probiotics - vitafoods insights

Vol. 2, Issue 5 May 2017 €36 www.vitafoods.eu.com

Probiotics: Beyond the

Gut Instinct

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CONTENT

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Simplifying the EU Regulatory Framework For the last four years, the probiotic food sector has been looking to provide a harmonised regulatory framework in the EU for the term ‘contains probiotics’. Rosanna Pecere, Executive Director of IPA Europe, outlines the voluntary approach IPA has developed to help the recognition of probiotic food health claims based on scientific evidence.

The Oral Microbiome and Periodontal DiseaseProbiotics are well-known for their effects on digestive health, but their health benefits extend beyond the gut. Prof Michel Messora and Prof Flávia Furlaneto provide insight into the clinical trials studying the effects of probiotics in the treatment of periodontitis.

Human Intestinal Barrier Function in Health and DiseaseThe probiotic sector remains innovative and fast-growing—the perfect platform for abundant research. Julia König details the human intestinal barrier function and how the intake of specific probiotic strains could also support the gastrointestinal tract.

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Viewpoint4

Takeaways28

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What’s inside some dietary supplements is just as beneficial to you as it is to consumers. That’s because our probiotics come with the scientific expertise that only DuPont Nutrition & Health can provide. Plus clinical research, unrivaled product stability, new product formulations, and dosage forms that deliver unique health benefits, marketing insights, and, of course, safety. Take a look inside DuPont Nutrition & Health to see how we can deliver on your dietary supplement needs. Visit dupont.com/itswhatsinside to learn more.

Welcome to the Global Collaboratory.™

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Nutrition & Health

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Jade Mitchell-RossAssistant Editor, Vitafoods [email protected]

@jmitchellross

PProbiotics have become a household term, as awareness of their digestive health benefits

is widespread and prolific. But consumers are confused by the communication about products

containing probiotics.

For the last four years, the probiotic food sector has been looking to provide a harmonised

regulatory framework in the EU for the term ‘contains probiotics’. The International Probiotics

Association (IPA) Europe advocates an EU framework to help the recognition of probiotic food

health claims based on scientific evidence.

In this issue, Rosanna Pecere, Executive Director of IPA Europe, outlines the voluntary

approach IPA has developed and details the reasons consumers are confused and

disadvantaged by the current system in an article beginning on page 5.

As the probiotic sector remains innovative and fast-growing, research into the potential

health benefits abounds. We hear from Julia König from the Nutrition-Gut-Brain Interactions

Research Centre at Orebro University, Sweden, on page 12, detailing the human intestinal

barrier function and how the intake of specific probiotic strains could also support the

gastrointestinal (GI) tract and address conditions including coeliac disease and irritable bowel

syndrome (IBS).

Recent studies indicate that probiotics may help beyond the gut. On page 20, Prof Michel

Messora and Prof Flávia Furlaneto provide insight into the clinical trials studying the effects of

probiotics in periodontitis treatment. Although the evidence is limited so far and the biological

mechanisms of the effects of probiotics are not yet fully elucidated, they can be considered a

potential adjuvant therapy in the management of periodontal diseases.

Probiotics continue to be one of the most popular topics in science and the

food industry. I hope with this digital magazine you’ll feel at the forefront

of the cutting-edge research and innovation.

Exploring the Probiotics Market

Viewpoint

IN THIS ISSUE Regulatory Framework p.5 Table of Contents p.2


mailto:[email protected]

FFor the last four years, the probiotic food sector—supported by a growing number of

Member States and partner industries—has been looking for a legal, sound, and practical

solution that will provide a harmonised regulatory framework in the European Union (EU) for

using the term ‘contains probiotics’ on labels and in marketing communication. This would

certainly help what used to be the fastest-growing and most innovative food sector prior to

2012, before the EU Claims Regulation came into force.

Consumers are confused and disadvantaged because of a lack of communication about

probiotics and products containing probiotics. While the term has essentially been outlawed in

some (but not all) EU countries, many products are still labelled as ‘probiotic’ without clear or

harmonised criteria or conditions in most cases, and official government websites in the UK

and Italy refer to the term ’probiotic’.

The International Probiotics Association (IPA) Europe advocates an EU framework that makes

information regarding the presence of probiotics in food available to consumers—which should

also help the recognition of probiotic food health claims that are based on scientific evidence.

In fact, the industry was at the forefront of the request for regulation and is willing to ensure

clear conditions of use. In this context, IPA Europe has developed a voluntary approach.

Due to the 2007 interpretation issued with guidance on the implementation of

the Nutrition and Health Claims Regulation 1924/2006 (NHCR), per which the

term ‘probiotic’ should be interpreted as a health claim, only by first submitting a

health claim authorisation to the European Food Safety Authority (EFSA) could

the probiotics industry use the word ‘probiotic’. But this interpretation is based

on a guidance that has no legal value and, above all, is not coherent with a more

comprehensive communication of the presence of probiotics in foods. Based on

the EU legal framework, other aspects must be considered.

First, the aim of the information on the label is to help consumers make

informed choices and use food safely; therefore, the term ‘probiotic’ can be

considered part of the information that describes the characteristics of the

product. Second, NHCR generally allows the use of nutrition information regarding

substances with a nutritional or physiological effect. The indication ‘contains

probiotics’ fits with this definition, which differs from claiming the health benefits

of a specific probiotic strain. It should be noted mere consumer association of a

term with a beneficial effect cannot transform a named ingredient into a health

claim as, based on the Claims Regulation, all nutrition claims imply a beneficial

effect. However, it can be argued the term ‘probiotic’ is not subject to an

Simplifying the EU Regulatory Framework for Probioticsby Rosanna Pecere

Regulatory Framework

IN THIS ISSUE Viewpoint p.4 Oral Microbiome p.12 Table of Contents p.2


http://www.nhs.uk/Conditions/probiotics/Pages/Introduction.aspx

http://www.salute.gov.it/imgs/C_17_pubblicazioni_1016_ulterioriallegati_ulterioreallegato_0_alleg.pdf)

http://ipaeurope.org/images/image/pdf/IPA%20Europe%20Guidelines%20to%20qualify%20a%20microorganism%20as%20probiotic.pdf


authorisation as a health claim since ‘probiotic’ is a generic word that does not describe any

health effect or relationship between the substance and any effect on the body.

The Regulatory FrameworkIn the meantime, probiotic technology is innovating at a very fast pace, creating urgency for

a more efficient and streamlined regulatory framework for consumers, regulators and industry.

A different approach will be crucial for the future growth and development of the sector.

Pertinent human studies are an absolute requirement for the scientific substantiation of

health claims. However, much of the clinical evidence to date has been derived from diverse

probiotic strains in trials of various designs in multiple settings. There have been difficulties in

deciding appropriate controls, and often very different clinical endpoints have been measured.

Food-based probiotics face an additional obstacle, because those products are intended for

healthy populations rather than diseased patients, meaning biomarkers of risk are more

suitable endpoints than actual clinical outcomes. Moreover, there is a disproportionate

decision-making process, as claims have been rejected despite trials showing benefits in most

trial subjects.

To remedy this, rules could be created for different claims categories to recognise traditional

use substantiated by research, and to allow for innovation by small and medium-sized

enterprises (SMEs). It should be noted that today, probiotics in the animal feed space have a

clearer regulatory framework than in the human food space, and their role with intestinal flora

is acknowledged.

A recent report from the European Commission’s (EC) science and knowledge service, the

Joint Research Centre, shows movement in the right direction, as it recognises the need to

adapt the current approach; discusses the challenges to adapt the regulatory framework to a

dynamic sector; and offers scenarios on how to address the ongoing changes in food

innovation, nutrition and consumers’ demand for a healthy lifestyle.

As part of the regulatory framework previously mentioned—and to address the salient issue

of performance and health enhancement claims, as well as references to prevention,

treatments or cure of specific diseases—NHCR will need to be revised. Rather than designing

separate authorisation systems, one possibility would be having a single system with different

levels of claim strength relating to the different strength levels of supporting scientific evidence

(e.g., soft vs. hard claims). However, the probiotic sector cannot wait any longer. There is an

urgent need to find concrete, pragmatic solutions.


It should be noted that today,

probiotics in the animal feed space have a clearer regulatory framework than in the human food space, and their role with intestinal flora is acknowledged.




A Pragmatic Approach to Boost Innovation Ambiguity impacts the sector negatively and goes against the EU’s declared objectives to

sustain and promote economic growth and quality jobs. It also poses serious problems for

consumers and health care professionals, who receive conflicting answers to their questions

about probiotics.

With the probiotic industry suffering from the impact of the probiotic labelling ban in the

EU, 2015 brought surprisingly fast growth in the rest of the world. After a decade of 5 percent

annual growth for the probiotic foods sector, the decline was about 8 percent for 2013 in the

EU, while the market is growing outside Europe: 7 percent growth in the United States, 7

percent in Latin America, 4 percent in the Middle East, and 11 percent in Asia (Euromonitor).

Forecasts indicate a decline of 9 percent for probiotic yoghurts in the EU between 2013-2018.

During the last three years, a complete shift has been observed in the type of products with

probiotics still marketed under the ‘probiotic’ descriptor.

In 2012, a Mintel study1 revealed 85 percent of foods containing probiotics were dairy

products. The percentage of food with probiotics versus non-food products was about 75

percent across Europe.

A recent study conducted in 10 European countries revealed of all ‘probiotics’ products, the

percentage of those under the heading of ‘foods’ was less than 65 percent, of which more

than 95 percent were dietary supplements sold in specialist health shops or similar. The fact

that the term ‘probiotic’ is not used anymore in dairy products is also illustrated in the

following MINTEL data2:


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2011 2012 2013 2014 2015

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In addition, it should be noted the use of new terms such as probioceuticals,

pharmabiotics, psychobiotics, immunobiotics, eubiotics or post-biotics (some of them being

trademarks) has proliferated. The use of these terms is not regulated, but will undoubtedly

increase consumer confusion.

IPA Europe believes a harmonised European solution is essential for the growth of the

probiotic sector, a multibillion euro industry in Europe. This will help promote economic growth

and quality jobs, enhance research and innovation of products and the competitiveness of the

European industry, and encourage a healthy society.

Clear Consumer InformationToday’s consumer is increasingly moving toward an effective personalised nutrition regime,

which requires access to specific food products with accurate, appropriate and comprehensive

information. The current EU approach, while encouraging transparency and providing more

information regarding probiotics to consumers, may leave them with unintended

misinformation or no information at all.

The impasse is even more regrettable given probiotic consumption not only has a beneficial

effect on quality of life and general wellbeing, but may also contribute to substantial cost

savings for society3.

It has been estimated, with generalised probiotic use, the French national health care system

(La Sécurité Sociale) could save 2.4 million respiratory tract infection (RTI) sick days, 291,000

antibiotic courses and 581,000 lost work days. Another study by Cochrane shows 6.6 million

sick days, 473,000 antibiotic courses and 1.5 million lost work days would be saved with

generalised probiotic use. From the national health care service perspective, the economic

impact of probiotic use was calculated to be a saving of €14.6 million using data from the

York Health Economics Consortium and €37.7 million using Cochrane data. Higher savings

were observed in children, active smokers and people with more frequent human contact.

Scientific Approach & Possible RoutesAt the same time, the EU probiotic industry will continue to apply considerable efforts to

meet the requirements of EFSA, with the aim of securing successful health claim applications.


Date Published Number of Volume

2011

2012

2013

2014

2015

Total Sample

275

235

82

41

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655



One of IPA Europe’s key objectives is to coordinate the efforts of the probiotic industry in the

development of scientific standards to recognise the benefits of probiotics and related products.

Probiotics are defined as ‘live microorganisms that, when administered in adequate amounts,

confer a health benefit on the host’ (FAO/WHO 2001). As of 2016, close to 1,000 clinical trials

(or observational studies in humans) have been performed with probiotic strains. From the

positive health effects observed with many individual strains across multiple studies, it can be

concluded that probiotics could share some core properties that

positively impact host health. This helps to develop the idea of a core

benefit associated to probiotics strains as recognised in Canada, Italy

(on healthy gut microbiota) and, recently, in Turkey, supported by an

International Science Association for Probiotics and Prebiotics (ISAPP)

consensus paper4 reinforcing two common general health benefits

often associated with probiotics: supporting a healthy digestive tract

and a healthy immune system. However, there is also compelling

evidence that there are also likely to be species- and even strain-specific

health effects. It is probable that a single strain can have multiple modes

of action (some core and some specific).

Recurrent perturbations (antibiotics use, stress, diet) lead to a

decrease in the microbiome’s resilience capability. Evidence suggests

probiotics can affect the resilience capability of a given microbiota.

Recent studies demonstrate that maintaining a protective microbiota

could be critical in preventing dysbiosis-related diseases such as

allergies, autoimmune disorders and metabolic syndrome.

Antimicrobial ResistanceExperts from EFSA and the European Medicines Agency (EMA) have reviewed the measures

taken in the EU to reduce antimicrobial use in animals to combat antimicrobial resistance

(AMR) and they stress there is no one-size-fits-all solution.

On 23 February 2017, EFSA and the European Centre for Disease Prevention and Control

(ECDC) published their annual report on the levels of antimicrobial resistance in food, animals

and humans across the EU. The survey5 highlighted a lack of awareness of antimicrobial

resistance among consumers, and that veterinarians and farmers observed a decline in the

effectiveness of antibiotics on swine and poultry. These results correlate with the information

gathered by the Eurobarometer survey on AMR6 published by the European Commission in

June 2016. In addition, EFSA, EMA and ECDC are working on a report that assesses the link

between consumption of antimicrobials and the development of resistance in bacteria found in

animals and humans—due to be published at the end of July 2017.

It is interesting to note the ways EFSA recommends to reduce or replace antibiotics in

animals: ‘Alternatives to antimicrobials have been shown to improve animal health and

thereby reduce the need to use antimicrobials include vaccines, probiotics, prebiotics,

bacteriophages and organic acids’7.





Antibiotic Use in Humans If probiotics are considered as effective alternatives to antibiotics

for animals, would it make sense for the EU, EFSA or other

organisations to investigate whether this is also the case for

humans? The World Health Organization (WHO), IPA Europe,

ISAPP and many other organisations believe reducing the

misuse and overuse of antibiotics in humans is crucial in

combating the complex problem of AMR and constitutes an

urgent mandate in healthcare.

Probiotics is currently one of the most popular topics in the field of

science and food industry. The EU situation must be apprehended from a

combination of regulatory, economic, social, and scientific approaches.

Probiotic foods are among the most studied foods in the world and fostering a

favourable environment for probiotics will benefit not only a serious and innovative

industry but also consumers.

Rosanna Pecere is Executive Director of IPA Europe.

References:

1. MINTEL 2012, The use of Probiotics in FMCGs – study conducted for YLFA, showing the number of new launches with a probiotic as sales name in the F&D retail market in Europe, for the period 1996/2012.

2. MINTEL 2016, Use of the term probiotic in dairy products.

3. Lenoir-Wijnkoop I, et al, Public health and budget impact of probiotics on common respiratory tract infections: a modelling study. PLoS One. 2015; 10: e0122765.

4. Expert consensus document: The International Scientific Association for Probiotics and Prebiotics consensus statement on the scope and appropriate use of the term probiotic, Reviews Gastroenterology & Hepatology | Consensus Statement

5. The European Union summary report on antimicrobial resistance in zoonotic and indicator bacteria from humans, animals and food in 2015. http://www.efsa.europa.eu/en/efsajournal/pub/4694

6. Eurobarometer results on Antimicrobial Resistance awareness http://ec.europa.eu/dgs/health_food-safety/amr/index_en.htm

7. EFSA 2017, It’s time to reduce, replace and re-think the use of antimicrobials in animals. https://www.efsa.europa.eu/en/press/news/170124-0


http://uniquebiotech.com/


TThe oral cavity is a complex microbial system that harbours more than 700 different bacterial

species1 and the biofilm formed by bacterial communities can reside on soft and hard tissues

covered with saliva and crevicular fluid.² Oral biofilms are associated with infectious diseases,

such as tooth decay, also known as caries, and periodontal disease. Periodontal disease (PD) is

a chronic immunoinflammatory polymicrobial disease that includes gingivitis, when affecting

only the gingiva, and periodontitis, which also affects the tooth supporting structures (alveolar

bone, cementum and periodontal ligament) and can lead to tooth loss. PD affects a large part

of the population3 with epidemiological data evaluating the percentage of occurrence of PD in

the United States showing one in two Americans aged 30 years or older had PD.4 Of these,

47 percent, representing 64.7 million adults, had periodontitis in mild (8.7 percent), moderate

(30 percent) and severe (8.5 percent) forms. Furthermore, moderate or severe periodontitis

occurred in 64 percent of adults over 65 years old.4

The host microbial community is referred to as the microbiome, a term that defines an

ecological community of commensal, symbiotic and pathogenic microorganisms that share the

body and are determinants of health and disease states.5,6-8 Although the biofilms are

associated with infectious diseases, it has been suggested that microbial communities can also

play a beneficial role in protecting the host against infectious conditions.9 The reason for this

apparent duality may be based on the bacterial interactions that influence the composition and

pathogenicity of the microbial community present in the biofilm.10 Therefore, strategies aiming

to modify the composition of the biofilm—promoting a conversion from a dysbiotic state to

homeostasis—may be a promising approach to modulate the interactions between bacteria

and host, consequently influencing the prevention or treatment of infectious oral diseases.

These new approaches differ from antibiotics and intend to reduce the capacity of pathogens

to cause disease and to maintain a commensal microbiota free of damage.

The presence of the bacterial biofilm is the primary etiological factor for the onset of gingival

inflammation and subsequent destruction of tooth-supporting tissues.2,11 However, it is

important to highlight that the isolated presence of the biofilm accounts for a small proportion

(20 percent) of the variation in PD expressions. Following a new model of pathogenesis, the

main factor contributing to the destruction of hard and soft tissues in PD would be the

activation of the immunoinflammatory response to bacterial aggressions.12 In addition,

acquired and environmental risk factors (e.g. diabetes, smoking and stress) and some

genetically transmitted characteristics (e.g. gene polymorphisms for interleukin [IL] -1) may

accentuate the inflammatory response and, eventually, the susceptibility to PD.12

Currently, the therapy of choice for the treatment of periodontitis is scaling and root planing

(SRP) to remove the dental biofilm.13 However, the isolated use of SRP does not produce the

Oral Microbiome

IN THIS ISSUE Regulatory Framework p.5 Intestinal Barrier Function p.20 Table of Contents p.2

The Oral Microbiome and Periodontal DiseaseBy Michel Messora, DDS, PhD, Pedro Henrique Silva, DDS, Renata Cardoso, DDS, Flávia Furlaneto, DDS, PhD



desired clinical results in some advanced cases of PD. In these situations, pathogens recolonise

the periodontal sites and disease reoccurs,13 which may require the clinician to use

antimicrobial therapy (antibiotics) with SRP. Considering the limitations of SRP in the treatment

of PD, the recolonisation of periodontal sites after SRP,14 and the participation of several host

immune system mechanisms in a disease’s pathogenesis, the use of new adjuvant therapies,

such as probiotics, in the treatment of periodontitis has aroused the interest of the scientific

community, since they can modulate the immunoinflammatory host response and modify the

bacterial microenvironment.15 It is important to emphasise that this approach avoids the

development of resistant bacterial strains, as may be seen with antibiotics. In 2015, the

pathogenic agents resistant to antibiotics caused more than 50,000 deaths in Europe and in

the United States. It is estimated this number will increase to 10 million deaths per year

worldwide by 2050.16

To be a good candidate as an oral probiotic, it is essential that the microorganism can adhere

to buccal surfaces coated with saliva, can form biofilm, can survive in oral cavity conditions and

avoids producing malodour. The aim of probiotic therapy is to replace non-resident pathogens

with non-pathogenic bacteria. Thus, it is necessary that the probiotic is antagonistic towards

the pathogens to be replaced in the oral environment, succeeds in colonising the

microenvironment, resists the environmental conditions and can host defence mechanisms.17,18

Potential strains should not demonstrate toxicity, should not be able to spread antibiotic-

resistant genes and should not promote the development of caries.17 The strains should also be

of human origin and be isolated from the oral environment, since they work better in an

environment like the one from which they were originally isolated.17 The immunoinflammatory

mechanisms, which are determinants of the host health-disease process, occur in similar ways

in periodontal tissues and in intestinal mucosa. Therefore, it is believed that the

immunoinflammatory action of probiotics in the oral cavity is comparable to that described in

the intestinal mucosa. Some clinical and preclinical studies, using salivary, gingival crevicular

fluid and gingival biopsy analyses, have demonstrated that probiotic consumption may interfere

with the levels of various inflammatory and anti-inflammatory markers.18,19,20-25

Probiotics versus Periodontal Diseases: Scientific RelevanceGingivitis

In treating gingivitis, Lactobacillus species are the most commonly used in clinical trials which

address the experimental or established model of the disease. Some studies using Lactobacillus

reuteri demonstrated promising results considering the parameters plaque index (PI), gingival

bleeding index (GI) and bleeding on probing (BOP).26-27 Iniesta et al. also observed a reduction in

the total number of anaerobic microorganisms, including the species Porphyromonas gingivalis

Oral Microbiome

The aim of probiotic therapy is to replace non-resident pathogens with non-pathogenic bacteria.



and Prevotella intermedia, in the saliva of individuals with gingivitis after consumption of the

Lactobacillus reuteri probiotic strain for 28 days.28

The reduction of nitrous oxide (NO) levels may attenuate the development of gingivitis.

Using an experimental model of gingivitis, Lee et al. observed a decrease in NO levels in

gingival tissues when patients consumed Lactobacillus brevis CD2 prior to the suspension of

their oral hygiene.29 Similar results were found by Staab et al.,30 who used Lactobacillus casei

to prevent the development of experimental gingivitis. Analysing the gingival crevicular fluid,

the authors identified a decrease in the levels of elastase and matrix-metalloproteinase-3

(MMP-3), which are important inflammatory markers of periodontal tissue degradation.

On the other hand, a recent study found conflicting results when evaluating individuals with

generalised gingivitis using Bacillus species in their toothpaste, mouthwash and toothbrush

cleaning solution.31 No significant differences in PI, GI and BOP were observed among

participants who used products containing probiotics or placebo. This could be explained by

the low concentration of probiotic microorganisms in the products used in the study.

PeriodontitisPreclinical studies are extremely important when evaluating new probiotic strains for

periodontitis treatment because they provide data regarding the safety and efficacy of the

probiotics. Among the strains most commonly used in preclinical studies with experimental

periodontitis are the bacteria from the genera Lactobacillus, Streptococcus and

Bifidobacterium.19 In a proof-of-concept study, Streptococcus species could promote a delay in

the recolonisation of periodontal sites by periodontopathogens and reduce periodontal

inflammation in dogs with experimental periodontitis.32

Our group evaluated the effects of SRP with and without probiotic therapy, using

Bacillus subtilis and Bacillus licheniformis strains, in rats.25 The use of probiotics

promoted lower levels of alveolar bone loss and connective tissue attachment loss,

demonstrating an adjuvant potential in the non-surgical treatment of periodontitis.

Using the same strains, other studies from our group observed similar results

regarding reduced alveolar bone loss and attachment loss in animals with

experimental periodontitis.24,33 Another interesting finding with the use of these strains is

related to the intestinal villi aspect of the animals. The rats with experimental periodontitis not

treated with probiotics presented a higher number of intestinal villi damaged when compared

with the animals that received probiotics.

Our group also demonstrated that the topical use of Bifidobacterium animalis subsp. lactis

HN019 in animals with experimental periodontitis promoted positive microbiological results,

since there was a greater proportion of Actinomyces and Streptococcus species, compatible

with periodontal health, and decreased proportions of species compatible with disease—like

Veillonella parvula, Capnocytophaga sputigena, Eikenella corrodens and Prevotella

intermedia—in the oral biofilm.19 Administering HN019 was also promising for connective

tissue attachment, bone volume and porosity, separation of bone trabeculae, expression of

osteoprotegerin (OPG), beta-defensins, IL-1β and receptor-activator of nuclear factor kappa

beta ligand (RANKL). These results were obtained through the preclinical investigation by

Oliveira et al.,19 who evaluated HN019 as a solution for subgingival irrigation in rats with

experimental periodontitis.

Oral Microbiome


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Maekawa and Hajishengallis evaluated the effects of local administration of Lactobacillus

brevis in mice with induced periodontitis.23 The animals treated presented decreased bone loss,

a lower number of anaerobic microorganisms, as well as reduced levels of pro-inflammatory

markers (IL-1β, IL-6, IL-17 and TNF-∝) when compared to the control group.

In addition to bacteria, other microorganisms may act as probiotics. Garcia et al. evaluated

the effects of the yeast Sacharomyces cerevisiae as a monotherapy or adjunctive therapy to

mechanical debridement in the treatment of experimental periodontitis in rats.34 The animals

were assigned to four experimental groups: group C (no treatment performed), group SRP,

group PRO (subgingival irrigation with S. cerevisiae) and group SRP/PRO (SRP and irrigation

with S. cerevisiae). By analysing periodontal tissues, the authors concluded that the irrigating

solution containing S. cerevisiae used as a monotherapy or adjunctive therapy was effective in

controlling periodontitis in rats.

Clinical trials studying the effects of probiotics have been centred on their potential as

adjuvants to SRP in periodontitis treatment. In these studies, probiotics were administered in

tablets, lozenges, mouth rinses or solutions for subgingival irrigation. Several trials presented

favourable results with the use of Lactobacillus reuteri as an adjuvant therapy in the treatment

of periodontitis.32,35,36,37 Patients with chronic periodontitis treated with L. reuteri presented a

delay in the recolonisation of periodontal sites.37 Reductions in periodontitis progression as

well as the need for surgical periodontal treatment were also observed.32 The anti-

inflammatory and antimicrobial actions, as well as the inhibitory effects on dental biofilm

formation, led to the recommendation of probiotic therapy during the nonsurgical and

maintenance phases of the periodontal treatment.35

Shah et al. investigated the actions of the probiotic Lactobacillus brevis and doxycycline,

alone or in association, in patients with aggressive periodontitis.38 In this study, probiotic

therapy proved to be a good alternative for the use of antibiotics in the treatment of

aggressive periodontitis. Using mouthwashes containing Bacillus subtilis as an adjuvant

therapy, Tsubura et al. conducted a randomised controlled clinical trial with patients presenting

chronic periodontitis.39 The participants were treated with SRP and used mouthwashes

containing Bacillus species for 30 days. The authors observed significantly lower scores for the

N-benzoyl-DL-arginine-2-naphthylamide (BANA) test in subjects who used the probiotic-

containing mouthwash when compared to those using the placebo solution.

Another controlled clinical trial evaluated solutions for subgingival irrigations and

mouthwashes with Lactobacillus salivarius and Lactobacillus reuteri. Patients presenting chronic

periodontitis received SRP and were assigned to test or control groups.40 In the test group, four

subgingival irrigations were performed and mouthwashes containing the probiotic solution

were used for 15 days. In the control group, placebo solutions were used. After three months,

the authors observed significantly better results in relation to PI, modified gingival index and

bleeding index in individuals of the test group. In addition, the test group presented better

results in the reduction of probing depths in moderate pockets and a greater microbiological

reduction, evaluated through the BANA test.

Different from the findings obtained in clinical trials using the probiotic strains previously

mentioned, no advantageous clinical results were observed with the use of Lactobacillus

Oral Microbiome



Oral Microbiome

rhamnosus and Streptococcus species as adjuvants to SRP.41,42 Furthermore, Lactobacillus casei

has not shown beneficial effects when used as a monotherapy in the treatment of patients

with chronic periodontitis.43 In this context, it is important to emphasise that the findings

obtained with the use of probiotics in PD are dependent on the strain, dosage, frequency and

form of administration.44 Furthermore, although the evidence is limited and biological

mechanisms of the effects of probiotics are not yet fully elucidated,45 they can be considered a

potential adjuvant therapy in the management of periodontal diseases.

Michel Messora is a full-time professor in the School of Dentistry of Ribeirao Preto, University of Sao Paulo and Vice-Chairman of the Department of Oral Surgery and Periodontology.

Flávia Furlaneto is a Postdoctoral Research Fellow in the School of Dentistry of Ribeirao Preto, University of Sao Paulo and advisor in the Post-Graduate Program in Dentistry (Periodontology).

References:

1. Aas JA, Paster BJ, Stokes LN, Olsen I, Dewhirst FE. ‘Defining the normal bacterial flora of the oral cavity’. J Clin Microbiol. 2005;43(11):5721-32.

2. Kolenbrander PE. ‘Oral microbial communities: biofilms, interactions, and genetic systems’. Annu Rev Microbiol. 2000;54:413-37.

3. Darveau RP. ‘Periodontitis: a polymicrobial disruption of host homeostasis’. Nat Rev Microbiol. 2010;8(7):481-90.

4. Eke PI, Dye BA, Wei L, Thornton-Evans GO, Genco RJ. CDC Periodontal Disease Surveillance workgroup: James Beck (University of North Carolina, Chapel Hill, USA), Gordon Douglass (Past President, American Academy of Periodontology), Roy Page (University of Washin). ‘Prevalence of periodontitis in adults in the United States: 2009 and 2010’. J Dent Res. 2012; 91:914-20.

5. Turnbaugh PJ, Ley RE, Hamady M, Fraser-Liggett CM, Knight R, Gordon JI. ‘The human microbiome project’. Nature. 2007;449(7164):804-10.

6. Lederberg J, Mccray A. ‘‘Ome sweet ‘omics – a genealogical treasury of words’. Scientist. 2001;15:8–10.

7. Wade WG. ‘The oral microbiome in health and disease’. Pharmacol Res. 2013;69(1):137-43.

8. Kilian M, Chapple IL, Hannig M, Marsh PD, Meuric V, Pedersen AM et al. ‘The oral microbiome - an update for oral healthcare professionals’. Br Dent J. 2016;221(10):657-66.

9. Sbordone L, Bortolaia C. ‘Oral microbial biofilms and plaque-related diseases: microbial communities and their role in the shift from oral health to disease’. Clin Oral Investig. 2003;7(4):181-8.

10. Kuramitsu HK, He X, Lux R, Anderson MH, Shi W. ‘Interspecies interactions within oral microbial communities’. Microbiol Mol Biol Rev. 2007;71(4):653-70.

11. Haffajee AD, Socransky SS. ‘Microbial etiological agents of destructive periodontal diseases’. Periodontol 2000. 1994;5:78-111.

12. Salvi GE, Lang NP. ‘Host response modulation in the management of periodontal diseases’. J Clin Periodontol. 2005;32(6):108-29.

13. Berezow AB, Darveau RP. ‘Microbial shift and periodontitis’. Periodontol 2000. 2011;55:36-47.

14. Quirynen M, Avontroodt P, Peeters W, Pauwels M, Coucke W, van Steenberghe

D. ‘Effect of different chlorhexidine formulations in mouthrinses on de novo plaque formation’. J Clin Periodontol. 2001;28(12):1127-36.

15. Greenstein G. ‘Local drug delivery in the treatment of periodontal diseases: assessing the clinical significance of the results’. J Periodontol. 2006;77:565-578.

16. Langdon A, Crook N, Dantas G. ‘The effects of antibiotics on the microbiome throughout development and alternative approaches for therapeutic modulation’. Genome Med. 2016;8(1):39.

17. Bosch M, Nart J, Audivert S, Bonachera MA, Alemany AS, Fuentes MC, Cuñé

J. ‘Isolation and characterization of probiotic strains for improving oral health’. Arch Oral Biol. 2012;57(5):539-49.

18. Stamatova I, Meurman JH. ‘Probiotics and periodontal disease’. Periodontol 2000. 2009;51:141-51.

19. Oliveira LF, Salvador SL, Silva PH, Furlaneto FA, Figueiredo L, Casarin R et al. ‘Benefits of bifidobacterium animalis subsp lactis probiotic in experimental periodontitis’. J Periodontol. 2016:1-20.

20. Riccia DN, Bizzini F, Perilli MG, Polimeni A, Trinchieri V, Amicosante G et al. ‘Anti-inflammatory effects of Lactobacillus brevis (CD2) on periodontal disease’. Oral Dis. 2007;13(4):376-85.

21. Shimauchi H, Mayanagi G, Nakaya S, Minamibuchi M, Ito Y, Yamaki K et al. ‘Improvement of periodontal condition by probiotics with Lactobacillus salivarius WB21: a randomized, double-blind, placebo-controlled study’. J Clin Periodontol. 2008;35(10):897-905.



Oral Microbiome

22. Szkaradkiewicz AK, Stopa J, Karpinski TM. ‘Effect of oral administration involving a probiotic strain of Lactobacillus reuteri on pro-inflammatory cytokine response in patients with chronic periodontitis’. Arch Immunol Ther Exp (Warsz). 2014;62(6):495-500.

23. Maekawa T, Hajishengallis G. ‘Topical treatment with probiotic Lactobacillus brevis CD2 inhibits experimental periodontal inflammation and bone loss’. J Periodontal Res. 2014;49(6):785-91.

24. Foureaux Rde C, Messora MR, de Oliveira LF, Napimoga MH, Pereira AN, Ferreira MS et al. ‘Effects of probiotic therapy on metabolic and inflammatory parameters of rats with ligature-induced periodontitis associated with restraint stress’. J Periodontol. 2014;85(7):975-83.

25. Messora MR, Pereira LJ, Foureaux R, Oliveira LF, Sordi CG, Alves AJ et al. ‘Favourable effects of Bacillus subtilis and Bacillus licheniformis on experimental periodontitis in rats’. Arch Oral Biol. 2016;66:108-19.

26. Krasse P, Carlsson B, Dahl C, Paulsson A, Nilsson A, Sinkiewicz G. ‘Decreased gum bleeding and reduced gingivitis by the probiotic Lactobacillus reuteri’. Swed Dent J. 2006:30(2):55-60.

27. Twetman S, Derawi B, Keller M, Ekstrand K, Yucel-Lindberg T, Stecksen-Blicks C. ‘Short-term effect of chewing gums containing probiotic Lactobacillus reuteri on the levels of inflammatory mediators in gingival crevicular fluid’. Acta Odontol Scand. 2009;67(1):19-24.

28. Iniesta M, Herrera D, Montero E, Zurbriggen M, Matos AR, Marin MJ et al. ‘Probiotic effects of orally administered Lactobacillus reuteri-containing tablets on the subgingival and salivary microbiota in patients with gingivitis. A randomized clinical trial’. J Clin Periodontol. 2012;39(8):736-44.

29. Lee JK, Kim SJ, Ko SH, Ouwehand AC, Ma DS. ‘Modulation of the host response by probiotic Lactobacillus brevis CD2 in experimental gingivitis’. Oral Dis. 2015;21(6):705-12.

30. Staab B, Eick S, Knofler G, Jentsch H. ‘The influence of a probiotic milk drink on the development of gingivitis: a pilot study’. J Clin Periodontol. 2009;36(10):850-6.

31. Alkaya B, Laleman I, Keceli S, Ozcelik O, Cenk Haytac M, Teughels W. ‘Clinical effects of probiotics containing Bacillus species on gingivitis: a pilot randomized controlled trial’. J Periodontal Res 2016.

32. Teughels W, Newman MG, Coucke W, Haffajee AD, Van Der Mei HC, Haake SK et al. ‘Guiding periodontal pocket recolonization: a proof of concept’. J Dent Res. 2007;86(11):1078-82.

33. Messora MR, Oliveira LF, Foureaux RC, Taba M, Jr., Zangeronimo MG, Furlaneto FA et al. ‘Probiotic therapy reduces periodontal tissue destruction and improves the intestinal morphology in rats with ligature-induced periodontitis’. J Periodontol. 2013;84(12):1818-26.

34. Garcia VG, Knoll LR, Longo M, Novaes VC, Assem NZ, Ervolino E et al. ‘Effect of the probiotic Saccharomyces cerevisiae on ligature-induced periodontitis in rats’. J Periodontal Res. 2016;51(1):26-37.

35. Vivekananda MR, Vandana KL, Bhat KG. ‘Effect of the probiotic Lactobacilli reuteri (Prodentis) in the management of periodontal disease: a preliminary randomized clinical trial’. J Oral Microbiol. 2010;2.

36. Ince G, Gursoy H, Ipci SD, Cakar G, Emekli-Alturfan E, Yilmaz S. ‘Clinical and Biochemical Evaluation of Lozenges Containing Lactobacillus reuteri as an Adjunct to Non-Surgical Periodontal Therapy in Chronic Periodontitis’. J Periodontol. 2015;86(6):746-54.

37. Tekce M, Ince G, Gursoy H, Dirikan Ipci S, Cakar G, Kadir T et al. ‘Clinical and microbiological effects of probiotic lozenges in the treatment of chronic periodontitis: a 1-year follow-up study’. J Clin Periodontol. 2015;42(4):363-72.

38. Shah MP, Gujjari SK, Chandrasekhar VS. ‘Evaluation of the effect of probiotic (inersan(R)) alone, combination of probiotic with doxycycline and doxycycline alone on aggressive periodontitis - a clinical and microbiological study’. J Clin Diagn Res. 2013;7(3):595-600.

39. Tsubura S, Mizunuma H, Ishikawa S, Oyake I, Okabayashi M, Katoh K et al. ‘The effect of Bacillus subtilis mouth rinsing in patients with periodontitis’. Eur J Clin Microbiol Infect Dis. 2009;28(11):1353-6.

40. Penala S, Kalakonda B, Pathakota KR, Jayakumar A, Koppolu P, Lakshmi BV et al. ‘Efficacy of local use of probiotics as an adjunct to scaling and root planing in chronic periodontitis and halitosis: A randomized controlled trial’. J Res Pharm Pract. 2016;5(2):86-93.

41. Laleman I, Yilmaz E, Ozcelik O, Haytac C, Pauwels M, Herrero ER et al. The effect of a streptococci containing probiotic in periodontal therapy: a randomized controlled trial’. J Clin Periodontol. 2015;42(11):1032-41.

42. Morales A, Carvajal P, Silva N, Hernandez M, Godoy C, Rodriguez G et al. ‘Clinical effects of lactobacillus rhamnosus in non-surgical treatment of chronic periodontitis: a randomized placebo-controlled trial with 1-year follow-up’. J Periodontol. 2016;87(8):944-52.

43. Imran F, Das S, Padmanabhan S, Rao R, Suresh A, Bharath D. ‘Evaluation of the efficacy of a probiotic drink containing Lactobacillus casei on the levels of periodontopathic bacteria in periodontitis: A clinico-microbiologic study’. Indian J Dent Res. 2015;26(5):462-8.

44. Teughels W, Loozen G, Quirynen M. ‘Do probiotics offer opportunities to manipulate the periodontal oral microbiota?’ J Clin Periodontol. 2011 Mar;38 Suppl 11:159-77.

45. Chapple IL, Bouchard P, Cagetti MG, Campus G, Carra MC, Cocco F, Nibali L, Hujoel P, Laine ML, Lingstrom P, Manton DJ, Montero E, Pitts N, Rangé H, Schlueter N, Teughels W et al. ‘Interaction of lifestyle, behavior or systemic diseases with dental caries and periodontal diseases: consensus report of group 2 of the joint EFP/ORCA workshop on the boundaries between caries end periodontal diseases’. J Clin Periodontol. 2017;44(18):39-51.


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TThe gastrointestinal (GI) tract comprises an enormous surface area that is optimised

to efficiently absorb nutrients, water and electrolytes from food. Concomitantly, it

provides a selective barrier against the ingress of harmful substances and pathogens

from the external environment. A dysfunctional intestinal barrier or ‘leaky gut’ is

associated with many diseases and disorders. This article is a summary of a recently

published review article written by several experts in the field1, discussing the role of

intestinal barrier function in common disorders, including infections with intestinal

pathogens, inflammatory bowel diseases (IBD), irritable bowel syndrome (IBS),

obesity, coeliac disease, non-coeliac gluten sensitivity and food allergies.

The intestinal barrier comprises the mucus layer, the epithelial cells, and the

underlying layer of connective tissue containing immune system cells (lamina

propria). The intestinal epithelial cells are connected by tight junction proteins that

regulate permeability between the cells. The intestinal microbiota and antimicrobial

peptides also play crucial roles in providing a functional gut barrier. A disruption of this

barrier results in increased intestinal permeability, meaning harmful substances and pathogens

can enter the bloodstream.

The Intestinal Epithelial Barrier in Infection Infectious intestinal pathogens, including various bacteria and viruses, have different

mechanisms to gain access to the host. Some directly adhere to and invade the intestinal

epithelial barrier, while others disrupt this barrier via the secretion of toxic compounds. Many

common pathogens have developed mechanisms that directly target tight junction proteins,

increasing permeability between cells and facilitating the pathogens’ invasion. One example is

enteropathogenic E. coli (EPEC), which is a common cause of diarrhoea, particularly in infants.

Other pathogenic E. coli such as enteroaggregative E. coli (EAEC) and enterotoxigenic E. coli

(ETEC) colonise the epithelial layer and produce enterotoxins that can cause diarrhoea by

directly increasing chloride ion secretion from the intestinal epithelial cells2. In addition, some

of these endotoxins also damage the tight junction proteins, again leading to increased

permeability3. Helicobacter pylori (H. pylori) bacteria act in a similar way. They secrete a toxin,

CagA, into the host cells, which leads to disruption of the tight junctions and thus the barrier4.

It is thought that in this way, the bacteria gain access to iron and nutrients to support their

growth. The disruption of the barrier also allows H. pylori to enter the lamina propria. Vibrio

cholerae bacteria produce zonula occludens toxins (ZOT), which cause diarrhoea by directly

acting on the tight junction proteins5.

Human Intestinal Barrier Function in Health and Diseaseby Julia König

Intestinal Barrier Function

IN THIS ISSUE Oral Microbiome p.12 Takeaways p.28 Table of Contents p.2



In summary, several GI pathogens mediate changes in tight junction proteins to increase

intestinal permeability and, thereby, facilitate release of nutrients and gain access to the host.

Pharmacological or nutritional approaches to maintain the integrity of tight junctions and the

epithelium may interfere with the pathogenesis of disease caused by these GI pathogens. This

could involve the intake of specific probiotics which support the tight junctions6, or can replace

existing pathogens or inhibit their adherence7. Accordingly, several probiotic strains have been

shown to successfully prevent traveller’s diarrhoea8.

Inflammatory Bowel Diseases IBDs are characterised by excessive inflammation in the gut wall. The most common IBD

types are Crohn’s disease and ulcerative colitis. In Crohn’s disease, the entire GI tract can be

affected, and the inflammation extends into the deeper layers of the gut wall. Ulcerative colitis

is restricted to the colon, and the inflammation is more superficial. The causes of IBD are still

not understood.

Patients with active IBD have clear epithelial barrier defects, manifested by clearly visible

ulcers (holes or breaks in the protective lining of the intestine). When patients enter remission,

barrier function improves; however, it rarely returns to normal. This is most likely due to the

low level of inflammation present even in remission in those patients9. It is difficult to

investigate whether the increased intestinal permeability in IBD is a result of the severe

intestinal inflammation, or if it is important as an independent risk factor. Unaffected relatives

of IBD patients are known to have a 30-fold increase in the risk of developing IBD. Permeability

tests in these individuals are normal, however, in response to an insult, such as a non-steroidal

anti-inflammatory drug (NSAID), a subset of relatives showed markedly increased

permeability10. Thus, even though the epithelial barrier may not be leaky in IBD, the response

to injury may be diminished, perhaps due to impaired healing or delayed epithelial reparation.

Many studies have shown there is a dysbiosis of the intestinal microbiota in active IBD, which

could contribute to a disturbed epithelial barrier function. Crohn’s disease patients often show

reduced complexity of the phylum Firmicutes, and a decreased quantity of Faecalibacterium

prausnitzi11. Several Firmicutes species ferment complex carbohydrates in the colon and

produce butyrate, which has been shown to reduce visceral perception in healthy subjects, and

has anti-inflammatory as well as barrier-strengthening properties12. Additionally, E. coli

pathobionts displaying pathogen-like behaviours that disrupt the epithelial barrier are more

frequently cultured from IBD patients13.

Several genetic susceptibility loci related to barrier function have also been associated with

the development of IBD14. Defects in NOD2—an intracellular receptor recognising bacterial cell

wall components and activating a respective immune response15—are suggested to result in

IBDs are characterised by excessive inflammation in the gut wall. The most common IBD types are Crohn’s disease and ulcerative colitis.





lower α-defensin secretion from Paneth cells in the intestine and, thus, in an increase in

mucosal bacteria16. However, it is important to note that genetically-encoded variants are not

causal and only have a very small effect on IBD compared to environmental factors.

Even though IBD patients have clear intestinal barrier defects, it is not known whether

sustaining the barrier would allow patients to remain in remission longer. In that case,

nutritional or pharmaceutical compounds that show a positive effect on barrier function could

have the potential to prolong remission.

Irritable Bowel SyndromeIBS is a common chronic GI disorder that affects 10 to 20 percent of the adult population in

Western countries17. It is characterised by recurrent abdominal pain or discomfort that occurs

in association with altered bowel habits. IBS is a multi-factorial disease and its underlying

mechanisms are not well understood. However, there is consensus that aberrations along the

gut-brain axis play an important role. These aberrations involve the gut microbiota, mucosal

immune activation, the intestinal barrier, afferent sensory signalling (‘visceral hypersensitivity’)

and brain function. The intestinal barrier plays a central role in this interplay and might act as a

‘surrogate’ marker for aberrations involving the other factors. Indeed, many IBS patients show

signs of increased intestinal permeability, as measured by sugar recovery in urine after oral

administration18,19. Ex vivo experiments show an almost two-fold increased permeability in

colonic biopsies of IBS patients compared to healthy controls, which correlates with lower gene

expression of ZO-1, a tight junction protein, in biopsies from IBS patients20,21. Further in vitro

analysis showed that soluble factors in the colonic epithelium might mediate this effect. The

supernatant of cultured colonic biopsies from IBS patients increased permeability in a cell

model of the intestinal barrier (Caco-2 cells), and increased the degranulation rate of intestinal

mast cells isolated from rats22. The activation of mast cells results in the release of proteases

and histamine that can directly damage the intestinal barrier23. Intestinal mast cells can also be

activated by the corticotropin-releasing hormone as part of the acute stress response. A large

proportion of IBS patients (more than 35 percent) suffer from increased anxiety and perceived

stress, providing a possible link to a disturbed barrier function24. In addition, in some IBS

patients, a low-grade intestinal inflammation characterised by mast cell activation can be

found. Visceral hypersensitivity, defined as an increased perception of pain originating in the

intestines, has also been linked to increased intestinal permeability and is a hallmark of IBS25.

Like IBD, the gut microbiota in IBS shows alterations and butyrate-producing bacteria

are affected26.


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Intestinal barrier function plays a central role in IBS and needs to be further investigated.

Clinical tests that assess barrier function and are easy to perform could support the

identification of subgroups of patients with barrier dysfunctions. IBS is often a lifelong disorder,

and there is an unmet need for non-pharmaceutical treatments. Nutritional compounds that

improve barrier function could be a promising treatment option.

Obesity Obesity is classically associated with metabolic alterations such as glucose intolerance, type 2

diabetes and insulin resistance, as well as with cardiovascular risk factors, including

hypertension and dyslipidaemia27. A hallmark of metabolic syndrome and its related disorders is

systemic low-grade inflammation28, which is directly related to intestinal barrier dysfunction.

The factors triggering this low-grade inflammation and their effect on disease progression are

currently being investigated. Studies in mice have shown gut microbiota-derived

lipopolysaccharide (LPS) is an important factor involved in the onset and progression of

inflammation associated with obesity29. LPS are cell wall components of gram-negative

bacteria, which are potent inducers of inflammation and can initiate severe systemic effects.

Under healthy physiological conditions, the intestinal epithelium acts as a barrier that prevents

translocation of LPS. Cani et al. demonstrated that in mice, a high-fat diet resulted in

chronically increased plasma LPS levels, defined as metabolic endotoxemia30. Among the

factors explaining metabolic endotoxemia after a high-fat diet, gut barrier dysfunction seems

to play an especially important role. A high-fat diet led to reduced expression of epithelial tight

junction proteins in mice31, reduced mucus layer thickness and impaired antimicrobial peptides

production, which could be counteracted by prebiotic treatment as well as treatment with

Akkermansia muciniphila32,33.

Similar processes have also been shown for humans. Erridge et al. demonstrated that a

high-fat meal induced metabolic endotoxemia with high enough LPS concentrations to induce

a significant degree of inflammation34. Amar et al. found a positive relationship between

energy intake and metabolic endotoxemia in a cohort of 201 healthy men35. Furthermore, it

has been shown that metabolic endotoxemia increases adipose tissue markers of inflammation

such as tumour necrosis factor-α (TNF-α) and interleukin-6 (IL-6), as well as insulin resistance in

healthy volunteers36. Several studies have shown that circulating LPS levels are also increased

in type 2 diabetes37,38 and probably play an important role in chronic liver diseases39,40.

Gummesson et al. showed waist circumference, as well as visceral fat and liver fat, correlated

positively with large intestinal permeability in obese subjects41.

These and future studies will hopefully provide the basis for new diet-based therapeutic

possibilities to improve intestinal barrier function in obese subjects.

Intestinal Permeability in Coeliac DiseaseCoeliac disease is an immune-mediated disorder of the small intestine that occurs in

genetically susceptible individuals (HLA-DQ2/DQ8 haplotype). It is triggered by an abnormal

reaction towards gliadin, a component of gluten proteins found in wheat and related proteins

of other grains. Coeliac disease is characterised by various degrees of villous atrophy of the

small bowel mucosa, malabsorption and impaired integrity of the small bowel epithelium with

increased lymphocytic infiltration.




Coeliac disease patients are known to have an abnormal tight junction structure42,43,44 and

increased intestinal permeability45,46,47. Even though the mechanisms are unknown, it is

hypothesised that in coeliac disease, gliadin can pass through the intestinal epithelium into the

lamina propria, where it triggers an immune reaction, whereas a healthy intestinal epithelial

layer prevents gliadin from entering48. Gliadin has been shown to increase intestinal

permeability by enhancing the release of zonulin49, a protein that modulates tight junction

proteins. The expression of zonulin has been found to be increased in the intestinal submucosa

of patients with active coeliac disease compared to healthy controls. Accordingly, ZO-1 was

reduced in duodenal biopsies of coeliac disease patients, but returned to normal levels after a

gluten-free diet50.

Intestinal Permeability in Non-Coeliac Gluten SensitivityIn the last few years, it has become more recognised that a clinical reaction to food

containing gluten can also occur without the involvement of allergic or autoimmune

mechanisms. This condition is classified as non-coeliac gluten sensitivity51. It is not completely

clear whether gluten or other components in wheat are responsible for the symptoms, and not

much is known yet about its pathophysiology. Gluten-sensitive individuals are negative for

anti-tissue transglutaminase antibodies, and epithelial lesions in the small intestine or illous

atrophy are absent, but some studies have shown signs of a mild mucosal immune activation52.

Studies so far could not find increased permeability in gluten-sensitive subjects53,54. Further

studies with larger numbers of participants are necessary before conclusions regarding an

increased permeability in non-coeliac gluten sensitivity can be drawn.

Intestinal Permeability in Food AllergyAn increased intestinal permeability has been reported in children and adults suffering from

food allergy or intolerance. Even when adhering to strict allergen diets, this increased

permeability can persist. Ventura et al. showed that patients with food allergy and food

hypersensitivity who had been on an allergen-free diet for six months had about a three-fold

increase in intestinal permeability compared to healthy controls (measured with the lactulose/

mannose urinary excretion test)55. Intestinal permeability correlated positively with symptom

severity. Järvinen et al. reported 38 percent of asymptotic children with food allergies still had

an increased permeability even though they were on strict elimination diets56. It is hypothesised

that in those patients, food particles/allergens can cross the epithelial barrier and cause an

allergic reaction characterised by mast cell recruitment and allergen-specific IgE production. In

turn, inflammatory mediators (cytokines, proteases) lead to further disintegration of barrier

function and increased passage of allergens57. Even though studies suggest increased

permeability can be a risk factor for developing a food allergy in a subset of patients, the

increased intestinal permeability could also be a consequence of the allergic reaction, and more

clinical studies are needed to investigate this further.

A dysfunctional intestinal barrier is involved in a variety of disorders and diseases, and the

maintenance of a functional barrier is important for health. Conditions not discussed here in

which intestinal barrier dysfunction plays an important role include alcohol abuse, intake of




certain drugs (proton pump inhibitors, NSAIDs), strenuous exercise and enteral feeding. Further

research on the causes and prevention of intestinal barrier dysfunction—as well as how to

restore its function—will lead to the development of new therapeutic strategies.

Julia König is a Postdoctoral Research Fellow at the Nutrition-Gut-Brain Interactions Research Centre, Faculty of Health and Medicine, School of Medical Sciences, Orebro University, Orebro, Sweden.

References:

1. König J, ‘Human intestinal barrier function in health and disease’. Clin Transl Gastroenerol. 2016; 7(10): e196

2. Okhuysen PC, DuPont HL, ‘Enteroaggregative Escherichia coli (EAEC): a cause of acute and persistent diarrhea of worldwide importance’. J Infect Dis. 2010; 202: 503-505.

3. Mukiza CN, ‘Escherichia coli heat-stable toxin b impairs intestinal epithelial barrier function by altering tight junction proteins’. Infect Immun. 2013; 81: 2819-2827.

4. Bagnoli F et al, ‘Helicobacter pylori CagA induces a transition from polarized to invasive phenotypes in MDCK cells’. Proc Natl Acad Sci USA. 2005; 102: 16339-16344.

5. Fasano A et al, ‘Vibrio cholerae produces a second enterotoxin, which affects intestinal tight junctions’. PNAS. 1991; 88(12): 5242–5246

6. Karczewski J et al, ‘Regulation of human epithelial tight junction proteins by Lactobacillus plantarum in vivo and protective effects on the epithelial barrier’. American Journal of Physiology – Gastrointestinal and Liver Physiology. 2010; 298: G851-G859.

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15. Hugot JP et al, ‘Association of NOD2 leucine-rich repeat variants with susceptibility to Crohn’s disease’. Nature. 2001; 411: 599-603.

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17. Delvaux M, ‘Functional bowel disorders and irritable bowel syndrome in Europe’. Aliment Pharmacol Ther. 2003; 18: 75-79.

18. Mujagic Z, ‘Small intestinal permeability is increased in diarrhoea predominant IBS, while alterations in gastroduodenal permeability in all IBS subtypes are largely attributable to confounders’. Aliment Pharmacol Ther. 2014; 40(3): 288-97.

19. Zhou Q et al, ‘MicroRNA-29a regulates intestinal membrane permeability in patients with irritable bowel syndrome’. Gut. 2010; 59:13.

20. Zhou Q et al, ‘Intestinal membrane permeability and hypersensitivity in the irritable bowel syndrome’. Pain. 2009; 146: 41-46.

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T

Takeaways

Takeaways for Your BusinessThe probiotic food sector used to be the fastest-growing and most innovative food sector

prior to 2012, when the EU Claims Regulation came into force. While the term ‘probiotic’ has

been essentially outlawed in some (but not all) EU countries, many products are still labelled as

‘probiotic’ without clear or harmonised criteria or conditions in most cases. As a result,

consumers are confused, suffering from the lack of communication about probiotics and

products containing probiotics.

Ambiguity impacts the sector negatively and goes against the EU’s declared objectives to

sustain and promote economic growth and quality jobs. It also poses serious problems for

consumers and health care professionals, who receive conflicting answers to their questions

about probiotics.

In the meantime, probiotic technology is innovating at a very fast pace, creating urgency for

a more efficient and streamlined regulatory framework for consumers, regulators and the

industry. The probiotic sector cannot wait any longer—there is an urgent need to find

concrete, pragmatic solutions.

The use of probiotics in the treatment of periodontitis has aroused the interest of the

scientific community, since they can modulate the immunoinflammatory host response and

modify the bacterial microenvironment. The oral cavity is a complex microbial system that

harbours more than 700 different bacterial species, and the biofilm is associated with

infectious diseases such as periodontal disease. The aim of probiotic therapy is to replace

non-resident pathogens with non-pathogenic bacteria, meaning the probiotic must be

antagonistic toward the pathogens to be replaced, must resist the environmental conditions,

and must host defence mechanisms while avoiding promoting the development of caries.

The intake of specific probiotic strains could also support the gastrointestinal (GI) tract, an

enormous surface area that is optimised to efficiently absorb nutrients, water and electrolytes

from food. Concomitantly, it provides a selective barrier against the ingress of harmful

substances and pathogens from the external environment. A dysfunctional intestinal barrier is

associated with many diseases and disorders, including coeliac

disease, irritable bowel syndrome (IBS) and inflammatory

bowel diseases (IBD). Several probiotic strains have

been shown to successfully prevent traveller’s

diarrhoea and prebiotic treatment could counteract

some GI effects of obesity.

IN THIS ISSUE Intestinal Barrier Function p.20 Contacts p.29 Table of Contents p.2



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Informa Exhibitions2nd Floor5 Howick PlaceLondon SW1P 1WGUnited Kingdom

Phone: +44 (0) 20 3777 3616www.vitafoods.eu.com

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Andrew Rosseau Art Director

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Informa Exhibitions LLC3300 N Central Ave, Ste 300Phoenix, AZ 85012United States

Phone: +1 480 990 1101www.naturalproductsinsider.com

Informa Exhibitions’ Global Health & Nutrition Network is one of the world’s leading knowledge providers. We create and deliver highly specialised information through events, digital media and publishing to provide business, learning and networking opportunities. Informa’s Global Health & Nutrition Network has an unrivalled offering within the health and nutrition marketplace for individuals, businesses and organisations around the globe.

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