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A new probiotic modulates gut microbiota against hepatocellular carcinoma

24th August 2016

Over the last years the beneficial effects of the human intestinal microbiota on various health markers have been displayed, such as inflammation, immune response, metabolic function and weight. The importance of these symbiotic bacteria of ours has been proved. You can see these other posts related with our microbiota: “The good clostridia avoid us from allergies“, “Gut bacteria controlling what we eat” or “Good bacteria of breast milk

At the same time it has been seen that probiotics can be a good solution for many diseases with affected gut microbiota. Indeed, the beneficial role of probiotics to reduce gastrointestinal inflammation and prevent colorectal cancer has been proven.

However, recently it has been found that probiotics may have beneficial effects in other parts of the body beyond the gastrointestinal tract, particularly with immunomodulatory effects on an hepatocellular carcinoma (HCC). In this way, researchers at the University of Hong Kong, along with other from University of Eastern Finland, have published a study (Li et al, PNAS, 2016), where they have seen reductions of 40% in weight and size of HCC liver tumours in mice which were administered with a new mixture of probiotics, “Prohep.”

Hepatocellular carcinoma (HCC) is the most common type of liver cancer is the 2nd most deadly cancers, and it is quite abundant in areas with high rates of hepatitis. In addition, sorafenib, the drug most widely used to reduce the proliferation of tumour, is very expensive. The cost of this multikinase inhibitor is €3400 for 112 tablets of 200 mg, the recommended treatment of four pills a day for a month. Instead, any treatment with probiotics that would proved to be effective and could replace this drug would be much cheaper.

The new probiotics mix Prohep consists of several bacteria: Lactobacillus rhamnosus GG (LGG), Escherichia coli Nissle 1917 (ECN) and the whole inactivated by heat VSL#3 (1: 1: 1) containing Streptococcus thermophilus, Bifidobacterium breve, Bf. longum, Bf. infantis, Lb. acidophilus, Lb. plantarum, Lb. paracasei and Lb. delbrueckii.

In the mentioned work, Li et al. (2016) fed mice with Prohep for a week before inoculating them with a liver tumour, and observed a 40% reduction in tumour weight and size in comparison to control animals. As shown in Figure 1, the effect was significant at 35 days, and also for those who were given the Prohep the same day of tumour inoculation. Obviously, the effect of tumour reduction was much more evident when the antitumour compound Cisplatin was administered.

These researchers saw that tumour reduction was due to the inhibition of angiogenesis. This is the process that generates new blood vessels from existing ones, something essential for tumour growth. In relation to the tumour reduction, high levels of GLUT-1 + hypoxic were found. That meant that there was hypoxia caused by the lower blood flow to the tumour, since this was 54% lower in comparison to controls.

 

Fig 1 Li-Fig1B tumor size - days tumor

Figure 1. Change in tumour size. ProPre: administration of Prohep one week before tumour inoculation; ProTreat: administration of Prohep the same day of tumour inoculation; Cisplatin: administration of this antitumoral. (Fig 1B from Li et al, 2016).

 

These authors also determined that there was a smaller amount of pro-inflammatory angiogenic factor IL-17 and of Th17 cells of the immune system, cells also associated with cancer. The lower inflammation and angiogenesis could limit the tumour growth.

Moreover, these researchers established that the beneficial effects of probiotics administration were associated with the abundance of beneficial bacteria in the mice gut microbiota, analysed by metagenomics. So, probiotics modulate microbiota, favouring some gut bacteria, which produce anti-inflammatory metabolites such as cytokine IL-10 and which suppress the Th17 cell differentiation.

 

Fig 2 gut microbiota Eye of Science

Figure 2. Bacteria of the human intestinal microbiota seen by scanning electron microscope (SEM) (coloured image of Eye of Science / Science Source)

 

Some of the bacteria identified by metagenomics in the microbiota of mice that were administered with Prohep were Prevotella and Oscillibacter. The first is a bacteroidal, gram-negative bacterium, which is abundant in the microbiota of rural African child with diets rich in carbohydrates. Oscillibacter is a gram-positive clostridial, known in humans as a producer of the neurotransmitter GABA. Both are an example of the importance of some clostridial and bacteroidals in the gut microbiota. In fact, they are majority there, and although they are not used as probiotics, are found increasingly more positive functions, such as avoiding allergies (see “The good clostridia avoid us from allergies“).

It is known that these bacteria produce anti-inflammatory metabolites and therefore they would be the main involved in regulating the activity of immune cells that cause tumour growth. The observed reduction of tumour in these experiments with mice would be the result of combined effect of these administered probiotic bacteria together with the microbiota itself favoured by them. We see a potential outline of these actions in Figure 3.

Fig 3 Sung fig 2

Figure 3. Simplified diagram of the possible mechanisms of gut bacteria influencing on the polarization of Th17 cells in the lamina propria of the intestinal mucosa. The microbiota bacteria activate dendritic cells, which secrete cytokines (IL-22, IL-23, IL-27). The bacteria can promote Th17 immunity inducing IL-23, which can be involved by means of TLR ligands signal or extracellular ATP or serum amyloid A (SAA). Meanwhile, some probiotic strains could inhibit the development of Th17 by means of the production of IL-12 and IL-27, in addition to promoting the growth and colonization of the bacteria that induce Th17 (Sung et al 2012, Fig. 2).

 

Although we know that the cancer progression is a very complex process and that in the tumour microenvironments there is an infiltration of many different types of immune system cells, such as T cells, neutrophils, killer cells, macrophages etc, the Th17 helper cell subpopulation appears to be prevailing in the tumour progression, and therefore these effects of probiotics and microbiota open good prospects.

It is still early to say whether these findings will contribute to the treatment of human liver cancer, and therefore research in humans is needed, in order to see if these probiotics could be used as such or in tandem with some drug, depending on the tumour stage and size. In any case, all this opens a new range of possibilities for research of the molecular mechanisms of the beneficial effects of probiotics beyond the intestinal tract.

 

Bibliography

El-Nezami H (2016 april 27) HKU develops novel probiotic mixture “Prohep” that may offer potential therapeutic effects on liver cancer. The University of Hong Kong (HKU) 27 Apr 2016

El-Nezamy H, Lee PY, Huang J, Sung YJ (2015) Method and compositions for treating cancer using probiotics. Patent WO 2015021936 A1

Li J, Sung CYJ, Lee N, Ni Y, Pihlajamäki J, Panagiotou G, El-Nezami H (2016) Probiotics modulated gut microbiota suppresses hepatocellular carcinoma growth in mice. PNAS E1306-E1315

Oelschlaeger TA (2010) Mechanisms of probiotic actions – A review. Int J Med Microbiol 300, 57-62

Packham C (2016) Probiotics dramatically modulate liver cancer growth in mice. Medical Press, Med Research 23 Feb 2016

Silgailis M (2016) Treating some cancers with probiotics in the future ? Probiotic Prohep. Lacto Bacto: Health, Microbes and More 23 Feb 2016

Sung CYJ, Lee NP, El-Nezami H (2012) Regulation of T helper by bacteria: an approach for the treatment of hepatocellular carcinoma. Int J Hepatology ID439024, doi:10.1155/2012/439024

UEF News and Events (2016) A novel probiotic mixture may offer potential therapeutic effects on hepatocellular carcinoma. University of Eastern Finland 1 Mar 2016

 

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The giant panda is herbivore but has the gut microbiota of a carnivore

September 30th, 2015

The giant panda (Ailuropoda melanoleuca, literally Greek for “white and black cat feet”) is one of the most intriguing evolutionary mammal species. Despite its exclusively herbivorous diet, phylogenetically it is like a bear because it belongs to Ursids family, order Carnivores. Its diet is 99% bamboo and the other 1% is honey, eggs, fish, oranges, bananas, yams and leaves of shrubs.

It lives in a mountain area in central China, mainly in Sichuan province, and also in provinces of Shaanxi and Gansu. Due to the construction of farms, deforestation and other development, the panda has been driven out of the lowland where he lived. It is an endangered species that needs protection. There are about 300 individuals in captivity and 3000 in freedom. Although the numbers are increasing, it is still endangered, particularly due to its limited space (20,000 km2) and its very specific habitat (bamboo forests).

Fig0 panda bamboo

Thus, the giant panda has an almost exclusive diet of different species of bamboo, mainly the very fibrous leaves and stems, and buds in spring and summer. It is therefore a poor quality -digestive diet, with little protein and plenty of fibre and lignin content. They spend about 14 hours a day eating and can ingest about 12 kg of bamboo a day.

Most herbivores have modifications of the digestive tract that help them to retain the food in digestion process and contain microbial populations that allow them to eat exclusively plant materials, rich in complex polysaccharides such as cellulose and hemicellulose. These specializations may be compartmentalization of the stomach of ruminants and other typical non-ruminants (kangaroos, hamster, hippopotamus and some primates) or enlargement of the large intestine, characteristic of equines, some rodents and lagomorphs (rabbits and hares).

However, despite his exclusively herbivorous diet, surprisingly the giant panda has a typical carnivorous gastrointestinal tract, anatomically similar to dog, cat or raccoon, with a simple stomach, a degenerated caecum and a very short colon. The gastrointestinal tract of pandas is about 4 times the size of the body, such as other carnivores, whereas herbivores have about 10-20 times the size of the body, to efficiently digest large amounts of forage. With this, the panda intestinal transit time is very short, less than 12 hours. This severely limits the ability of potential fermentation of plant materials (Williams et al. 2013).

For these reasons, the digestion of bamboo for panda is very inefficient, despite their dependency. Pandas consume the equivalent of 6% of their body weight per day, with a 20% digestibility of dry matter of bamboo. Of this, 10% corresponds to the low protein content of bamboo, and the rest are polysaccharides, particularly with coefficients of digestion of 27% for hemicellulose and 8% for the pulp.

It seems as if the giant panda would have specialized in the use of a plant with high fibre content without having modified the digestive system, by means of an efficient chewing, swallowing large quantities, digesting the contents of cells instead of plant cell walls, and quickly excreting undigested waste (Dierenfield et al. 1982).

In addition, having a dependency on one type of plant such as bamboo can lead to nutritional deficiencies depending on seasonal cycles of the plant. In this regard, recently Nie et al. (2015) have studied the concentrations of calcium, phosphorus and nitrogen from different parts of the bamboo that a population of free pandas eat. They have seen that pandas in their habitat have a seasonal migration in two areas of different altitudes throughout the year and that fed two different species of bamboo. Both species have more calcium in the leaves and more phosphorus and nitrogen in the stems. As the seasonal variation in appearance and fall of leaves of two species is different due to the different altitude, when pandas are in one of the areas eat the leaves of a species and stems of the other while they do the reverse when they are in the other zone. So, pandas synchronize their seasonal migrations in order to get nutritionally the most out of both species of bamboo.

Another drawback of the bamboo dependence is flowering. It is a natural phenomenon that happens every 40-100 years, and when bamboo flowers, it dies, reducing the availability of food for pandas. During 1970-1980 there were two large-scale blooms in the habitat of pandas, and there were more than 200 deaths for this reason. However, and given that probably pandas have found during their evolution with many other massive blooms, in these occasions they are looking for other species of bamboo or travel long distances to meet their food needs (Wei et al. 2015).

In return, and as adaptation to eat this so specific food, the giant panda has a number of unique morphological features, such as strong jaws and very powerful molars, and especially a pseudo-thumb, like a 6th finger, which is actually a modified enlarged sesamoid bone, as an opposable thumb, which serves to hold bamboo while eating (Figure 1).

Fig1 panda's thumb

Figure 1. The “pseudo-thumb” of giant panda. Image from Herron & Freeman (2014).

And how is that the panda became an herbivore ?

It has been estimated that the precursor of the giant panda, omnivorous as other Ursids, began to eat bamboo at least 7 million years ago (My), and became completely dependent on bamboo between 2 and 2.4 My. This dietary change was probably linked to mutations in the genome, leading to defects in the metabolism of dopamine in relation to the appetite for meat, and especially the pseudogenization of Tas1r1 gene (Figure 2) of umami taste receptor (Jin et al. 2011). The umami is one of the five basic tastes, along with sweet, salty, sour and bitter. Umami is like “pleasant savoury taste”, usually recalls meat, and is related to L-glutamic acid, abundant in meat. This mutation in pandas favoured the loss of appetite for meat and reinforced their herbivore lifestyle. However, other additional factors had probably been involved, since Tas1r1 gene is intact in herbivores such as horses and cows (Zhao et al. 2010).

Fig2 Zhao F1 large

Figure 2. Phylogenetic tree of some carnivores with data for giant panda deduced from fossils (in blue) and from the molecular study of TasTr1 gene made by Zhao et al. (2010).

The intestinal microbiota of giant panda

As expected, when sequencing the complete genome of the giant panda (Li et al. 2010), specific genes responsible for the digestion of cellulose and hemicellulose have not been found. Logically, these complex polysaccharides of bamboo fibres would be possibly digested by cellulolytic microorganisms of the intestinal tract. So, their presence in panda must be studied.

When studying the sequences of 16S ribosomal DNA from faecal microbiota of various mammals, an increase in bacterial diversity is generally observed in sense carnivores – omnivores – herbivores (Ley et al. 2008). This diversity is lower in the panda than in herbivores, and as shown in Figure 3, pandas are grouped with carnivores (red circles) despite being herbivorous from the diet point of view.

Fig3 Ley

Figure 3. Principal component analysis (PC) of faecal bacterial communities from mammals with different colours according to the predominant diet (Law et al. 2008)

The intestinal microbiota of most herbivores contains anaerobic bacteria mainly from groups of Bacteroides, Clostridials, Spirochetes and Fibrobacterials, that have enzymatic ability to degrade fibrous plant material and thus provide nutrients for its guests. Instead, omnivores and carnivores have a particularly dominant microbiota of facultative anaerobes, such as Enterobacteriaceae, besides some Firmicutes, including lactobacilli and some Clostridials and Bacteroides.

As for the giant panda, the first studies made with culture-dependent methods and analysis of amplified 16S rRNA genes (Wii et al. 2007) identified Enterobacteriaceae and Streptococcus as predominant in the intestinal microbiota. Therefore, this study suggests that the microbiota of panda is very similar to that of carnivores, as we see in the mentioned comparative study with various mammals (Law et al. 2008), and therefore with little ability to use cellulose or hemicellulose.

However, a later study done with sequencing techniques of 16S (Zhu et al. 2011) from faecal samples of 15 giant pandas arrived at very different conclusions and it seemed that they found the first evidence of cellulose digestion by microbiota of giant panda. In 5500 sequences analysed, they found 85 different taxa, of which 83% were Firmicutes (Figure 4), and among these there were 13 taxa of Clostridium (7 of them exclusive of pandas) and some of these with ability to digest cellulose. In addition, in metagenomic analysis of some of the pandas some putative genes for enzymes to digest cellulose, xylans and beta-glucosidase-1,4-beta-xilosidase for these Clostridium were found. Altogether, they concluded that the microbiota of the giant panda had a moderate degradation capacity of cellulose materials.

Fig4 Zhu 2011-Fig1C

Figure 4. Percentage of sequences of the main bacterial groups found in faecal samples from wild individuals of giant panda (W1-W7) and captive (C1-C8), according to Zhu et al. (2011). Under each individual the n. sequences analysed is indicated.

But just three months ago a work (Xue et al. 2015) has been published that seems to go back, concluding that the intestinal microbiota of the giant panda is very similar to that of carnivores and have little of herbivores. It is an exhaustive study of last-generation massive sequencing of 16S rRNA genes of faecal samples from 121 pandas of different ages over three seasons. They obtained some 93000 sequences corresponding to 781 different taxa.

They found a predominance of Enterobacteriaceae and Streptococcus (dark red and dark blue respectively, Figure 5A) and very few representatives of probable cellulolitics as Clostridials. Moreover, these are not increased when more leaves and stems of bamboo are available (stage T3). These results correspond with what was already known of the low number of genes of cellulases and hemicellulases (2%), even lower than in the human microbiome. This negligible contribution of microbial digestion of cellulose, together with the commented fact that the panda is quite inefficient digesting bamboo, contradicts the hypothetical importance of digestion by the microbiota that had suggested a few years earlier, as we have seen before.

In addition, in this work a lot of variety in composition of microbiota between individuals has been found (Figure 5 B).

Fig5 Xue F1 large

Figure 5. Composition of the intestinal microbiota from 121 giant pandas, with (A) the dominant genera in all samples and (B) the relative contribution of each individual dominant genera, grouped by age and sampling time (Xue et al. 2015).

In this paper, a comparative analysis between the compositions of the intestinal microbiota of giant panda with other mammals has been made, and it has confirmed that the panda is grouped again with carnivores and is away from herbivores (Figure 6).

Fig6 Xue Fig4

Figure 6. Principal component analysis (PCoA) of microbiota communities from faecal samples of 121 giant pandas (blank forms), compared with other herbivores (green), omnivores (blue) and carnivores (red). The different forms correspond to different works: the circles are from Xue et al. (2015), where this Figure has been obtained.

All in all, the peculiar characteristics of the giant panda microbiota contribute to the extinction danger of this animal. Unlike most other mammals that have evolved their microbiota and digestive anatomies optimizing them for their specific diets, the aberrant coevolution of panda, its microbiota and its particular diet is quite enigmatic. To clarify it and know how to preserve this threatened animal, studies must be continued, combining metagenomics, metatranscriptomics, metaproteomics and meta-metabolomics, in order to know well the structure and metabolism of gut microbiota and its relationship with digestive functions and the nutritional status of the giant panda (Xue et al. 2015).

References

Dierenfield ES, Hintz HF, Robertson JB, Van Soest PJ, Oftedal OT (1982) Utilization of bamboo by the giant panda. J Nutr 112, 636-641

Herron JC, Freeman S (2014) Evolutionary Analysis, 5th ed. Benjamin Cummings

Jin K, Xue C, Wu X, Qian J, Zhu Y et al. (2011) Why Does the Giant Panda Eat Bamboo? A Comparative Analysis of Appetite-Reward-Related Genes among Mammals. PLos One 6, e22602

Ley RE, Hamady M, Lozupone C, Turnbaugh PJ, Ramey RR et al. (2008) Evolution of Mammals and Their Gut Microbes. Science 320, 1647-1651

Li R, Fan W, Tian G, Zhu H, He L et 117 al. (2010) The sequence and de novo assembly of the giant panda genome. Nature 463, 311–317

Nie Y, Zhang Z, Raubenheimer D, Elser JJ, Wei W, Wei F (2015) Obligate herbivory in an ancestrally carnivorous lineage: the giant panda and bamboo from the perspective of nutritional geometry. Functional Ecology 29, 26–34

Rosen M (2015) Pandas’ gut bacteria resemble carnivores. Science News 19/05/2015

Wei G, Lu H, Zhou Z, Xie H, Wang A, Nelson K, Zhao L (2007) The microbial community in the feces of the giant panda (Ailuropoda melanoleuca) as determined by PCR-TGGE profiling and clone library analysis. Microb Ecol 54, 194–202

Wei F, Hu Y, Yan L, Nie Y, Wu Q, Zhang Z (2014) Giant Pandas Are Not an Evolutionary cul-de-sac: Evidence from Multidisciplinary Research. Mol Biol Evol 32, 4-12

Williams CL, Willard S, Kouba A, Sparks D, Holmes W et al. (2013) Dietary shifts affect the gastrointestinal microflora of the giant panda (Ailuropoda melanoleuca). J Anim Physiol Anim Nutr 97, 577-585

Xue Z, Zhang W, Wang L, Hou R, Zhang M et al. (2015) The bamboo-eating giant panda harbors a carnivore-like gut microbiota, with excessive seasonal variations. mBio 6(3), e00022-15

Zhao H, Yang JR, Xu H, Zhang J (2010) Pseudogenization of the Umami Taste Receptor Gene Tas1r1 in the Giant Panda Coincided with its Dietary Switch to Bamboo. Mol Biol Evol 27(12), 2669–2673

Zhu LF, Wu Q, Dai JY, Zhang SN, Wei FW (2011) Evidence of cellulose metabolism by the giant panda gut microbiome. Proc Natl Acad Sci USA 108, 17714–17719.

We have good clostridia in the gut and some of them prevent allergies

21st March 2015

Clostridia: who are they ?

The clostridia or Clostridiales, with Clostridium and other related genera, are Gram-positive sporulating bacteria. They are obligate anaerobes, and belong to the taxonomic phylum Firmicutes. This phylum includes clostridia, the aerobic sporulating Bacillales (Bacillus, Listeria, Staphylococcus and others) and also the anaerobic aero-tolerant Lactobacillales (id est, lactic acid bacteria: Lactobacillus, Leuconostoc, Oenococcus, Pediococcus, Lactococcus, Streptococcus, etc.). All Firmicutes have regular shapes of rod or coccus, and they are the evolutionary branch of gram-positive bacteria with low G + C content in their DNA. The other branch of evolutionary bacteria are gram-positive Actinobacteria, of high G + C and irregular shapes, which include Streptomyces, Corynebacterium, Propionibacterium, and Bifidobacterium, among others.

 

flora_cover

 

Being anaerobes, the clostridia have a fermentative metabolism of both carbohydrates and amino acids, being primarily responsible for the anaerobic decomposition of proteins, known as putrefaction. They can live in many different habitats, but especially in soil and on decaying plant and animal material. As we will see below, they are also part of the human intestinal microbiota and of other vertebrates.

The best known clostridia are the bad ones (Figure 1): a) C. botulinum, which produces botulin, the botulism toxin, although nowadays has medical and cosmetic applications (Botox); b) C. perfringens, the agent of gangrene; c) C. tetani, which causes tetanus; and d) C. difficile, which is the cause of hospital diarrhea and some postantibiotics colitis.

 

clostridium_bacteria

Figure 1. The four more pathogen species of Clostridium. Image from http://www.tabletsmanual.com/wiki/read/botulism

 

Clostridia in gut microbiota

As I mentioned in a previous post (Bacteria in the gut …..) of this blog, we have a complex ecosystem in our gastrointestinal tract, and diverse depending on each person and age, with a total of 1014 microorganisms. Most of these are bacteria, besides some archaea methanogens (0.1%) and some eukaryotic (yeasts and filamentous fungi). When classical microbiological methods were carried out from samples of colon, isolates from some 400 microbial species were obtained, belonging especially to proteobacteria (including Enterobacteriaceae, such as E. coli), Firmicutes as Lactobacillus and some Clostridium, some Actinobacteria as Bifidobacterium, and also some Bacteroides. Among all these isolates, some have been recognized with positive effect on health and are used as probiotics, such as Lactobacillus and Bifidobacterium, which are considered GRAS (Generally Recognized As Safe).

But 10 years ago culture-independent molecular tools began to be used, by sequencing of ribosomal RNA genes, and they have revealed many more gut microorganisms, around 1000 species. As shown in Figure 2, taken from the good review of Rajilic-Stojanovic et al (2007), there are clearly two groups that have many more representatives than thought before: Bacteroides and Clostridiales.

 

Rajilic 2007 Fig 1

Figure 2. Phylogenetic tree based on 16S rRNA gene sequences of various phylotypes found in the human gastrointestinal tract. The proportion of cultured or uncultured phylotypes for each group is represented by the colour from white (cultured) passing through grey to black (uncultured). For each phylogenetic group the number of different phylotypes is indicated (Rajilic-Stojanovic et al 2007)

 

In more recent studies related to diet such as Walker et al (2011) — a work done with faecal samples from volunteers –, population numbers of the various groups were estimated by quantitative PCR of 16S rRNA gene. The largest groups, with 30% each, were Bacteroides and clostridia. Among Clostridiales were included: Faecalibacterium prausnitzii (11%), Eubacterium rectale (7%) and Ruminococcus (6%). As we see the clostridial group includes many different genera besides the known Clostridium.

In fact, if we consider the population of each species present in the human gastrointestinal tract, the most abundant seems to be a clostridial: F. prausnitzii (Duncan et al 2013).

 

Benefits of some clostridia

These last years it has been discovered that clostridial genera of Faecalibacterium, Eubacterium, Roseburia and Anaerostipes (Duncan et al 2013) are those which contribute most to the production of short chain fatty acids (SCFA) in the colon. Clostridia ferment dietary carbohydrate that escape digestion producing SCFA, mainly acetate, propionate and butyrate, which are found in the stool (50-100 mM) and are absorbed in the intestine. Acetate is metabolized primarily by the peripheral tissues, propionate is gluconeogenic, and butyrate is the main energy source for the colonic epithelium. The SCFA become in total 10% of the energy obtained by the human host. Some of these clostridia as Eubacterium and Anaerostipes also use as a substrate the lactate produced by other bacteria such as Bifidobacterium and lactic acid bacteria, producing finally also the SCFA (Tiihonen et al 2010).

 

Clostridia of microbiota protect us against food allergen sensitization

This is the last found positive aspect of clostridia microbiota, that Stefka et al (2014) have shown in a recent excellent work. In administering allergens (“Ara h”) of peanut (Arachis hypogaea) to mice that had been treated with antibiotics or to mice without microbiota (Germ-free, sterile environment bred), these authors observed that there was a systemic allergic hyper reactivity with induction of specific immunoglobulins, id est., a sensitization.

In mice treated with antibiotics they observed a significant reduction in the number of bacterial microbiota (analysing the 16S rRNA gene) in the ileum and faeces, and also biodiversity was altered, so that the predominant Bacteroides and clostridia in normal conditions almost disappeared and instead lactobacilli were increased.

To view the role of these predominant groups in the microbiota, Stefka et al. colonized with Bacteroides and clostridia the gut of mice previously absent of microbiota. These animals are known as gnotobiotic, meaning animals where it is known exactly which types of microorganisms contain.

In this way, Stefka et al. have shown that selective colonization of gnotobiotic mice with clostridia confers protection against peanut allergens, which does not happen with Bacteroides. For colonization with clostridia, the authors used a spore suspension extracted from faecal samples of healthy mice and confirmed that the gene sequences of the extract corresponded to clostridial species.

So in effect, the mice colonized with clostridia had lower levels of allergen in the blood serum (Figure 3), had a lower content of immunoglobulins, there was no caecum inflammation, and body temperature was maintained. The mice treated with antibiotics which had presented the hyper allergic reaction when administered with antigens, also had a lower reaction when they were colonized with clostridia.

 

fig 4 skefta

Figure 3. Levels of “Ara h” peanut allergen in serum after ingestion of peanuts in mice without microbiota (Germ-free), colonized with Bacteroides (B. uniformis) and colonized with clostridia. From Stefka et al (2014).

 

In addition, in this work, Stefka et al. have conducted a transcriptomic analysis with microarrays of the intestinal epithelium cells of mice and they have found that the genes producing the cytokine IL-22 are induced in animals colonized with clostridia, and that this cytokine reduces the allergen uptake by the epithelium and thus prevents its entry into the systemic circulation, contributing to the protection against hypersensitivity. All these mechanisms, reviewed by Cao et al (2014), can be seen in the diagram of Figure 4.

In conclusion, this study opens new perspectives to prevent food allergies by modulating the composition of the intestinal microbiota. So, adding these anti-inflammatory qualities to the production of butyrate and other SCFA, and the lactate consumption, we must start thinking about the use of clostridia for candidates as probiotics, in addition to the known Lactobacillus and Bifidobacterium.

 

fig 4 Cao b

Figure 4. Induction of clostridia on cytokine production by epithelial cells of the intestine, as well as the production of short chain fatty acids (SCFA) by clostridia (Cao et al 2014).

 

References

Cao S, Feehley TJ, Nagler CR (2014) The role of commensal bacteria in the regulation of sensitization to food allergens. FEBS Lett 588, 4258-4266

Duncan SH, Flint HJ (2013) Probiotics and prebiotics and health in ageing populations. Maturitas 75, 44-50

Rajilic-Stojanovic M, Smidt H, de Vos WM (2007) Diversity of the human gastrointestinal tract microbiota revisited. Environ Microbiol 9, 2125-2136

Rosen M (2014) Gut bacteria may prevent food allergies. Science News 186, 7, 4 oct 2014

Russell SL, et al. (2012) Early life antibiotic-driven changes in microbiota enhance 
susceptibility to allergic asthma. EMBO Rep 13(5):440–447

Stefka AT et al (2014) Commensal bacteria protect against food allergen sensitization. Proc Nat Acad Sci 111, 13145-13150

Tiihonen K, Ouwehand AC, Rautonen N (2010) Human intestinal microbiota and healthy aging. Ageing Research Reviews 9:107–16

Walker AW et al (2011) Dominant and diet-responsive groups of bacteria within the human colonic microbiota. The ISME J 5, 220-230

 

 

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