Lactobacillus plantarum HEAL19 - Probi plantarum HEAL19 For further information please contact Probi AB who owns the commercial rights 1 Lactobacillus plantarum HEAL19 CONTENT Consumption

Professor emeritus Göran Molin, Dept. Food Technology, Engineering and Nutrition, Lund University 2015-10-29

Lactobacillus plantarum HEAL19 For further information please contact Probi AB who owns the commercial rights http://probi.se/en

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Lactobacillus plantarum HEAL19

CONTENT

Consumption of live lactic acid bacteria (probiotics) – p. 2

Functional groups and scientifically based taxa – p. 3

Lactic acid bacteria – p. 3

The species Lactobacillus plantarum – p. 4

The bacterial strain Lactobacillus plantarum HEAL19 – p. 5

Tannin degradation – p. 7

Health effects – p. 8

Animal experimental models – p. 8

Fermentation in the gut – p. 8

Body weight – p. 8

Blood pressure – p. 9

Insulin resistance – p. 9

Colitis – p. 9

Liver injury – p. 10

Multiple sclerosis – p. 10

Oxidative stress – p. 10

Interaction with green tea – p. 11

Protection from cortical bone loss – p. 11

Human trials – p. 12

Recovery after oral administration – p. 12

Incorporated in a health promoting diet – p. 12

Phagocytic activity – p. 12

References – p. 13

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Consumption of live lactic acid bacteria

Consumption of live lactic acid bacteria (LAB), included in fermented foods,

has been a regular part of the human food intake for a long time. In fact, there

are archaeological signs that humankind has used this technique from the

beginning of time; it was presumably invented 1.5 million years ago by the

early humanoids (Leakey 1993; Leakey 1995). Thus, humans have in this way

consumed large numbers of live LAB throughout their entire history.

Fermentation is the simplest and often the safest way to preserve food, and

before the Industrial Revolution, fermentation was applied just as much in

Europe as it still is in many rural areas of the World. Thus, it could very well

be that the human digestive tract evolved to adapt to a more or less daily

supply of live LAB. This supply of live LAB ceased in many industrialized

countries during the twentieth century, which eventually may have led to

increased frequency of gastro-intestinal (GI) and immunological dysfunctions

in urbanised humans.

When beneficial effects of certain types of live bacteria have been discussed,

these types of bacteria have been gradually called “probiotics”. The original

concept of probiotics implies that the balance between beneficial and harmful

bacteria in the microbiota of the GI-tract can be positively affected by eating

the right type of live microorganisms (Parker 1974; Fuller 1989). However, the

concept of probiotics is today used more generally for describing live bacteria

that after ingestion, exercise health beneficial effects beyond conventional

nutrition. It is presupposed that these health beneficial effects have been

scientifically proved.

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Functional groups and taxonomically based taxa

Lactic acid bacteria

The bacteria performing the conversion of carbohydrates to carboxylic acids,

mainly lactic acid in traditional fermented foods, are called lactic acid bacteria

(LAB). Food microbiologists used the term early, and 1919 the Danish

bacteriologist Orla Jensen tried to define key features of LAB, unaware of the

fact that LAB is not forming a systematically defined group based on

evolutionary relationships; instead it can be regarded as a functional group

used by food microbiologists, aiming at those bacteria that occur and multiply

spontaneously in traditional lactic acid fermented foods. Furthermore, it is

understood that LAB are harmless to human health. Already 2002, it was

shown in meta-analyses of published clinical trials that different kind of LAB

can be used to prevent antibiotic associated diarrhoea (D’Souza et al. 2002)

and shorten the duration of acute diarrhoeal illness in children (Huang et al. 2002).

From the taxonomic point of view, LAB means a relatively wide variety of

different taxonomically based groups (taxa). The only absolute condition for

organisms involved in lactic acid fermentation of food must be that the

bacteria mainly produce lactic acid and that they are harmless to consume in

high numbers, even for consumers with underlying sicknesses that may have

weaken their immunological defence. The different kind of lactic acid

producing bacteria frequently occurring in high numbers in traditional,

spontaneously fermented foods belong to genera as Lactobacillus, Pediococcus,

Weissella, Leuconostoc, Oenococcus, Lactococcus, and the species

Streptococcus thermophilus (and similar species).

The genera Lactobacillus and Pediococcus belong to the family

Lactobacillaceae which also includes the relatively new genera

Paralactobacillus and Sharpea. They can all be included in the trivial

expression "lactobacilli”.

Leuconostoc, Weissella and Oenococcus belong to the family Leuconostocaceae

together with the genus Fructobacillus.

Lactococcus and S. thermophilus have from the phylogenetic point of view

relatively little in common with Lactobacillaceae and Leuconostocaceae even if

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they all are included in the order of Lactobacillales.

The species Lactobacillus plantarum

L. plantarum is one bacterial species in the huge and relatively diverse genus

of Lactobacillus, which comprises about 90 validly named species and

subspecies. By tradition, the Lactobacillus spp. have been divided into three

functional groups depending on their fermentation abilities; the obligate

homofermentatives (Group I), the facultative heterofermentatives (Group II)

and the obligate heterofermentatives (Group III) (Kandler and Weiss 1986).

Group I ferment hexoses exclusively to lactic acid, and can't ferment gluconate

or pentoses, while Group II also ferments hexoses to lactic acid but is

additionally able to ferment pentoses and/or gluconate. Group III ferments

hexoses to lactic acid, acetic acid and/or ethanol and carbon dioxide. L. plantarum is facultatively heterofermentative. The type strain of L. plantarum

is ATCC 14917T (Kandler and Weiss 1986).

L. plantarum differs from many other Lactobacillus spp. in the following

points:

1) L. plantarum has a relatively large genome in comparison with many other

Lactobacillus spp. This indicates an adaptive ability for many different

conditions (Kleerebezem et al. 2003).

2) L. plantarum can ferment many different carbohydrates.

3) L. plantarum has a high growth requirement for manganese and can

accumulate high intercellular levels of manganese (Archibald and Fridovich

1981b). Manganese provides a defence for L. plantarum against oxygen

toxicity by the reduction of oxygen free radicals to hydrogen peroxide (H2O2;

Archibald and Fridovich 1981a). The produced H2O2 can then be converted to

oxygen (O2) and water by manganese cofactored pseudocatalase (Kono and

Fridovich 1983a, 1983b).

4) L. plantarum have a high tolerance to low pH (Daeschel and Nes 1995). The

fact that L. plantarum frequently predominate in spontaneously, lactic acid

fermented foods where the final pH usually is below 4.0, and also can survive

the passage through the acid conditions of the human stomach (Johansson et al. 1993), points to the high resistance to acid conditions.

5) L. plantarum can possess tannase activity (Osawa et al. 2000; Vaquero et al. 2004) and are also able to metabolise phenolic acids (Barthelmebs et al. 2000;

Barthelmebs et al. 2001).

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L. plantarum frequently occurs and multiply spontaneously to high numbers

in most lactic acid fermented foods, especially when the foods are based on

plant material, for example, in brined olives (Fernández Gonzalez et al.1993),

capers (caper berries; Pulido et al. 2005), sauerkraut (Dedicatoria et al.1981;

Plengvidhya et al. 2007), salted gherkins (McDonald et al. 1993), sour-dough

(Lönner and Ahrné 1995), Nigerian ogi (made from maize or sorghum)

(Johansson 1995a), Ethiopian kocho (made from starch from Ensete ventricosum) (Gashe 1985; Nigatu 1998), Ethiopian sour-dough made out of tef

(Eragrostis tef) (Gashe 1987; Nigatu 1998) and cassava (Oyewole and Odunfa

1990; Moorthy and Mathew 1998). L. plantarum also occurs in grape juice and

wine (Vaquero et al. 2004). Thus, it is obvious that individuals consuming

traditionally fermented products of plant origin that haven’t been heat-treated

also consume large amounts of live L. plantarum. Not surprisingly, L. plantarum frequently occurs in the human GI-tract, from the mouth to the

rectum (Molin et al. 1993; Ahrné et al. 1998).

In order to get an idea how humans acquire immune tolerance against

harmless, food-associated bacteria, van Baarlen et al. (2009) studied the

stimulating effect of Lactobacillus plantarum (strain WCFS1) on the immune

system of adult, healthy volunteers in a randomized double-blind placebo-

controlled cross-over study. The subjects ingested either live or heat-killed L. plantarum. The expression profiles in biopsies taken from the intestinal

duodenal mucosa were analyzed using whole-genome microarrays and by

biological pathway reconstructions. The expression profiles displayed

differences in modulation of NF-kappaB-dependent pathways, notably after

consumption of live L. plantarum. In other words, it was seen that the mucosal

gene expression patterns and cellular pathways correlated with the

establishment of immune tolerance after consumption of live L. plantarum

(van Baarlen et al. 2009). This demonstrates a close relationship between L. plantarum and the immune-affected physiology of humans.

Furthermore, genotyping of twenty different strains of L. plantarum from

various sources have been assessed by microarrays containing a subset of

small genomic fragments from the strain, L. plantarum WCFS1 (Molenaar et al. 2005). It was shown that genes involved in sugar transport and catabolism

were highly variable between strains while those involved in biosynthesis or

degradation of structural compounds like proteins, lipids and DNA were

conserved (Molenaar et al. 2005).

The bacterial strain Lactobacillus plantarum HEAL19

L. plantarum HEAL19 (= DSM 15313 = 52A) has been isolated from the

gastro-intestinal (GI) mucosa of a healthy human. HEAL stands for “Human

Eatable Abdominal Lactobacillus” and DSM stands for Deutsche Sammlung

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von Mikroorganismen. The latter is the label for the international culture

collection, German collection of microorganisms and cell cultures

[http://www.dsmz.de].

L. plantarum strain HEAL19 can be defined and identified by restriction

endonculease analysis (REA) of total chromosomal DNA, with the use of

relatively frequently cutting restriction enzymes such as EcoRI and ClaI, and

traditional agarose gel electrophoresis (Johansson et al. 1995b). L. plantarum

HEAL19 can in this way easily be separated from other L. plantarum strains,

e.g. L. plantarum 299; L. plantarum 299v, L. plantarum HEAL9 and L. plantarum HEAL99.

L. plantarum HEAL19 has been selected on the basis of its high tannase

activity and the pronounced ability to attach to human mucosa cells in vitro. L. plantarum HEAL19 has also a strong tendency of auto-agglutination.

In comparison with the well known probiotic strain L. plantarum 299v (=DSM

9843), L. plantarum HEAL19 have higher cell-binding capacity in vitro and

higher tannase activity, but it lack the mannose-sensitive adhesion of L. plantarum 299v (Rask et al. 2013).

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Tannin degradation

Polyphenols or phenolics are molecules with an aromatic ring bearing one or

more hydroxyl groups. Tannins are polyphenols and they are known as anti-

nutrients, i.e. they decrease the efficiency of the body to convert digested

nutrients to new body constituents. Traditionally, tannins have been defined

as water-soluble phenolics that can precipitate proteins from aqueous solution.

There are two classes of tannins, the hydrolysable tannins, deriving from gallic

acid and ellagic acid, and the condensed tannins, i.e. proanthocyanidins, which

are oligomers and polymers of flavanols.

Tannins and other polyphenols are secondary metabolites of plants and more

than 8 000 different phenolics isolated from plants have been described (Bravo

1998; Ross and Kasum 2002). Phenolics are involved in plant growth and

reproduction and provide protection for the plant from ultraviolet radiation,

oxidative stress and pathogens (Ross and Kasum, 2002). Tannins inhibit the

growth of a number of micro-organisms and are often resistant to microbial

degradation (Chung et al. 1998). Moulds and yeasts and some aerobic bacteria

are usually best fitted to degrade tannins but also anaerobic degradation

occurs, e.g. in the intestinal tract (Bhat et al. (1998). The anaerobic breakdown

products of polyphenols in the digestive tract can have health beneficial effects

(Bhat et al. 1998). Such breakdown compounds are, for example, derivates of

phenylpropionic or phenylacetic acids (Bhat et al. 1998). When absorbed in the

digestive tract, these phenolic compounds can have anti-inflammatory effects.

Polyphenols can also have antimicrobial capacities in the digestive tract but

the susceptibility differs between different types of microorganisms and

between different phenolics.

L. plantarum possesses the enzyme tannin acylhydrolase (tannase) which

enable L. plantarum to degrade hydrolyzable tannins and tannic acid, thereby

producing gallic acid and the antioxidant pyrogallol (Osawa et al, 2000;

Vaquero et al. 2004). Hydrolysable tannins are composed of esters of gallic acid

or ellagic acid with a sugar moiety, usually glucose, and may be hydrolysed

into monomeric products.

L. plantarum also have phenolic acid decarboxylase enzymes that can

transform phenolic acids into their vinyl derivates and phenylpropionic acids

(Barthelmebs et al, 2000; Barthelmebs et al. 2001; Rodríguez et al, 2009).

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Health effects

Animal experimental models

Fermentation in the gut

L. plantarum HEAL19 together with Lactobacillus crispatus DSM 16743 and

L. gasseri DSM16737, and with or without blueberry husks, were given to

healthy rats in metabolic cages (Bränning et al. 2009). The dietary fibres of

blueberry husks were fermented to 61% in colon, and the elevated faecal

excretion of fibre and protein contributed to a high faecal bulking capacity. The

supplement of the mixture of Lactobacillus strains lowered the total caecal

amount of carboxylic acids when added to blueberry husks, while the

concentration of propionic acid increased. Administrating the Lactobacillus

supplement resulted in an increase in the median viable counts of lactobacilli.

L. plantarum HEAL19 was recovered from the caecal mucosa in rats fed the

Lactobacillus strains, while L. crispatus DSM 16743 and L. gasseri DSM

16737 were left undetected. Thus, as it seems L. plantarum HEAL19 became

the far most dominant Lactobacillus strain in the rat gut after administration

(Bränning et al. 2009).

Rats fed blackcurrant in the diet got a higher caecal pool of short-chain fatty

acids than rats fed blackberries or raspberries (Jacobsdottir et al. 2013).

Furthermore, anthocyanins were detected in the urine after consumption of

blackcurrants but not from the other berries. When L. plantarum HEAL19 was

added to the blackcurrant supplemented diet, the total amount of short-chain

fatty-acids in distal colon increased, and no anthocyanins were any longer

detected in the urine (Jacobsdottir et al. 2013). It seems as L. plantarum

HEAL19 enhanced the rat’s capability to metabolize anthochyanins.

Body weight

Long-term effects of a high-energy-dense diet on weight gain, fattening and the

gut microbiota have been followed in rats. Since the mother’s dietary habits

can influence offspring physiology, dietary regimens started with the dams at

pregnancy and throughout lactation and continued with the offspring for six

months (Karlsson et al. 2011). When the high-energy-dense diet throughout

the period had been supplemented with live L. plantarum HEAL19 the weight

gain was reduced, and there was a tendency towards a more diverse GI-

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microbiota (Karlsson et al. 2011).

Blood pressure

With the aim to examine the anti-hypertensive capacity

of two food supplements, combining fermented blueberries and Lactobacillus plantarum DSM 15313, rats were divided into groups of nine each (Lazou

Ahrén et al. 2014). Some of the groups were given NG-nitro-L-arginine methyl

ester (L-NAME) in the drinking water to induce a hypertensive state, and

some were untreated (healthy rats). Two fermented blueberry products with L. plantaum HEAL19 and different content of phenolic acids were tested, and

each rat received 2 g products per day for 4 weeks. Healthy rats consuming

the fermented blueberries with L. plantarum HEAL19 showed a significant

reduction in blood pressure, and a change in gut microbiota. In rats with L-

NAME induced hypertension, there was a significant reduction of the blood

pressure after two weeks. In conclusion, blueberries fermented with L. plantarum HEAL19 possessed anti-hypertensive properties (Lazou Ahrén et al. 2014).

Insulin resistance

With the objective to evaluate the metabolic effects of oral supplement with L. plantarum HEAL19 to high-fat diet, mice were fed high-fat diet for 20 weeks,

after which the high-fat diet had induced an insulin-resistant state (Andersson

et al. 2010). Fasting plasma glucose levels were lower in mice fed L. plantarum

HEAL19, whereas insulin and lipids were unchanged in the control. An oral

glucose tolerance test showed that mice fed L. plantarum HEAL19 had a

significantly lower insulin release compared to control mice, although the rate

of glucose clearance did not differ. It was suggested that L. plantarum

HEAL19 has anti-diabetic properties when fed together with a high-fat diet

(Andersson et al. 2010).

Colitis

Treatment with L. plantarum HEAL19 attenuated the severity of Dextran

Sulphate Sodium (DSS) induced colitis (Osman et al. 2008). Disease activity

index was significantly lower in treated rats compared to a colitis control. Also

the inflammatory marker myeloperoxidase (MPO) and the bacterial

translocation to the liver and the mesenteric lymph-nods decreased (Osman et al. 2008). Orally administrated L. plantarum HEAL19 could be found in high

numbers in caecum also when the animals had eaten large doses of blueberry

(Osman et al. 2008).

L. plantarum HEAL19 together with L. gasseri DSM16737 and

Bifidobacterium infantis DSM 16737, and with or without blueberry husks,

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were given to rats subjected to long-term, cyclic treatment with dextran

sulphate sodium (DSS) (Håkansson et al. 2010). The probiotic mixture

decreased faecal viable count of Enteobacteriaceae, mitigated hepatic injuries

by decreasing parenchymal infiltration an incidence of stasis and translocation

(Håkansson et al. 2010). However, the contribution of each individual strain

was not be evaluated.

Liver injury

Pre-treatment with L. plantarum HEAL19 in a rat liver injury model

mitigated the liver injury (decreased levels of bilirubin in the blood) and

inflammation (decreased TNF-alfa, IL-1beta and myeloperoxidase, and

increased glutathione values in the liver) (Osman et al. 2007). Also the

translocation of gut bacteria to the liver and the mesenteric lymph nodes was

decreased by the pre-treatment with L. plantarum HEAL19 (Osman et al. 2007).

In a mixture of probiotics, L. plantarum HEAL19 was used together with L. gasseri DSM 16737 and B. infantis DSM 15158, and given to rats subjected to

a long term, cyclic treatment with DSS (Håkansson et al. 2010). The probiotics

mitigated hepatic injuries by decreasing parenchymal infiltration and

incidence of stasis and translocation. However, the contribution of each

individual strain was not evaluated (Håkansson et al. 2010).

L. plantarum HEAL19 together with fermented blueberries showed a

protective effect on liver cells in a hypertensive rat-model where increasing

blood pressure is induced by L-NAME (Xu et al. 2013).

Multiple sclerosis

Multiple sclerosis (MS) is a Th1 cell-mediated chronic inflammatory disease of

the central nervous system. Treatment with L. plantarum HEAL19 in a mouse

model for experimental autoimmune encephalomyelitis (EAE), mimicking MS,

prevented and delayed the onset of the clinical signs of EAE compared to

control mice (Lavasani et al. 2010). In contrast, treatment with Lactobacillus paracasei PCC 101 or Lactobacillus delbrueckii subsp. bulgaricus DSM 20081

had no effect on the disease development. L. plantarum HEAL19 increased

serum levels of IL-27 (Lavasani et al. 2010).

Oxidative stress

Ischemia-reperfusion (I/R) in the intestines is an inflammatory condition

which activates leukocytes and reactive oxygen species (ROS) and leads to

lipid peroxidation and DNA damage. Fruits rich in polyphenols may act as

antioxidants and prevent lipid peroxidation, and L. plantarum may improve

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the microbial status in the intestines and increase the metabolic activity

towards polyphenolic degradation. In an I/R-model in mice it was seen that

bilberry (Vaccinium myrtillus) alone or in combination with L. plantarum

HEAL19 decreased lipid peroxidation (with malondialdehyde as marker;

Jakesevic et al. 2011)

Interaction with green tea

Green tea is rich in polyphenols, and L. plantarum HEAL19 has the ability to

metabolize phenolics. Mice were for 22 weeks fed a high-fat diet with or

without a supplement of 4% green tea powder, and given L. plantarum

HEAL19 through the drinking water, alone or together with the supplement of

green tea (Axling et al. 2012). The gut microbiota was examined together with

different parameters related to obesity, glucose tolerance, lipid metabolism,

hepatic steatosis and inflammation. L. plantarum HEAL19 and green tea

powder in combination increased the load of lactobacilli in both the small

intestine and in caecum, but it also increased the diversity of the gut

microbiota. Furthermore, the combination of L. plantarum HEAL19 and green

tea mitigated inflammation induced by the high fat diet and up-regulated

genes regulating cholesterol synthesis (Axling et al. 2013). The results are in

support of the hypothesis that a tannase active strain of L. plantarum

consumed together with food rich in phenolics can impose health promoting

effect above that achieved with each individual component.

Protection from cortical bone loss

With the aim to determine if probiotics can protect from ovariectomy-inuced

bone loss, mice were given a mixture of Lactobacillus paracasei DSM13434, L. plantarum HEAL9 and L. plantarum HEAL19 in the drinking water for 6

weeks, starting 2 weeks prior before ovariectomy (Ohlsson et al. 2014). It was

found that the probiotic mixture decreased the serum levels of the resorption

marker C-terminal telopeptides and the urinary fractional excretion of

calcium after ovariectomy, and reduced the expression of the two inflammatory

cytokines, TNF-alfa and IL-1-beta, and increased the expression of

osteoprotegerin (OPG) which is a potent inhibitor of osteoclastogenesis, in

cortical bone. The probiotic treatment also improved the frequency of

regulatory T cells in bone marrow (Ohlsson et al. 2014). The authors conclude

that “treatment with the probiotic mixture prevents ovariectomy-induced cortical bone loss”, and the findings “indicate that the probiotic treatment alter the immune status in bone resulting in attenuated bone resorptione” (Ohlsson

et al. 2014). The effect of only L. plantarum HEAL19 without the other strains

was not tested.

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Human trials

Recovery after oral administration

In an administration study where 10 healthy women were orally administered

the strain HEAL19 together with eleven other Lactobacillus strains suspended

in an oat-milk/blueberry drink for 10 days (HEAL19 was given in a daily dose

of 109 CFU) (Vásquez et al. 2005). L. plantarum HEAL19 was isolated from

faeces of seven of the volunteers after 10 days of administration and in vagina

from three of the volunteers (Vásquez et al. 2005).

Incorporated in a health promoting diet

With the aim to demonstrate dietary effects on cardio-metabolic risk factors in

overweight health y individuals, 44 volunteers participated in a randomized

crossover intervention comparing a multifunctional diet (low glycemic impact

meals, antioxidant-rich foods, oily fish, viscous dietary fibres, soybean and

whole barley kernel products, almonds, stanols and L. plantarum HEAL19)

with a control diet without the active components (Tovar et al. 2012). While

the control diet did not modify the metabolic measurements, the active diet

lowered total serum cholesterol, LDL-cholesterol, triglycerides, LDL/HDL,

apoB/apoA, HbA1C, hs-CRP and systolic blood pressure (Tovar et al. 2012).

Phagocytic activity

In a blinded, placebo-controlled trial, the effect of a daily intake of L. plantarum HEAL19 for two weeks on the innate and acquired immune system

was investigated in healthy volunteers (Rask et al. 2013). Blood lymphocyte

subsets were quantified by flow cytometry and the expression of activation and

memory markers was determined. The strain was also examined for its

capacity to be phagocytosed by human peripheral blood mononuclear cells. The

phagocytic activity of granulocytes towards Escherichia coli was increased

following intake of L. plantarum HEAL19, but no effect was seen on any of the

other examined parameters (Rask et al. 2013).

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References

Lazou Ahrén, I., Xu, J., Önning, G., Olsson, C., Ahrné, S. and Molin, G. (2014).

Antihypertensive activity of blueberries fermented by Lactobacillus plantarum DSM 15313 and effects on the gut microbiota in healthy rats.

Clinical Nutrition http://dx.doi.org/10.1016/j.clnu.2014.08.009

Ahrné, S., Nobaek, S., Jeppsson, B., Adlerberth, I., Wold, A., and Molin, G.

(1998). The normal Lactobacillus flora of healthy human rectal and oral

mucosa, J. Appl. Microbiol., 85, 88-94.

Andersson, U., Bränning, C., Ahrné, S., Molin, G., Alenfall, J., Önning, G.,

Nyman, M. and Holm, C. (2010). Probiotics lower plasma glucose in the high-

fat fed C57BL/6J mouse. Beneficial Microbes 1: 89-196.

Archibald, F. and Fridovich, I. (1981a). Manganese, superoxide dismutase, and

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Axling, U., Olsson, C., Xu, J., Fernandez, C., Larsson, S., Ström, K., Ahrné,

S., Holm, C., Molin, G. & Berger, K. (2012). Green tea powder and

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Barthelmebs, L., Divies, C., and Cavin, J-F. (2001). Molecular characterization

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Håkansson, Å., Bränning, C., Molin, G., Adawi, D., Hagslätt, M-L., Jeppsson,

B., Nyman, M. and Ahrné, S. (2012). Blueberry husks and probiotics attenuate

colorectal inflammation and oncogenesis, and liver injuries in rats exposed to

cycling DSS-treatment. PLOS ONE 7 (3): e33510.

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