lactobacillus, bifidobacterium and pediococcus are described in the literature as angiotensin-converting enzyme inhibitory peptides (ACE inhibitory peptides) producers [196,197,198], Table 7. Functional dairy products containing ACE-inhibitory peptides such as fermented milk [199,200,201,202] and cheese [203,204] have been developed. These products are characterized by a high degree of proteolysis, whereas products with a lower proteolytic activity such as yoghurt, fresh cheese and quark have a lower ACE-inhibitory activity [205].
Un-fermented whey already contains a certain amount of ACE-inhibitory peptides, but by fermenting it with the microbiota naturally present in cheese whey, the ACE-inhibitory activity increased from 22% in unfermented whey to 60-70% in fermented whey [210]. Another study by Ahn et. al. (2009) showed that a further supplementation of glucose and yeast extract to whey led to an increase in the biomass, thereby increasing the proteolytic activity and in turn a higher yield of peptides [197]. Here, L. brevis, L. helveticus and L. paracasei were used for peptide production, with the peptides derived from whey fermentation of L. helveticus showing high inhibitory activity with IC50 values of 5,3 and 7,8 µg/ml.
P. acidilactici is another species that has also been shown to exhibit good ACE inhibitory activity and was found by screening 34 different strains of LAB grown in a whey-based media [196]. P. acidilactici had an ACE-inhibitory activity of 84.7% with an IC50 of 19.78 µg/ml.
Sodium caseinate was used to produce a fermentate with ACE inhibitory activity by L. animalis [211]. The fermentate had an 85.51% ACE-inhibitory activity with an IC50 value of 8 µg/ml, which is only a slightly higher dose needed than the commercially available captopril that demonstrates inhibitory activity at a dose of 5 µg/ml [211]. Raveschot et. al. ( 2020) compared the production of ACE inhibitory peptide productivity of L. helveticus in 3 different fermentation setups: a simple batch, a continuous bioreactor and a continuous membrane bioreactor (MBR). The mean productivity of the MBR setup was 0,27 g/L/h which was comparable to that of the simple batch of 0,33 g/L/h but higher than the continuous bioreactor which had a mean productivity of 0,103 g/L/h. The specific productivity was also calculated as a function of bacterial biomass, where the MBR setup was superior to the other setups with a rate of 15.8 g/g compared to 9.99 g/g and 7.13 g/g in batch and continuous batch respectively. In this study, a fermentate with an IC50 value of 0.47 mg/L for L. helveticus was obtained [212].

4.1.1. Antihypertensive effect and cardiovascular diseases

Drugs that inhibit ACE are common for the treatment of hypertension. ACE is needed for the conversion of angiotensin 1 to angiotensin 2 which narrows the blood vessels and can cause higher blood pressure [213].
The blood-pressure-lowering effects of ACE inhibitory peptides have been demonstrated in several studies with subjects suffering from hypertension [214,215,216]. Ingestion of tablets of milk fermented with L. helveticus was administered for 4 weeks in subjects with either high-normal blood pressure or mild hypertension. For both groups, a lowered blood pressure was observed for subjects ingesting the tablets compared to a placebo group. The placebo tablets had a similar composition to the test-group tablets, but had no ACE inhibitory peptides, indicating the blood pressure-lowering effect was due to the presence of the peptides [214].
Another proposed effect of milk fermented with L. helveticus is the alleviation of arterial stiffness. Long-term administration of the milk-containing peptides showed a significant reduction in arterial stiffness compared to the placebo group [217]. This study also investigated the improvement of endothelial function but found no effects from the peptide-containing milk. Another study did however observe an improved vascular endothelial function when administering peptides to hypertensive subjects [218]. This mechanism was determined to be related to the enhanced production of vasodilating substances.

4.2. Peptides with antioxidant activity

Some LAB possess the ability to excrete peptides with antioxidant activity (Table 8). These peptides can decrease the risk of accumulation of reactive oxygen species (ROS) as well as degrading superoxide anions and hydrogen peroxide [219,220].
Virtanen et. al. (2007) screened 25 LAB strains for their ability to exhibit antioxidant activity in milk media [223]. While all strains had antioxidant activity to some degree, 6 strains had a higher inhibition rate: 2 Lc. cremoris, L. lactis, L. jensenii, L. acidophilus and L. helveticus. A correlation between the degree of hydrolysis and radical scavenging activity was found for all strains, with an additional correlation of bacterial growth to radical scavenging activity found for L. acidophilus and L. helveticus. Lipid peroxidation inhibitory activity was found to be more related to bacterial growth, than to proteolysis. When two or three of the strains were cultivated together, this increased antioxidant activity [223]. This mixed-strain approach to a higher antioxidant activity was used in the other two studies either co-cultivating yoghurt bacteria with lactobacilli [221].
The traditional yoghurt fermenting strains S. thermophilus and L. delbrueckii subsp. bulgaricus was used to produce yoghurt and test for its potential antioxidant activity. This study concluded that yoghurt can indeed have the potential as a natural antioxidant [220].
Another study also used the yoghurt strains but supplemented them with additions of L. casei, L. paracasei and/or L. acidophilus to enhance the antioxidant activity of yoghurt. The yoghurt fermenting strains alone demonstrated good antioxidant activity but the addition of the lactobacillus strains resulted in a lowering of the IC50 value. The highest antioxidant activity observed was when all 3 strains of lactobacillus were added [221]. and in another study by Lin and Yen (1999),
L. casei was used in a study to investigate the influence of several nutrients on the production of antioxidant peptides in goat milk fermentation [222]. Here, it was found that the addition of casein peptone, glucose and calcium lactate had significant positive effects on the antioxidant activity. The effect of glucose and calcium lactate are most likely caused by stimulation of L. casei growth. Casein peptone could increase the release of peptide, which has also been observed in another study that has shown for caseinate [224].

4.2.1. Health benefits of antioxidant peptides produced by LAB

Some of the antioxidant potential in fermented dairy products is considered to be caused by the high release of antioxidant peptides by the proteolytic systems in many LAB [225]. In vivo studies in either animal or human models demonstrating the specific effect of antioxidant peptides are scarce [225]. One study fed ageing rats with either unfermented milk or milk fermented with L. fermentum and observed that after 2 months, the numbers of the antioxidant enzymes superoxide dismutase, catalase and glutathione peroxidase were higher in the liver cells of rats fed the fermented milk compared to the unfermented milk [226]. The influence of fermented and unfermented milk on a weanling rat model was also compared in another study [227]. Here, the ability to reduce lipid peroxidative stress was evaluated, but no difference between the two milk types was observed. There was still observed an antiperoxidative effect when compared to the control, indicating the milk protein rather than the lactobacillus to be responsible for this effect. Both of the above-mentioned results were also demonstrated in a third study on rats fed either fermented or unfermented whey. Here, an observed increase in antioxidant enzymes and antiperoxidative activity was observed for both fermented and unfermented whey, although this study did observe peroxidative changes to be more pronounced in fermented whey [228].

5. Bioactive compounds

Some species of LAB have gained attention for their ability to produce the bioactive compounds gamma-aminobutyric acid (GABA) and carotenoids [229,230]. GABA is a neurotransmitter with known health benefits such as its ability to calm the nervous system while carotenoids are pigments with known antioxidant activity (Figure 3) [231,232].

5.1. Gamma-aminobutyric acid

γ-aminobutyric acid (GABA) is a bioactive amine that has been shown to confer health benefits. It acts as a neurotransmitter in the nervous system and can lower blood pressure in mildly hypertensive patients [233] and has also been suggested to have anti-tumour effects [234]. It is naturally present in several foods such as tomatoes, teas, soybeans and fermented foods and can therefore be obtained naturally through diet, but much higher concentrations are obtainable through LAB fermentations (Table 9) [235].

5.1.1. Production of GABA

The pH value during the fermentation plays an important role both in the cell growth of LAB and in their production of GABA. The synthesis of GABA is dependent on the enzyme glutamic acid decarboxylase (GAD) which acts as a catalysator, and pH is therefore an important factor when considering yields of GABA [264,267]. The importance of maintaining a pH value of between 4.5-5 has been reported in several studies that have documented optimal GABA synthesis when pH was kept at this level [236,237,238,248,251,264]. A pH value of 6 did result in higher biomass in a study cultivating L. brevis, but even with the higher biomass, the yield of GABA was still higher at pH 5 [238].
GABA production itself is not affected by lower temperatures of around 30°C but can lead to lower yields of biomass which in turn leads to less total yield of GABA [236,238]. Higher temperatures above 40°C did support growth but were inhibitory to GABA production [236,237,238,253]. The optimal temperature for both cell growth and GABA synthesis is therefore within the range of 35-40°C.
Due to the different optima for cell growth and GABA synthesis, a two-stage fermentation was developed for L. brevis. Here, cultures were maintained at 35°C and a pH value of 5 for the first 32 hours to stimulate cell growth and was subsequently adjusted to 40°C and a pH of 4.5. This resulted in an increase of GABA from 398 mmol/L in the one-stage fermentation to 474.70 mmol/L in the two-stage fermentation [239].
Another factor that can increase GAD activity is the addition of pyridoxal-5’-phosphate (PLP), which acts as a coenzyme. Studies have reported an increase in the GABA yield of L. paracasei from 200mM without PLP to 300 mM with PLP [251] and in S. thermophilus fermentation from 6 g/L without PLP to 8 g/L with PLP addition after 24 hours [264]. Other studies did however not observe any change in yield in L. brevis fermentations, but it was suggested to be due to sufficient synthesis in the fermentation broth [238,253].
Monosodium glutamate (MSG) is a stimulant of GABA production, but if it is present at too high levels, it has been shown to have inhibitory effects [240,264]. In L. plantarum cultivations, GABA synthesis was significantly influenced by the addition of 100 mM of MSG in the fermentation broth, as it induced an increase in production by 7.7 to a value of 721.35 mM [268]. This stimulatory effect has similarly been observed for L. brevis within a range of 2.25% and 4-6% v/w [237,254], for S. thermophilus within a range of 10-20 g/L [264] and L. lactis and L. plantarum at 1% v/w [253].
A strategy to overcome the inhibitory effects of high MSG concentrations is to supplement it to the feed in fed-batch fermentations [239,238,239]. In a study by Peng et. al. (2013) an initial concentration of 100mmol/L MSG was added to a defined medium consisting of glucose, yeast extract, peptone, sodium acetate and ions. The feed consisted of 106 mmol of MSG and was added at 32h and 56h. By the end of fermentation, the final yield of GABA was 526.33 mmol/L. The yield was only slightly higher than without the feed (474.79 mmol/L) but due to the additional increase in volume, a much higher total GABA productivity was obtained [239].
To a fermentation broth consisting of glucose, peptone, tween80 and MnSO4, 400mM of glutamate was added. It was found that concentrations exceeding 500mM strongly inhibited cell growth. The feed was added at 12h and 24h and consisted of 280.8g and 224.56g of glutamate. This feeding strategy was detrimental to the cell growth, but highly effective for a high yield of GABA in a short fermentation time, as it yielded 1095 mM [238].
A very high yield of 205.8 g/L GABA by L. brevis has also been found in a medium with 295 g/L of L-glutamic acid [241]. The issue with L-glutamic acid or glutamate is however the high production cost, making it less feasible for a cost-effective production [254].
Co-culturing microbes is another efficient approach to increase the yield of GABA and has been successfully applied in many studies. Fermentation of milk with a combination of a strain with high proteolytic activity together with a GABA-producing strain has led to efficient GABA production together with additional reports of a lowered fermentation time [247,261,266]. The proteolytic strains are capable of breaking down milk proteins into peptides which can then be used as substrates by the GABA-producing strain.
The addition of a GABA-producing LAB strain to fermentation with S. thermophilus and L. delbrueckii sups. bulgaricus enhanced the level of GABA in fermented milk with MSG in two studies [257,266].
Co-culturing of LAB and fungi has been reported with combinations of L. plantarum and Ceriporia lacerata leading to the production of 15.53 g/L while the combination of Lactobacillus futsaii and Candida rogusa lead to a GABA productivity of 135 mg/L/h [269,270].
Whey could be a suitable and low-cost option for GABA production by LAB and has been investigated as a substrate [245,261]. A GABA yield by cultivation of L. brevis of 553 mg/L by utilizing a media consisting of 14.95% of whey and 4.95% of MSG [245]. A higher GABA yield of 3.65 g/L was obtained in whey-fermentations of a co-culture of L. plantarum and L. lactis subsp lactis. In this study, soy protein hydrolysate was used as a source of glutamic acid and when added to the whey the yield increased from 1 g/L to 3.65 g/L [261]. Both of these studies utilize very simple media for GABA production on whey and do not use pH control, the addition of MSG, PLP, and tween80. It is possible that these additions and a potential fed-batch fermentation setup could further increase the yield of GABA.

5.1.2. Health benefits of GABA

GABA have a wide variety of different health benefits including hypotensive effect, it can act as a neurotransmitter and can aid diabetes, cancer and asthma [271].
The hypotensive effect of GABA is similar to that of ACE-inhibitory peptides, by inhibiting noradrenalin release which inhibits perivascular nerve stimulation and thereby facilitates a hypotensive effect [272]. Spontaneously hypertensive rats (SHR) and normotensive Wistar-Kyoto rats (WKY) were given GABA to investigate its blood pressure-lowering capabilities. This was given as a single dose of 0.5mg/kg and showed a significant lowering of the systolic blood pressure in SHR but not in WKY rats [272]. This was confirmed in the same two rat models in a later study dosing GABA either pure or in an enriched fermented milk product [273]. Here, a long-term dosage was also investigated and a significantly slower increase in blood pressure of both rat models was observed for those administered either GABA or GABA-enriched fermented milk, compared to controls [273]. Milk fermented with strain L. casei shirota and L. lactis product containing GABA was developed and tested in mildly hypertensive patients [233]. The blood pressure was significantly decreased in patients after 2 to 4 weeks and remained decreased through all 12 weeks [233].
Disruption in the GABA receptor expression has been associated with anxiety spectrum disorders and has also been shown to have a role in mood disorders like depression [274]. Administration of L. rhamnosus to mice modulated the GABA receptors, and mice showed a behaviour that was less anxious and reduced stress-related, and depressive behaviour compared to the control group [275]. This stress-reducing effect of GABA has also been demonstrated in humans through drinking GABA-enhanced water [276] and by ingestion of GABA-enriched chocolate [277].
By consuming a powdered preparation of GABA, an improvement in sleep was observed by reduced sleep latency as well as an increase in non-rapid eye movement sleep in healthy adults [278]. For a group of patients suffering from chronic fatigue, the ingestion of a GABA-enhanced drink before solving an arithmetic task resulted in reduced occupational fatigue afterwards [279]
A study has suggested GABA as a tool to prevent obesity induced by a high-fat diet. It was demonstrated that GABA improved oxidative stress and thyroid function and the treatment with GABA on high-fat diet mouse models prevented weight gain [280].
GABA also has potential as a therapeutic against diabetes and has shown an inducing effect on the secretion of insulin [281] and can even reverse established diabetes in a diabetic mouse model [282]. Based on the strong in vivo data of GABA on diabetes, the administration of a food product with GABA present serves as a promising tool in the treatment and prevention of diabetes.
Lastly, GABA could be used as an anti-cancer agent by having tumour-suppressing activity in lung adenocarcinoma cells [283] and inhibiting cell proliferation in colon cancer cells [284]. Mouse and human leukaemia cells as well as human cervical cancer cells were treated with germinated rice enhanced with GABA. Here, GABA had an inhibitory action on leukaemia cell proliferation and also showed a stimulatory action on cancer cell apoptosis [285].

5.2. Carotenoids

Carotenoids are bioactive molecules that are naturally occurring in most fruits and vegetables. They can be produced by a wide range of organisms such as plants, algae, fungi, yeast and bacteria. Humans, however, are unable to synthesise carotenoids and depend on uptake through the diet [230]. Intake of carotenoids is associated with many health benefits, primarily by exerting antioxidant activity [286]. Several carotenoids are produced industrially and can be used both as a source for fortification of foods and as colourants [287]. The majority of studies on the biotechnological production of carotenoids are from yeasts, with fewer reports of synthesis through bacterial production [288,289].

5.2.1. Production of carotenoids

The research conducted on the production of carotenoids by LAB is sparse as yeasts are preferred due to higher yields, however, some research has been conducted investigating this trait in LAB (Table 10). 158 different strains of LAB were screened for their ability to produce carotenoids and out of these only 36 produced the pigment. Specifically, strains belonging to L. plantarum, L. fermentum and P. acidilactici had this ability. All these strains did however produce carotenoids in low amounts, with a strain of L. fermentum yielding the highest amount of 765 µg/kg CDW [290].
Garrido-Fernández et. al. (2010) cultivated L plantarum in four different brands of MRS as well as two defined media and were able to obtain 54.55 mg/kg of cell dry weight in a defined media. The effect of length of cultivation was tested by sampling at 24H, 48H, 72H and 96H, but a decrease of carotenoid concentration in the broth was observed over time, and 24H was selected as the optimum cultivation time [291]. L. plantarum was also examined in another study that used a Plackett-Burman approach to media optimisation using date syrup as a carbon source which had a final maximum yield of 54.89 mg/kg of cell dry weight [292].
It has been found that the cultivation of LAB under aerobic conditions is essential for optimal carotenoid production as it increases the expression of genes in carotenoid biosynthesis [293].
A research group has investigated the co-culturing of LAB with the yeast R. rubra [294,295,296,297]. These studies however used R. rubra as the main carotenoid producer, while the LAB are added to the culture to create an optimal growth environment for R. rubra.
Table 10. Summary of carotenoid-producing strains and yields.
Table 10. Summary of carotenoid-producing strains and yields.
Microorganism(s) Fermentation Medium Yield Ref
L. fermentum Flask MRS 765 µg/kg CDW [290]
L. plantarum Flask Supplemented MRS 54.89 mg/kg CDW [292]
L. plantarum Flask Defined medium 54.55 mg/kg CDW [290]
L. casei
R.rubra 		Flask Supplemented whey ultrafiltrate 12.35 mg/ml [294]
L. delbrueckii. subsp. bulgaricus
S. thermophilus
R. rubra 		Flask Supplemented whey ultrafiltrate 13.09 mg/ml [295]
L. delbrueckii. subsp. bulgaricus
S. thermophilus
R. rubra 		Flask Supplemented whey ultrafiltrate 13.37 mg/L [296]
L. helveticus
R. glutinis 		Batch Supplemented whey ultrafiltrate 8.3 mg/L [297]

5.2.2. Health benefits of carotenoids

Carotenoids play an important role in human nutrition as they can act as a precursor for the synthesis of vitamin A [298]. Although vitamin A is naturally present in many food products such as dairy, fish, orange and yellow vegetables and leafy greens, deficiencies of vitamin A are still a prominent issue in some developing countries [299].
Low-density lipoprotein (LDL) is linked to the pathogenesis of atherosclerosis. Healthy adults consumed a carotenoid supplement in various concentrations, and it was found that a daily concentration over 3.6 mg of a carotenoid led to an inhibition of LDL oxidation, thereby having potential as a parameter for the prevention of atherosclerosis [300]. Carotenoid supplementation has also shown an effect on the improvement of lipid profiles. Non-obese subjects with mild hyperlipidaemia were given a dose of either 0, 6, 12 or 18 mg of carotenoids per day for 12 weeks. BMI and LDL levels remained unaffected, but triglyceride levels decreased significantly with doses of 12 and 18 mg/day and levels of high-density lipoprotein (HDL) increased significantly in doses of 6 and 12 mg/day [301]. Long-term supplementation of a carotenoid did however not show to impose any effects on the development of cardiovascular disease or mortality associated with cardiovascular disease [302,303].
In vitro and in vivo studies have indicated that carotenoids stimulate bone formation and bone cell proliferation while also having an inhibitory effect on bone resorption [304,305,306,307]. In human trials, the intake of carotenoids over a 4 year period was also associated with a beneficial effect on bone health and results showed a protective role of carotenoids for bone mineral density [308].
Human trials have demonstrated a positive effect of dietary supplementation of carotenoids in weight management and obesity [309]. Canas et al (2017) could report a decrease in the BMI z-score, waist-to-height ratio and subcutaneous adipose tissue in children with mild obesity over a period of 6 months of supplementation of a mixture of carotenoids. These results were concluded to be directly correlated with an increased concentration of serum β-carotene [310]. Similarly, in another study, healthy overweight adults were given a capsule containing carotenoids daily for 12 weeks. They observed a significant reduction in the BMI and the abdominal fat area [311].
A long-term study over 18 years with 4052 healthy participants receiving 50mg of beta carotene on alternate days or a placebo showed promising effects on cognitive function. A significant difference was observed for the global cognitive score as well as verbal memory scores for the group receiving beta-carotene. In addition, it was tested if there was an effect of shorter-term administration of 1 year by recruiting new subjects to either a treatment or placebo group, but here no significant difference between the two groups was observable [312]. It has been suggested that the antioxidant effect of carotenoids could have a preventative effect and act as a treatment for Alzheimer’s Disease [313], but a study has found no effect of carotenoids on the decreased risk of Alzheimer’s Disease and dementia [314].
The effects of carotenoid supplementation on the prevention of cancer show inconclusive results with some studies claiming a reduction of cases [315,316] while others observed no effect [317,318].

6. Conclusions

The introduction of novel functional products on the European Market can be a challenging process as claims related to health need to be scientifically substantiated and evaluated in a process that can be complicated for producers to navigate. This extensive framework of regulations does, however, simultaneously ensure trust from consumers in new food products.
LAB are an essential constituent of a wide range of fermented products which are already an integral part of the human diet. Here, they enhance the nutritional, organoleptic and functional properties of the products. Understanding the different bioactive ingredients such as vitamins, bacteriocins, bioactive peptides and bioactive compounds excreted during fermentation by LAB can aid in the targeted development of products with desired health claims. This includes the selection of appropriate strains, optimised media composition as well as selection of suitable bioprocess parameters.
Consumers are increasingly seeking products that offer additional health benefits to nutrition. Exploring the potential and understanding the production processes of the bioactive ingredients produced by LAB is therefore important as it can further drive forward the innovation and development of the functional food industry market.

Author Contributions

Conceptualization, H.M.S. and B.F.; writing—original draft preparation, H.M.S.; writing—review and editing, H.M.S., K.D.R., B.F., S.M., C.L., D.B. and G.M.; project administration, B.F., C.L. and D.B.; funding acquisition, B.F., C.L., and D.B. All authors have read and agreed to the published version of the manuscript.

Funding

This publication has emanated from research conducted with the financial support of Science Foundation Ireland (SFI), under grant number [20/FIP/PL/8940].

Institutional Review Board Statement

Not applicable.

Informed Consent Statement

Not applicable.

Data Availability Statement

Not applicable.

Conflicts of Interest

The authors declare no conflict of interest.

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Figure 1. Examples of functional dairy products including milk, yoghurt, cheese and milk powder (created with Bing Image Creator).
Figure 1. Examples of functional dairy products including milk, yoghurt, cheese and milk powder (created with Bing Image Creator).
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Figure 2. Total amount of dairy products sold in Europe in euros billions (€) from 2014-2023. The data include milk, yoghurt, dairy-based and soy-based desserts, cream, butter, and spreadable fats. The figure was made with data obtained from MarkeLine.
Figure 2. Total amount of dairy products sold in Europe in euros billions (€) from 2014-2023. The data include milk, yoghurt, dairy-based and soy-based desserts, cream, butter, and spreadable fats. The figure was made with data obtained from MarkeLine.
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Figure 3. Overview of health benefits related to consumption or usage of vitamins, bacteriocins, bioactive peptides and bioactive compounds.
Figure 3. Overview of health benefits related to consumption or usage of vitamins, bacteriocins, bioactive peptides and bioactive compounds.
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Table 3. Overview of cobalamin producing Propionibacteria.
Table 3. Overview of cobalamin producing Propionibacteria.
Microorganism(s) Fermentation Medium Yield Ref
P. acidipropionici 1 L fermentor Complex media 3.3 mg/L [72]
P. denitrificans 120 L Batch Complex media 177.49 µg/l [73]
P. denitrificans 120 L Batch Complex media 214.3 µg/mL [74]
P. freudenreichii 5 L fermentor Defined media 9.45 µg/mL [75]
P. freudenreichii Cell recycle system Complex media 24.93 µg/mL [76]
P. shermanii Flask Whey based medium 8.43 µg/l [77]
P. shermanii Flask Whey based medium 2.97 µg/l [78]
P. shermanii Flask Whey based medium 4.51 µg/l [79]
Table 4. Overview of riboflavin-producing microorganisms.
Table 4. Overview of riboflavin-producing microorganisms.
Microorganism(s) Fermentation Medium Yield Ref
L. acidophilus Flask Whey based medium 2.93 mg/L [97]
L. fermentum Flask CDM 1.2 mg/L [98]
L. fermentum Flask CDM 3.49 mg/L [99]
L. lactis Flask Whey based medium 2.61 mg/L [97]
L. plantarum Flask MRS 3.33 mg/L [100]
L. plantarum Flask Supplemented MRS 3.33 mg/L [101]
L. plantarum Flask CDM 5.72 mg/L [102]
Table 5. Overview of menaquinone-producing LAB.
Table 5. Overview of menaquinone-producing LAB.
Microorganism(s) Fermentation Medium Yield Ref
L. fermentum Flask Rogosa medium
Skim milk		 184 µg/L
63.93 µg/L		 [122]
L. lactis subsp. cremoris Flask Milk-based media 534 nmol/g of cells [123]
L. lactis subsp. lactis Flask Milk-based media 717 nmol/g of cells [123]
Leu. lactis Flask Milk-based media 173 nmol/g of cells [123]
P. freudenreichii 3 L fermentor Milk-based media 0.3 mM [124]
Table 7. Summary of ACEI peptide-producing LAB and their yields.
Table 7. Summary of ACEI peptide-producing LAB and their yields.
Microorganism(s) Fermentation Medium ACEI ability IC50 Ref
L. acidophilus Flask Skim milk-based media - 730 µg/mL [202]
L. brevis Flask MRS 79.03 1280 µg/mL [196]
L. brevis Flask Whey based media 64.7 1130 µg/mL [206]
L. casei Flask Skim milk-based media - 250 µg/mL [202]
L. casei Flask Skim milk-based media 100 [207]
L. casei Flask Goats milk-based media 34.3 - [208]
L. delbruckii subsp. bulgaricus Flask Skim milk-based media - 780 µg/mL [202]
L. helveticus Flask Whey based media 84.2 860 µg/mL
L. helveticus Flask Skim milk-based media - 1460 µg/mL [202]
L. helveticus Flask Skim milk-based media 67.18 - [209]
L. helveticus Flask Goats milk-based media 51.3 - [208]
L. paracasei Flask Whey based media 63.9 1130 µg/mL [206]
L. plantarum Flask MRS 84.0 65.53 µg/mL [196]
L. plantarum Flask Skim milk-based media - 910 µg/mL [202]
L. plantarum Flask Goats milk-based media 37.7 - [208]
L. rhamnosus Flask Skim milk-based media - 700 µg/mL [202]
L. rhamnosus Flask MRS 52.4 2130 µg/mL [196]
L. sakei Flask Skim milk-based media - 1220 µg/mL [202]
Lc. lactis Flask Skim milk-based media - 220 µg/mL [202]
E. durans Flask Skim milk-based media - 450 µg/mL [202]
E. faecium Flask MRS 55.4 70.5 µg/mL [196]
P. acidilactici Flask MRS 84.7 19.78 µg/mL [196]
P. pentosaceus Flask MRS 72.9 2070 µg/mL [196]
P. pentosaceus Flask Skim milk-based media - 780 µg/mL [202]
S. thermophilus Flask Skim milk-based media - 820 µg/mL [202]
Streptococcus thermophilus Flask Goats milk-based media 40 - [208]
Streptococcus thermophilus,
Lactobacillus casei,
Lactobacillus helveticus 		Flask Goats milk-based media 82 - [208]
S. thermophilus,
L. casei,
Lactobacillus plantarum 		Flask Goats milk-based media 43.3 - [208]
Table 8. Summary of antioxidant peptide-producing LAB and their reported activity.
Table 8. Summary of antioxidant peptide-producing LAB and their reported activity.
Microorganism(s) Fermentation Medium DPPH
(mg/ml) or %		 ABTS
(mg/ml)		 HFRSR
(%)		 Antimutagenic activity (% inhibition) Ref
S. thermophilus
L. bulgaricus 		Cups Skim milk-based media 2.23 mg/ml 2.43 mg/ml - 15.87 [221]
S. thermophilus
L. bulgaricus
L. acidophilus 		Cups Skim milk-based media 2.05 mg/ml 2.28
mg/ml		 - 18.35 [221]
S. thermophilus
L. bulgaricus
L. casei 		Cups Skim milk-based media 1.83
mg/ml		 1.91 mg/ml - 18.83 [221]
S. thermophilus
L. bulgaricus
L. paracasei 		Cups Skim milk-based media 1.82
mg/ml		 1.98 mg/ml - 18.48 [221]
S. thermophilus
L. bulgaricus
L. acidophilus
L. casei 		Cups Skim milk-based media 1.8
mg/ml		 1.73 mg/ml - 20.25 [221]
Cups Skim milk-based media 1.77
mg/ml		 1.8 mg/ml - 23.06 [221]
L. casei Flask Goat milk-based media 63.48 % - 88.01 - [222]
L. mesenteroides subsp. cremoris Flask Skim milk-based media - 0.7 nmol-1/mmol-1 - - [223]
L. lactis subsp. lactis Flask Skim milk-based media 0.15 nmol-1/mmol-1 - - [223]
L. acidophilus Flask Skim milk-based media - 0.6nmol-1/mmol-1 [223]
L. jensenii Flask Skim milk-based media - 0.6 nmol-1/mmol-1 - - [223]
L. helveticus Flask Skim milk-based media - 0.4 nmol-1/mmol-1 - - [223]
Table 9. Summary of GABA-producing strains and yields.
Table 9. Summary of GABA-producing strains and yields.
Microorganism(s) Fermentation Medium Yield Ref
L. acidophilus Flask Goats milk-based media 1.92 mg/kg [208]
L. brevis Packed bed reactor Defined media 55 mM [236]
L. brevis Batch Modified MRS 44.4 mg/ml [237]
L. brevis Fed-batch Defined media 1005.81 mM [238]
L. brevis Fed-batch Complex 526.33 mmol/L [239]
L. brevis Flask MRS + MSG 255 mM [240]
L. brevis Batch Defined media 205.8 g/L [241]
L. brevis Batch Defined media 62.5 g/L [242]
L. brevis Flask Supplemented MRS 265 mM [243]
L. brevis Entrapped cell Defined media + MSG, 223 mM [244]
L. brevis Flask Whey permeate-based media + MSG 553.5 mg/L [245]
L. brevis Flask MRS + MSG 2.5 g/L [246]
L. brevis
L. sakei 		Flask Skim milk-based media + MSG 22.41 mM [247]
L. buchneri Flask Modified MRS 251mM [248]
L. buchneri Flask MRS + MSG 4.4 g/L [249]
L. casei Flask Skim milk-based media 677.35 mg/kg [207]
L. casei Flask Goats milk-based media 1.65 mg/kg [208]
L. delbrueckii subsp. bulgaricus Flask Skim milk-based media 9 mg/kg [250]
L. helveticus Flask Skim milk-based media 165.11 mg/L [209]
L. helveticus Flask Goats milk-based media 0.06 mg/kg [208]
L. paracasei Flask Modified MRS 302 mM [251]
L. paracasei Flask Skim milk-based media 20 mg/kg [250]
L. paracasei and L. plantarum Flask Skim milk base dmedia 6.7 mg/100ml [252]
L. plantarum Flask Skim milk + MSG 629 mg/ml [253]
L. plantarum Flask Defined media + MSG 19.8 g/L [254]
L. plantarum Flask MRS 4.156 mg/L [255]
L. plantarum Flask MRS + MSG 821.24 mg/L [256]
L. plantarum Flask Skim milk basd media + MSG 314 mg/100g [257]
L. plantarum Flask MRS + MSG 7.15 mM [258]
L. plantarum Flask Grape must 4.85 mM [259]
L. plantarum Flask MRS + MSG 201.78 mg/L [260]
L. plantarum Flask Skim milk-based media 6 mg/kg [250]
L. plantarum Flask Skim milk + yeast extract 77.4 mg/kg [202]
L. plantarum Flask Goats milk 12.84 mg/kg [208]
L. plantarum and L. sakei Flask Whey based media 365.6 mg/100 ml [261]
L. rhamnosus Flask Complex media + MSG + PLP 187 mM [262]
L. sakei Batch MRS + MSG 265.3 mM [263]
L. sakei Batch MRS + MSG 217 mM [263]
S. salivarius subsp. thermophilus Flask Complex media 7984.75 mg/L [264]
S. thermophilus Flask Skim milk-based media + MSG 2.2 mg/ml [265]
S. thermophilus Flask Goats milk-based media 1.59 mg/kg [208]
S. thermophilus
L. brevis 		Flask Skim milk + MSG 314.97 mg/kg [266]
S. thermophilus,
L. casei,
L. helveticus 		Flask Goats milk-based media 5.79 mg/kg [208]
S. thermophilus,
L. casei,
L. plantarum 		Flask Goats milk-based media 30.86 mg/kg [208]
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