Lactococcus lactis

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Lactococcus lactis
Lactococcus lactis.jpg
Scientific classification OOjs UI icon edit-ltr.svg
Domain: Bacteria
Phylum: Bacillota
Class: Bacilli
Order: Lactobacillales
Family: Streptococcaceae
Genus: Lactococcus
Species:
L. lactis
Binomial name
Lactococcus lactis
(Lister 1873)
Schleifer et al. 1986
Subspecies

L. l. cremoris
L. l. hordniae
L. l. lactis
L. l. lactis bv. diacetylactis
L. l. tructae

Contents

Lactococcus lactis is a gram-positive bacterium used extensively in the production of buttermilk and cheese, [1] but has also become famous as the first genetically modified organism to be used alive for the treatment of human disease. [2] L. lactis cells are cocci that group in pairs and short chains, and, depending on growth conditions, appear ovoid with a typical length of 0.5 - 1.5  µm. L. lactis does not produce spores (nonsporulating) and are not motile (nonmotile). They have a homofermentative metabolism, meaning they produce lactic acid from sugars. They've also been reported to produce exclusive L-(+)-lactic acid. [3] However, [4] reported D-(−)-lactic acid can be produced when cultured at low pH. The capability to produce lactic acid is one of the reasons why L. lactis is one of the most important microorganisms in the dairy industry. [5] Based on its history in food fermentation, L. lactis has generally recognized as safe (GRAS) status, [6] [7] with few case reports of it being an opportunistic pathogen. [8] [9] [10]

Lactococcus lactis is of crucial importance for manufacturing dairy products, such as buttermilk and cheeses. When L. lactis ssp. lactis is added to milk, the bacterium uses enzymes to produce energy molecules (ATP), from lactose. The byproduct of ATP energy production is lactic acid. The lactic acid produced by the bacterium curdles the milk, which then separates to form curds that are used to produce cheese. [11] Other uses that have been reported for this bacterium include the production of pickled vegetables, beer or wine, some breads, and other fermented foodstuffs like soymilk kefir, buttermilk, and others. [12] L. lactis is one of the best characterized low GC Gram positive bacteria with detailed knowledge on genetics, metabolism and biodiversity. [13] [14]

L. lactis is mainly isolated from either the dairy environment, or plant material. [15] [16] [17] Dairy isolates are suggested to have evolved from plant isolates through a process in which genes without benefit in the rich milk were lost or downregulated. [14] [18] This process, called genome erosion or reductive evolution, has been described in several other lactic acid bacteria. [19] [20] The proposed transition from the plant to the dairy environment was reproduced in the laboratory through experimental evolution of a plant isolate that was cultivated in milk for a prolonged period. Consistent with the results from comparative genomics (see references above), this resulted in L. lactis losing or downregulating genes that are dispensable in milk and the upregulation of peptide transport. [21]

Hundreds of novel small RNAs were identified by Meulen et al. in the genome of L. lactis MG1363. One of them, LLnc147, was shown to be involved in carbon uptake and metabolism. [22]

Cheese production

L. lactis subsp. lactis (formerly Streptococcus lactis) [23] is used in the early stages for the production of many cheeses, including brie, camembert, Cheddar, Colby, Gruyère, Parmesan, and Roquefort. [24] The state Assembly of Wisconsin, also the number one cheese-producing state in the United States, voted in 2010 to name this bacterium as the official state microbe; it would have been the first and only such designation by a state legislature in the nation, [25] however the legislation was not adopted by the Senate. [26] The legislation was introduced in November 2009 as Assembly Bill 556 by Representatives Hebl, Vruwink, Williams, Pasch, Danou, and Fields; it was cosponsored by Senator Taylor. [27] The bill passed the Assembly on May 15, 2010, and was dropped by the Senate on April 28. [27]

The use of L. lactis in dairy factories is not without issues. Bacteriophages specific to L. lactis cause significant economic losses each year by preventing the bacteria from fully metabolizing the milk substrate. [24] Several epidemiologic studies showed the phages mainly responsible for these losses are from the species 936 , c2, and P335 (all from the family Siphoviridae). [28]

Therapeutic benefits

The feasibility of using lactic acid bacteria (LAB) as functional protein delivery vectors has been widely investigated. [29] Lactococcus lactis has been demonstrated to be a promising candidate for the delivery of functional proteins because of its noninvasive and nonpathogenic characteristics. [30] Many different expression systems of L. lactis have been developed and used for heterologous protein expression. [31] [32] [33]

Lactose fermentation In one study that sought to prove that some fermentation produced by L. lactis can hinder motility in pathogenic bacteria, the motilities of Pseudomonas , Vibrio , and Leptospira strains were severely disrupted by lactose utilization on the part of L. lactis. [34] Using flagellar Salmonella as the experimental group, the research team found that a product of lactose fermentation is the cause of motility impairment in Salmonella . It is suggested that the L. lactis supernatant mainly affects Salmonella motility through disruption of flagellar rotation rather than through irreversible damage to morphology and physiology. Lactose fermentation by L. lactis produces acetate that reduces the intracellular pH of Salmonella, which in turn slows the rotation of their flagella. [35] [36] These results highlight the potential use of L. lactis for preventing infections by multiple bacterial species.

Secretion of Interleukin-10 Genetically engineered L. lactis can secrete the cytokine interleukin-10 (IL-10) for the treatment of inflammatory bowel diseases (IBD), since IL-10 has a central role in downregulating inflammatory cascades [37] and matrix metalloproteinases. [38] A study by Lothar Steidler and Wolfgang Hans [39] shows that in situ synthesis of IL-10 by genetically engineered L. lactis requires much lower doses than systemic treatments like antibodies to tumor necrosis factor (TNF) or recombinant IL-10.

The authors propose two possible routes by which IL-10 can reach its therapeutic target. Genetically engineered L. lactis may produce murine IL-10 in the lumen, and the protein may diffuse to responsive cells in the epithelium or the lamina propria. Another route involves L. lactis being taken up by M cells because of its bacterial size and shape, and the major part of the effect may be due to recombinant IL-10 production in situ in intestinal lymphoid tissue. Both routes may involve paracellular transport mechanisms that are enhanced in inflammation. After transport, IL-10 may directly downregulate inflammation. In principle, this method may be useful for intestinal delivery of other protein therapeutics that are unstable or difficult to produce in large quantities and an alternative to the systemic treatment of IBD.[ citation needed ]

Tumor-suppressor through Tumor metastasis-inhibiting peptide KISS1 Another study, led by Zhang B, created a L. lactis strain that maintains a plasmid containing a tumor metastasis-inhibiting peptide known as KISS1. [40] L. lactis NZ9000 was demonstrated to be a cell factory for the secretion of biologically active KiSS1 protein, exerting inhibition effects on human colorectal cancer HT-29 cells.

KiSS1 secreted from recombinant L. lactis strain effectively downregulated the expression of Matrix metalloproteinases (MMP-9), a crucial key in the invasion, metastasis, and regulation of the signaling pathways controlling tumor cell growth, survival, invasion, inflammation, and angiogenesis. [41] [42] [43] The reason for this is that KiSS1 expressed in L. lactis activates the MAPK pathway via GPR54 signaling, suppressing NFκB binding to the MMP-9 promoter and thus downregulating MMP-9 expression. [44] This, in turn, reduces the survival rate, inhibits metastasis, and induces dormancy of cancer cells.

In addition, it was demonstrated that tumor growth can be inhibited by the LAB strain itself, [45] [46] due to the ability of LAB to produce exopolysaccharides. [47] [48] This study shows that L. lactis NZ9000 can inhibit HT-29 proliferation and induce cell apoptosis by itself. The success of this strain's construction helped to inhibit migration and expansion of cancer cells, showing that the secretion properties of L. lactis of this particular peptide may serve as a new tool for cancer therapy in the future. [49]

Related Research Articles

<span class="mw-page-title-main">Lactic acid</span> Group of stereoisomers

Lactic acid is an organic acid. It has the molecular formula CH3CH(OH)COOH. It is white in the solid state and it is miscible with water. When in the dissolved state, it forms a colorless solution. Production includes both artificial synthesis as well as natural sources. Lactic acid is an alpha-hydroxy acid (AHA) due to the presence of a hydroxyl group adjacent to the carboxyl group. It is used as a synthetic intermediate in many organic synthesis industries and in various biochemical industries. The conjugate base of lactic acid is called lactate. The name of the derived acyl group is lactoyl.

<span class="mw-page-title-main">Lactic acid fermentation</span> Series of interconnected biochemical reactions

Lactic acid fermentation is a metabolic process by which glucose or other six-carbon sugars are converted into cellular energy and the metabolite lactate, which is lactic acid in solution. It is an anaerobic fermentation reaction that occurs in some bacteria and animal cells, such as muscle cells.

<i>Lactococcus</i> Genus of bacteria

Lactococcus is a genus of lactic acid bacteria that were formerly included in the genus Streptococcus Group N1. They are known as homofermenters meaning that they produce a single product, lactic acid in this case, as the major or only product of glucose fermentation. Their homofermentative character can be altered by adjusting environmental conditions such as pH, glucose concentration, and nutrient limitation. They are gram-positive, catalase-negative, non-motile cocci that are found singly, in pairs, or in chains. The genus contains strains known to grow at or below 7˚C.

<i>Lactobacillus acidophilus</i> Species of bacterium

Lactobacillus acidophilus is a rod-shaped, Gram-positive, homofermentative, anaerobic microbe first isolated from infant feces in the year 1900. The species is most commonly found in humans, specifically the gastrointestinal tract, oral cavity, and vagina, as well as various fermented foods such as fermented milk or yogurt. The species most readily grows at low pH levels, and has an optimum growth temperature of 37 °C. Certain strains of L. acidophilus show strong probiotic effects, and are commercially used in dairy production. The genome of L. acidophilus has been sequenced.

Lactiplantibacillus plantarum is a widespread member of the genus Lactiplantibacillus and commonly found in many fermented food products as well as anaerobic plant matter. L. plantarum was first isolated from saliva. Based on its ability to temporarily persist in plants, the insect intestine and in the intestinal tract of vertebrate animals, it was designated as a nomadic organism. L. plantarum is Gram positive, bacilli shaped bacterium. L. plantarum cells are rods with rounded ends, straight, generally 0.9–1.2 μm wide and 3–8 μm long, occurring singly, in pairs or in short chains. L. plantarum has one of the largest genomes known among the lactic acid bacteria and is a very flexible and versatile species. It is estimated to grow between pH 3.4 and 8.8. Lactiplantibacillus plantarum can grow in the temperature range 12 °C to 40 °C. The viable counts of the "L. plantarum" stored at refrigerated condition (4 °C) remained high, while a considerable reduction in the counts was observed stored at room temperature.

<span class="mw-page-title-main">Viili</span> Mesophilic fermented milk product

Viili (Finnish) is a mesophilic fermented milk product found in the Nordic countries, particularly Finland. Viili is similar to yoghurt or kefir, but when left unmixed, its texture is malleable, or "long". The metabolism of the bacteria used in the fermentation also gives viili a slightly different taste.

<i>Lacticaseibacillus casei</i> Species of bacterium

Lacticaseibacillus casei is an organism that belongs to the largest genus in the family Lactobacillaceae, a lactic acid bacteria (LAB), that was previously classified as Lactobacillus casei. This bacteria has been identified as facultatively anaerobic or microaerophilic, acid-tolerant, non-spore-forming bacteria.

<span class="mw-page-title-main">Lactic acid bacteria</span> Order of bacteria

Lactobacillales are an order of gram-positive, low-GC, acid-tolerant, generally nonsporulating, nonrespiring, either rod-shaped (bacilli) or spherical (cocci) bacteria that share common metabolic and physiological characteristics. These bacteria, usually found in decomposing plants and milk products, produce lactic acid as the major metabolic end product of carbohydrate fermentation, giving them the common name lactic acid bacteria (LAB).

<span class="mw-page-title-main">Lactobacillaceae</span> Family of bacteria

The Lactobacillaceae are a family of lactic acid bacteria. It is the only family in the lactic acid bacteria which includes homofermentative and heterofermentative organisms; in the Lactobacillaceae, the pathway used for hexose fermentation is a genus-specific trait. Lactobacillaceae include the homofermentative lactobacilli Lactobacillus, Holzapfelia, Amylolactobacillus, Bombilactobacillus, Companilactobacillus, Lapidilactobacillus, Agrilactobacillus, Schleiferilactobacillus, Loigolactobacillus, Lacticaseibacillus, Latilactobacillus, Dellaglioa, Liquorilactobacillus, Ligilactobacillus, and Lactiplantibacillus; the heterofermentative lactobacilli Furfurilactobacillus, Paucilactobacillus, Limosilactobacillus, Fructilactobacillus, Acetilactobacillus, Apilactobacillus, Levilactobacillus, Secundilactobacillus, and Lentilactobacillus, which were previously classified in the genus Lactobacillus; and the heterofermentative genera Convivina, Fructobacillus, Leuconostoc, Oenococcus, and Weissella which were previously classified in the Leuconostocaceae.

Leuconostoc mesenteroides is a species of lactic acid bacteria associated with fermentation, under conditions of salinity and low temperatures. In some cases of vegetable and food storage, it was associated with pathogenicity. L. mesenteroides is approximately 0.5-0.7 µm in diameter and has a length of 0.7-1.2 µm, producing small grayish colonies that are typically less than 1.0 mm in diameter. It is facultatively anaerobic, Gram-positive, non-motile, non-sporogenous, and spherical. It often forms lenticular coccoid cells in pairs and chains, however, it can occasionally form short rods with rounded ends in long chains, as its shape can differ depending on what media the species is grown on. L. mesenteroides grows best at 30 °C, but can survive in temperatures ranging from 10 °C to 30 °C. Its optimum pH is 5.5, but can still show growth in pH of 4.5-7.0.

<i>Streptococcus thermophilus</i> Species of bacterium

Streptococcus thermophilus formerly known as Streptococcus salivarius subsp. thermophilus is a gram-positive bacterium, and a fermentative facultative anaerobe, of the viridans group. It tests negative for cytochrome, oxidase, and catalase, and positive for alpha-hemolytic activity. It is non-motile and does not form endospores. S. thermophilus is fimbriated.

<span class="mw-page-title-main">Branched-chain amino acid aminotransferase</span> Aminotransferase enzyme

Branched-chain amino acid aminotransferase (BCAT), also known as branched-chain amino acid transaminase, is an aminotransferase enzyme (EC 2.6.1.42) which acts upon branched-chain amino acids (BCAAs). It is encoded by the BCAT2 gene in humans. The BCAT enzyme catalyzes the conversion of BCAAs and α-ketoglutarate into branched chain α-keto acids and glutamate.

<span class="mw-page-title-main">MMP28</span> Protein-coding gene in the species Homo sapiens

Matrix metalloproteinase 28 also known as epilysin is an enzyme that in humans is encoded by the MMP28 gene.

<span class="mw-page-title-main">MMP8</span> Protein-coding gene in the species Homo sapiens

Neutrophil collagenase, also known as matrix metalloproteinase-8 (MMP-8) or PMNL collagenase (MNL-CL), is a collagen cleaving enzyme which is present in the connective tissue of most mammals. In humans, the MMP-8 protein is encoded by the MMP8 gene. The gene is part of a cluster of MMP genes which localize to chromosome 11q22.3. Most MMP's are secreted as inactive proproteins which are activated when cleaved by extracellular proteinases. However, the enzyme encoded by this gene is stored in secondary granules within neutrophils and is activated by autolytic cleavage.

<span class="mw-page-title-main">Kefir</span> Fermented milk drink made from kefir grains

Kefir is a fermented milk drink similar to a thin yogurt or ayran that is made from kefir grains, a specific type of mesophilic symbiotic culture. It is prepared by inoculating the milk of cows, goats, or sheep with kefir grains.

<span class="mw-page-title-main">Genetically modified bacteria</span> First organisms to be modified in the laboratory

Genetically modified bacteria were the first organisms to be modified in the laboratory, due to their simple genetics. These organisms are now used for several purposes, and are particularly important in producing large amounts of pure human proteins for use in medicine.

<i>Lactobacillus delbrueckii</i> Species of bacterium

Lactobacillus delbrueckii is a species of bacteria in the family Lactobacillaceae. It is part of the microbiota of the lower reproductive tract of women.

<span class="mw-page-title-main">Microbial drug delivery</span>

Microbial drug delivery is an emerging form of drug administration characterized by the use of commensal microbes that have been genetically modified to produce medications for chronic diseases in humans. Only proteinaceous drugs can be produced by microbes, as DNA encodes for protein. Research into microbial drug delivery refers to this route of administration as topical, since the microbes release the drug directly to the surface of affected tissues, namely the gastrointestinal (GI) epithelium. Microbial drug delivery is not currently used as a standard route of drug administration due to its experimental nature. During clinical trials, it has been used to treat forms of inflammatory bowel disease (IBD). The most prominently studied vehicles of microbial drug administration are the bacterial species, Lactococcus lactis and Bacteroides ovatus.

<i>Zygosaccharomyces rouxii</i> Species of yeast

Zygosaccharomyces rouxii is a species of yeast in the genus Zygosaccharomyces. Initially described as Saccharomyces rouxii by Boutroux in 1883, it was then moved to the genus Zygosaccharomyces in the work of Barnett et al. It is remarkably tolerant of high concentrations of sugar or salt, making it a spoilage agent of otherwise stable foods, but also present in fermentation of products such as soy sauce or balsamic vinegar.

Leuconostoc lactis is a species of lactic acid bacteria that performs fermentation in acidic conditions, like those found in dairy products such as cheese and yogurt, and tend to culture best at moderate temperatures around 30°C. L. lactis typically produces volatile butter-like compounds that are typically used in fermented dairy products, as well as dextran-like exopolysaccharide in sourdough.

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