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EFFICACIA DEI PROBIOTICI NELLE MALATTIE DIGESTIVE

Antonio Gasbarrini, Gianluca Ianiro

Gastroenterologia Policlinico Universitario Gemelli

Università CaBolica del Sacro Cuore -‐ Roma

Come le conoscenze aBuali su Gut Microbiota influenzano la gesIone dei probioIci?

Microbiota

GUT BARRIER

Acquired and

Innate immunity

Mucosal Barrier

Epithelial barrier

Vascular and lymphatic systems

Neuroenteric system Digestive enzymes

Endocrine system

Virus Bacteriophages

Bacteria Yeast

Not only Bacteria..

Acquired and

Innate immunity

Mucosal Barrier

Epithelial barrier



Endocrine system

Helminth Parasite Archea

Protozoa

GUT MYCOME •  Yeasts are commensal to the gut at low concentrations

•  In the healthy gut dominant species are: Wallemia, Trichocomaceae, Rhodotorula, Saccharomycetaceae, Pleosporaceae, Agaricaceae, Metschnikowiaceae, Cystofilobasidiaceae, Ascomycota, Amphisphaeriaceae...

•  Yeast’s functions in the gut it is not clear

•  Yeasts overgrowth/dysbiosis (related to host genetic and physiology, lifestyle, antibiotic usage, immune system disfunction) could be pathogenic fo the gut

Dollive S, et al. Genome Biol 2012 Cui et al. Genome Medicine 2013 Thewes S, Mol Microbiol 2007

GUT VIROME

Berg Miller et al, Environ Microbiol 2011

•  Collection of all viruses of the gut •  Harmful viruses are a minority compared to benign viruses •  Bacterial virus are called bacteriophages

Random pyrosequencing of virus-enriched metagenomes have been isolated from bovine rumen. In the bovine rumen have been isolated up to 28.000 different viral genotypes; the majority (∼78%) of sequences did not match any previously described virus

Pro phages outnumbered lytic phages approximately 2:1

Metabolic profiling revealed an enrichment of sequences with putative functional roles in DNA and protein metabolism, but a low proportion of sequences assigned to carbohydrate and amino acid metabolism

GUT BACTERIOME

>9 phyla 95% genes identity

>1000 species

99% genes identity

>15000 strains 100% genes identity

900-1200 gr, >17.000.000 genes

Microbiome Metabolome

BACTERIAL TAXONOMY DOMINIUM

REGNUM

PHYLUM

CLASSE

ORDO

FAMILIA

GENUS

SPECIES

SUBSPECIES (STRAIN)

95%

99% 100%

Genes identity

MOLECULAR BACTERIOLOGY: most abundant PHYLA in the GUT (>70%)

Eckburg et al, Science 2005

BACTEROIDETES

FIRMICUTES

HUMAN GUT

ENTEROTYPE

of people as lean or obese can be made solely on the basis of their gut microbiota with 90% accuracy46,47, but they do not separate into distinct microbiota-based clusters on commonly used principal coordinates plots, which are used to identify statistical differences between groups. Thus, multiple statistical techniques are needed to show fully the differ-ences in the microbiota between different physiological states (Fig. 2).

Some differences in the microbiota can contribute directly to disease states. Gnotobiotic mice that were raised germ-free then colonized with the microbiota from an obese mouse gained fat more rapidly than those colonized with the microbiota of a lean mouse7,45. A phenotype can emerge from different compositional backgrounds, which may indicate that specific components of the microbiota can exert large effects or that many different changes can lead to the same functional result.

Differences in faecal microbial community diversity, composition and function have also been correlated with Crohn’s disease9, ulcerative coli-tis10, irritable bowel syndrome (IBS)48, Clostridium difficile- associated disease (CDAD)49 and acute diarrhoea50. Sometimes, the nature of the microbiota deviation from health is consistent across individuals with the same disease. For instance, a twin study of IBD found marked and reproducible deviations in patients with ileal Crohn’s disease relative to the controls, and more subtle, but characteristic, changes in patients with colonic Crohn’s disease51, and specific functional differences were also observed from metabolic profiling of the same samples24. Other diseases are associated with marked deviations from health that are inconsistent across individuals. For instance, individuals with recurrent CDAD had a phylum-level diversity that was very different from controls but not similar to each other49. Many disease studies are confounded by extensive use of treatments, such as antibiotics, that may obscure true disease-asso-ciated changes, highlighting the urgent need for prospective longitudinal studies that establish cause and effect.

Parallels between host physiological statesStudies of the microbiota often target one specific disease or state, but comparisons of the microbiota across many diseases can show common changes in the gut environment. Disturbed mucous lay-ers that line the intestinal cell wall and concomitant inflammation are seen in individuals with IBD, coeliac disease, HIV enteropathy, acute diarrhoea, diverticulosis, carcinoma and IBS52. Given these parallels, an increase or decrease in abundance of similar microbes across different disturbances might be expected53, but elucidation of these differences may require detailed biogeographical studies along the length of the gut — once safe and reliable means for such comprehensive sampling are developed.

Perturbed adult gut microbial communities are intriguingly simi-lar to infant gut microbial communities. Both systems may represent successional communities in which the same opportunistic or fast-growing species can predominate53. For instance, C. difficile is a normal gut resident that can cause disease when antibiotics com-promise the stable adult gut communities; it also colonizes 2–65% of infants, although most infants are asymptomatic54,55. Clostridium bolteae and Clostridium symbiosum are also associated with a dis-turbed gut and systemic infection, and are found in the infant gut53. The microbiota of individuals with ileal Crohn’s disease can also resemble that of infants: both have increased levels of Ruminococcus gnavus and Enterobacteriaceae in their stools, and an under-repre-sentation of the genera that are prevalent in healthy adults, including Faecalibacterium and Roseburia51. These examples show the impor-tance of understanding whether generally opportunistic members of the gut microbiota have a selective advantage during early succession or disruption caused by disease, and therefore whether they are the side effects of disease rather than causal agents.

Resilience of stable states Resilience is the amount of stress or perturbation that a system can tolerate before its trajectory changes towards a different equilib-rium state56. Macroecosystem studies of human interference such as

resource exploitation, pollution, land-use change and global warm-ing have shown how ecological systems can be transformed into less productive or less desirable states56. For example, in a tropical lake community, a regime in which submerged plants dominate is pre-ferred to one with extensive free-floating plant cover because dense mats of floating plants create anoxic conditions that reduce animal biomass and diversity. However, pollution can cause floating plants to predominate because they are better at competing for light and can exclude submerged plants when the nutrient load is high. By under-standing the environmental drivers of conversion between states, interventions can be used to induce a regime change. For example, harvesting the floating plants once can induce a permanent shift to the submerged-plant-dominant state, but only if the nutrient loading is not too high57.

Environmental studies can provide examples of the microbial response to perturbations, and perhaps an insight into how the gut microbiota might react. During the Deepwater Horizon oil spill in the Gulf of Mexico, the microbial community structure and func-tional gene repertoire in the deep-sea oil plume shifted, transiently, to an enrichment of microbes that were capable of hydrocarbon-degradation58,59. This is similar to the effect of an extreme dietary change on the gut microbiota of mice that were moved from a low-fat, plant-rich diet to a high-fat, high-sugar diet7. In both cases, the

Firmicutes

Phylum Function

ActinobacteriaBacteroidetesProteobacteriaFusobacteriaTenericutesSpirochaetesCyanobacteriaVerrucomicrobiaTM7

Central carbohydrate metabolismCofactor and vitamin biosynthesisOligosaccharide and polyol transport systemPurine metabolismATP synthesisPhosphate and amino acid-transport systemAminoacyl transfer RNAPyrimidine metabolismRibosomeAromatic amino-acid metabolism

Figure 4 | Functional redundancy. The functional redundancy in microbial ecosystems may mirror that in macroecosystems. As shown in the HMP data set14, oral communities (top panels) and faecal communities (bottom panels) analysed using 16S rRNA (coloured by microbial phyla, left panels) show tremendous abundance diversity. The same samples analysed by shotgun metagenomics (panels on right) have remarkably similar functional profiles. Reprinted with permission from ref. 14.

1 3 S E P T E M B E R 2 0 1 2 | V O L 4 8 9 | N A T U R E | 2 2 5

REVIEW INSIGHT

© 2012 Macmillan Publishers Limited. All rights reserved

Lozupone et al. Nature 2012

Phylum level diversity can have a marked variation even across healthy adults in the same population. Each individual has many unique phylotypes not found in the other.

INDIVIDUAL ENTEROTYPE

U.S. adults sampled >5 times up to 296 weeks apart revealed that they harbored 195±48 bacterial strains, representing 101 ± 27 species

..in stable conditions, microbiota is stable, with 60% of strains remaining over the course of 5 years: stable core of dominant species

David – Nature 2013

Ø The human gut microbiome can rapidly switch between herbivorous and carnivorous functional profiles Ø It may reflect past selective pressures during human evolution Ø Microbial communities that could quickly, and appropriately, shift their functional repertoire in response to diet change would have subsequently enhanced human dietary flexibility

Ø Examples of this flexibility may persist today in the form of the wide diversity of modern human diets

Microbiota composition is affected by life events Ottman et al. Functionality of the human microbiota

healthy

obese

65 to 80 years

>100 years

healthy

antibiotic treatment

malnutrition breast-fed

formula-fed

solid food

Baby Toddler Adult Elderly

16S

16S

16S

DNA 16S

DNA

16S

16S

DNA

16S

DNA

16S

16S

16S

Unborn

FirmicutesBacteroidetesActinobacteriaProteobacteriaothers

FIGURE 1 | Human microbiota: onset and shaping through life stages andperturbations. The graph provides a global overview of the relative abundanceof key phyla of the human microbiota composition in different stages of life.Measured by either 16S RNA or metagenomic approaches (DNA). Data

arriving from: Babies breast- and formula-fed (Schwartz et al., 2012), baby solidfood (Koenig et al., 2011), toddler antibiotic treatment (Koenig et al., 2011),toddler healthy or malnourished (Monira et al., 2011), adult, elderly, andcentenarian healthy (Biagi et al., 2010), and adult obese (Zhang et al., 2009).

foods. Diet-related diseases such as allergies and obesity are alsocharacterized by microbiota changes. Obesity is characterized bya typical Firmicutes to Bacteroides ratio. Energy harvest potentialand short chain fatty acids (SCFA) are determined by the micro-biota composition and have a direct effect on the host epithelialcell energy availability. A microbiota stimulated with probioticmicrobes can even decrease the incidence of infant diarrhea andatopic eczema due to host immune stimulation (Niers et al., 2009;Sjogren et al., 2009).

Numerous meta-omics approaches have vastly increased theknowledge available on the genome, activity and functionality ofthe complex ecosystem residing in the human gut. By far the mostcommonly applied technique is metagenomics, which is based ondirect isolation and, in most cases, sequencing of the completegenetic material obtained from an environmental sample, such asthe intestine. However, one of the biggest drawbacks of this tech-nique is its inability to display the actual metabolic activity due tothe fact that it detects both expressed and non-expressed genes.In addition, it may generate information from dead cells as it isknown that more than half of the cells in fecal samples are non-viable or heavily damaged (Ben-Amor et al., 2005). Instead offocusing on microbiota composition the purpose of this review isto combine the available knowledge on microbial genomics with

reports on the functional metagenomics, i.e., transcriptomics andproteomics approaches. This combination is expected to providea refined understanding of the role of the microbiota and itscapabilities in regulating human health.

ROLE OF THE MICROBIOTA IN EARLY AND LATE LIFEEARLY LIFEDuring natural birth, a newborn is exposed to the environmental,mainly maternal, microbiota which commences the acquisitionof what we assume is a normal microbiota. The mode of deliv-ery strongly affects the composition of the microbiota. In the caseof caesarean delivery (C-section), other environmental bacteriaform the basis for the microbiota instead of vaginal and faecalbacteria from the mother, reportedly resulting in a substantialreduction of bifidobacteria (Biasucci et al., 2008). In a compari-son of the microbiota of babies delivered either vaginally or viaC-section, it was shown that the newborns harbored undiffer-entiated bacterial communities across skin, oral, nasopharyngeal,and gut habitats regardless of delivery mode, and that the micro-biota of C-section babies was similar to the skin communities ofthe mothers whereas vaginally delivered infants acquired bacterialcommunities resembling the vaginal microbiota of their mothers(Dominguez-Bello et al., 2010). Other factors influencing the

Frontiers in Cellular and Infection Microbiology www.frontiersin.org August 2012 | Volume 2 | Article 104 | 2

Ottmann N et al. Front Cell Infect Microb 2012

…specific effects in each GI tract!

EFFECTS OF GUT MICROBIOTA ON HOST HEALTH

Ø Barrier effect Ø Immunocompetence/Tolerance Ø Synthesis

Ø Metabolism Ø Drug metabolism Ø Behavior conditioning

Lifelong immunostimulation by enteric commensal and pathogenic bacteria

Maynard CL et al. Nature 2012

‘‘NUTRIENT SENSOR PATHWAY’’

Tilg H, J Hepatology 2010

Hologenome theory of evolution The object of genomic natural selection is not a single organism, but the organism and its microbial communities

Rosenburg et al, 2007

•  Vibrio shiloi-mediated bleaching of the coral Oculina Patagonica (Coral probiotic hypothesis)

Rosenburg and Zilber, 2008

•  Commensal bacteria play a role in mate choice by the fruit fly Drosophila Melanogaster (microbial communities of the fly altered hydrocarbons, which function as insect pherormones)

Sharon et al; 2010 Ringo et al, 2011

Holobiont: any organism and all its associated symbiotic microbes (parasites, mutualists, synergists, amensalists)

Hologenome: genes of host and symbiotic microbes

Microbiota

GUT BARRIER

Acquired and

Innate immunity

Mucosal Barrier

Epithelial barrier



Endocrine system

•  The inner mucus layer is dense and does not allow bacteria to penetrate, thus keeping the epithelial cell surface free from bacteria

•  The inner mucus layer is converted into the outer layer, which is the habitat of the commensal flora

Epithelial cells

Loosely adherent mucus layer

Firmly adherent mucus layer

Good bacteria

IMPORTANCE OF THE MUCUS LAYERS

Johansson, M.E., Proc Natl Acad Sci U S A, 2010

GUT MICROBIOTA HAS TO BE UNDER CONTROL

Ø Mucosal barrier integrity Ø Secretion of :

Ø  Gastric acid Ø  Biliary salts Ø  Antimicrobial substances

Ø Mucosal pH Ø Local mucosal and systemic immunity Ø Intestinal motility Ø Interactions among different bacteria species

Failure of MICROBIOTA control’s mechanisms

Quali-quantitative alterations of oral, esophageal, gastric, small bowel and/or

colonic microbiota

DYSBIOSIS

Digestive and extradigestive diseases

EUBIOSIS

DYSBIOSIS

LEAKY GUT

•  Burns and trauma •  Major vascular surgery •  Sepsis •  MOF •  Renal failure •  Diabetes/Metabolic syndrome •  Joint disease •  Autoimmune diseases •  Psychiatric pathologies •  Heart and lung diseases

•  Coeliac disease •  IBD/IBS •  Food allergy •  Acute gastroenteritis •  Radiation enteritis •  Intestinal by-pass •  Intestinal obstruction •  Peritonitis •  Wipple’s disease •  Liver Diseases

Human diseases associated to LEAKY GUT/DYSBIOSIS

Digestive diseases associated to DYSBIOSIS/LEAKY GUT

•  Gastrointestinal infections •  Irritable Bowel Syndrome •  Intestinal Bacterial Overgrowth •  Diverticulosis •  Inflammatory Bowel Diseases •  Gastro-intestinal Cancers •  Food Intolerance/Allergy •  Celiac disease •  Liver diseases •  Pancreatic diseases •  Obesity, Diabetes and Metabolic Syndrome

Diet and Nutritional Support Ø Caloric amount, minerals, vitamins, sweeteners..

Ø Diet composition (fibers/high glicemic index/saturated fatty acids…)

Removal of predisposing conditions Ø Treat diabetes, endocrine, other motility disorders.. Ø Surgery or prokinetics when indicated

Ø Stop PPI or other antiacid, NSAIDs, antibiotic, immunodepressant….

Intervention Ø Antibiotics Ø Biotherapy (prebiotics, probiotics, symbiotics, postbiotics) Ø Microbiota Transplantation

How (re)modulate gut microbiota?

Need to know: mechanisms of Probiotic/Host interaction

Immunological benefits: Ø Activate macrophages to increase antigen presentation to B cells and IgA production

Ø Modulate cytokine profiles

Ø  Induce hyporesponsiveness to food antigens

Nonimmunological benefits: Ø  Digest food and compete for nutrients with pathogens

Ø  Alter local pH to create an unfavorable local environment for pathogens

Ø  Produce bacteriocins to inhibit pathogens

Ø  Scavenge superoxide radicals

Ø  Stimulate epithelial mucin production

Ø  Enhance intestinal barrier function

Ø  Compete for adhesion with pathogens

Ø  Modify pathogen-derived toxins WGO 2011

Needs for a Specie (Strain)-specific Microbial Therapy

Different action for each Probiotic: Knowledge of micro-organism functions and host genetic

modulation by different Species/Strain is crucial

From Gopubmed, 2013

Probiotics: fastly growing research area

Probiotics available on the market

FAO/WHO, 2001

Lactobacillus spp •  casei spp (Rhamnosus, DN..) •  reuteri •  acidophilus •  shirota •  delbrueckii, sp. Bulgaricus •  brevis •  plantarum • …

Bifidobacterium spp •  bifidum •  infantum •  longum •  thermophilum •  lactis • …

Cocci gram-positive •  Streptococcus thermophilus •  Enterococcus faecium •  Streptococcus intermedieus •  Streptococcus alfa-emoliticus • …

Bacillus gram-negative •  Escherichia coli Nissle (1917)

Bacillus gram-positive •  Bacillus clausii •  Bacillus subtilis

Yeast •  Saccharomyces boulardii •  Kluyveromyces marxianus fragilis • …

ROLE OF CURRENT PROBIOTICS IN GASTROINTESTINAL DISORDERS

ð Reduction of Antibiotic-associated Diarrhea

ð Prevention and treatment of Infectious Diarrhea

ð Adjuvant for H. pylori and C. difficile treatment

ð Treatment of Necrotizing enterocolitis

ð Treatment of Sugar Intolerance

ð Prevention and treatment of Pouchitis

ð Maintenance of remission of IBD

ð Treatment of IBS

Practice guidelines on Probiotics usage World Gastroenterology Organization (2011)

LACTOBACILLUS CASEI sp RHAMNOSUS







ð Maintenance of remission in Ulcerative Colitis



SACCHAROMYCES CEREVISAE sp BOULARDII



ð Adjuvant for H. pylori and C. Difficile treatment

ð Treatment of Traveller’s diarrhea



ð Maintenance of remission in IBD



ESCHERICHIA COLI sp NISSLE 1917



ð Adjuvant for H. pylori treatment




ð Maintenance of remission of Ulcerative Colitis



BACILLUS COAGULANS GBI-30, 6086







ð Treatment and maintenance of remission of Ulcerative Colitis



BIFIDOBACTERIUM INFANTIS 35624










Multistrains BACILLUS CLAUSII sp OC, NR, SIN, T




ð Prevention of Respiratory Tract Infection






LACTOBACILLUS DELBRUECKII sp BULGARICUS + STREPTOCOCCUS TERMOPHILUS







ð Maintenance of remission in IBD



Multispecies/strains combination VSL 3










Quali sono le evidenze di efficacia dei probioIci nella diarrea acuta?

Probiotics plus rehydration therapy reduce the duration and severity of diarrhoea

- 24.76 hours (IC95% 15.9-33.6)

Total patients n=8014 •  6489 children •  352 adults •  1173 age ndd

Patients: adults and children

… good results but more research is needed to identify a specific probiotic for each subjects

Duration of diarrhoea

Conclusions

Allen SJ, Cochrane Database Systematic Review 2010

Infectious acute diarrhea

Prevention of traveler’s diarrhea

ProbioIcs significantly prevent TD (RR 0.85, 95% CI 0.79,0.91, p<0.001)

Enterococcus faecium

LAB SF68

L. rhamnosus GG o Lactobacillus

paracasei B 21060

Saccharomices boulardii, ceppo di

S.cerevisiae

108 cfu, tid

109 cfu bid

109 cfu per capsule or

250 mg, 2-6 capsule/die

1b

2b

WGO: Organizzazione Mondiale di Gastroenterologia Cfu: unità formanti colonie WGO, 2011

1b

Evidence-based adult indications for probiotics

Disorder Probiotic strain Recommended dose Evidence level

Treatment of acute infectious diarrhea

Evidence-based pediatric indications for probiotics

Disorder Recommended dose Probiotic strain Evidence level

Treatment of acute infectious diarrhea

L. rhamnosus GG

Saccharomyces boulardii,

ceppo di S. cerevisiae

Indian Dahi: Lactococcus

lactis, L. lactis cremoris,

Leuconostoc mesenteroides

cremoris

1010 – 1011 cfu, bid

200 mg, tid

1010 cfu each

bid o tid

1a 1a

2b

WGO: World Gastroenterology Organisation WGO, 2011

Meta-‐analysis of RCTs; ESPGHAN/ESPID recommendaIon

Quali sono le evidenze di efficacia dei probioIci nella prevenzione della diarrea da anIbioIci?

Cremonini and Gasbarrini, Alim Pharm Ther 2002

[ A meta-analysis of 7 RCT shows a strong benefit of probiotic administration on AAD

[ The combined RR was 0.39 (95% CI: 0.27-0.57) of probiotics efficacy when compared to placebo

Probiotics and Antibiotic-associated Diarrhea


Prevention of antibiotic associated diarrhea in adults

E. faecium LAB SF68

S. boulardii, ceppo

di S. cerevisiae

L. rhamnosus GG

L. casei DN-114 001 in latte fermentato

Bacillus clausii

L. acidophilus

CL1285 + L. casei LBC80R

1 g o 4 x109 cfu die

1010- 1011 cfu bid

1010 cfu bid

2x109 spore tid

5x1010 cfu uid o bid

1b

1b

1b

1b

1b

1b

108 cfu, bid



WGO, 2011

S. boulardii, ceppo di S. cerevisiae

L. rhamnosus GG

Bifidobacterium

lactis Bb12 + Streptococcus thermophilus

L. rhamnosus GG

(ceppo E/N, Oxy e Pen)

250 mg, bid

1010 cfu, uid o bid

107 + 106 cfu/g di formula

2 x 1010 cfu, bid

1a

1b

1b

1b

Evidence-based pediatric indications for probiotics


Meta-‐analysis of RCTs

Prevention of antibiotic-associated diarrhea

C. difficile-associated diarrhea

v ProbioIcs have a significant protecIve effect for CDAD (RR 0.59 95% CI 0.41-‐0.85, z = 2.8, p = 0.005.)

v Only S. boulardii showed significant reducIons in recurrences of CDAD

Prevention of C. difficile diarrhea

1010 cfu, bid

2 x 1010 cfu each strain, uid

109 cfu each strain, uid

5x109 cfu uid o bid

2-3x109 for 28 days, Followed for another

4 weeks

1b

1b

2b

1b

1b


L. casei DN-114 001 in latte fermentato

L. acidophilus + B.

bifidum

L. rhamnosus HN001 + L. acidophilus NCFM

L. acidophilus CL1285

+ L. casei LBC80R

S. boulardii,

ceppo di S. cerevisiae



Quali sono le evidenze di efficacia dei probioIci nell’IBS?

•  Pooling of 8 trials for the outcome of clinical improvement yielded a significant RR of 1.22 (95% CI 1.07–1.4; P=0.0042)

•  Homogenous studies (Cochran Q test: P=0.4482

Probiotics may improve symptoms of IBS and can be used as supplement to standard therapy

Irritable Bowel Syndrome

Nikfar - Dis Colon Rectum 2008

•  Pooling of 8 trials for the outcome of clinical improvement yielded a significant RR of 1.22 (95% CI 1.07–1.4; P=0.0042)

•  Homogenous studies (Cochran Q test: P=0.4482

Probiotics may improve symptoms of IBS and can be used as supplement to standard therapy


Nikfar - Dis Colon Rectum 2008

“…There are some limitations of this meta-analysis, such as characteristics

of patients (age, sex, lifestyle, compliance), species, dosages,

treatment durations, and different endpoints of studies…”

•  Modest improvement in overall symptoms after several weeks of treatment:

Ø  For dichotomous data from 7 trials: OR 1.6 (95% CI, 1.2 to 2.2)

Ø  For continuous data from 6 trials: standardised mean difference (SMD) 0.23 (95% CI, 0.07 to 0.38)

•  Metanalysis of 7 RCT (398 pts): significant improvement in ABDOMINAL PAIN: OR 2.88 (95% CI, 1.84 to 4.50)

• 2 studies (101 participants) reported on improvement in abdominal pain. However, high heterogeneity (I2 = 63%) suggested pooling was inappropriate.


Hoveyda, BMC Gastroenterology 2009

•  Modest improvement in overall symptoms after several weeks of treatment:

Ø  For dichotomous data from 7 trials: OR 1.6 (95% CI, 1.2 to 2.2)

Ø  For continuous data from 6 trials: standardised mean difference (SMD) 0.23 (95% CI, 0.07 to 0.38)

•  Metanalysis of 7 RCT (398 pts): significant improvement in ABDOMINAL PAIN: OR 2.88 (95% CI, 1.84 to 4.50)

• 2 studies (101 participants) reported on improvement in abdominal pain. However, high heterogeneity (I2 = 63%) suggested pooling was inappropriate.


Hoveyda, BMC Gastroenterology 2009

“…Trials varied in relation to the length of treatment (4-26 weeks), dose, organisms and strengths of

probiotics used…”

•  19 RCTs/18 papers in 1650 patients

PROBIOTICS: EFFECT ON OVERALL SYMPTOMS

Symptoms described as a dichotomous outcome


Moayyedi – Gut 2010

Ø  Signif icant effect in reducing symptoms (RR of persistance: 0.71; 95%CI 0.57-0.9)

Ø No difference between different strains

•  19 RCTs/18 papers in 1650 patients

PROBIOTICS: EFFECT ON OVERALL SYMPTOMS

Symptoms described as a continuous outcome



Ø  Probiotics had a statistically significant effect in improving symptoms compared with placebo (SMD . 0.34; 95% CI 0.60 to 0.07)

Ø  Lactobacillus: no effect on IBS symptoms Ø  Bifidobacterium: non significant trend Ø  Combination: significant effect

PROBIOTICS: EFFECT ON INDIVIDUAL SYMPTOMS



ABDOMINAL PAIN (10 RCTs, 834 patients) Ø Significant efficacy - SMD= -0.51; 95% CI -0.91 to -0.09, p=0.016 Ø Significant heterogeneity

BLOATING (8 RCTs, 682 patients) Ø Trend – SMD= -0.54; 95% CI -1.10 to -0.02, p=0.058) Ø Significant heterogeneity FLATULENCE (6 RCTs, 566 patients) Ø Significant efficacy – SMD=-0.22; 95%CI -0.42 to -0.01, p=0.04) Ø No significant heterogeneity)

URGENCY (3 RCTs, 394 patients) Ø No significant efficacy –SMD=-0.08; 95%CI -0.3 to -0.14, p=0.49)


Ford – AJG 2014

•  35 RCTs, 3,452 patients

•  Low risk of bias in 14 RCTs

•  The RR of IBS symptoms persisting with probiotics vs. placebo was 0.79 (95 % CI 0.70 – 0.89)

•  Probiotics had beneficial effects on global IBS, abdominal pain, bloating, and flatulence scores.


Ford – AJG 2014

•  35 RCTs, 3,452 patients

•  Low risk of bias in 14 RCTs

•  The RR o f IBS symptoms persisting with probiotics vs. placebo was 0.79 (95 % CI 0.70 – 0.89)

•  Probiotics had beneficial effects on global IBS, abdominal pain, bloating, and fl atulence scores.

Alleviates some symptoms of irritable bowel syndrome

108 cfu, uid

1010 cfu, bid

1010 cfu, die

1010 cfu, die

1010 cfu, die

2x109 cfu, die

1b

1b

2b

1b

1b

2b WGO: Organizzazione Mondiale di Gastroenterologia

Cfu: unità formanti colonie WGO, 2011

Bifidobacterium infantis 35624

B. animalis DN- 173 010 in

fermented milk

L. acidophilus SDC 2012, 2013

L. rhamnosus GG,

L. rhamnosus LC705, B. breve Bb99 e

Propionibacterium freudenreichii ssp.

shermanii

B. longum 101 (29%), L. acidophilus 102 (29%),

Lactococcus lactis 103 (29%) e S. thermophilus 104 (13%)

Bacillus coagulans GBI-30, 6086



Quali sono le evidenze di efficacia dei probioIci nella malaYa diverIcolare?

Unlu – Int J Colorectal Dis 2012

v  Systematic review of RCTs

v  2 trials investigating probiotics

E. Coli (strains 01, 02, 055 and 0111) + Proteus vulgaris

VSL#3

v The use of probiotics decreases symptoms but does not reduce recurrence

v 210 pts - symptomatic uncomplicated diverticular disease (SUDD)

v 4 groups of treatment (10 days/month for 12 months) Ø Mesalazine + placebo Ø  Lactobacillus casei subsp. DG + placebo Ø  Lactobacillus casei subsp. DG + mesalazine Ø  Placebo + placebo

• Both cyclic mesalazine and Lactobacillus casei subsp. DG alone or in combination are significantly better than placebo for maintaining remission in SUDD

Quali sono le evidenze di efficacia dei probioIci nell’eradicazione dell’infezione da H. pylori?

Ø  14 RCTs included

Ø  First or second-line triple eradication therapy

Ø  Data for occurrence of total side effects can obtain from 7 RCTs

Ø  8 trials administrated single probiotic strain (4 different probiotic strains) and 6 trials administrated combining probiotic preparations

Tong – APT 2007

Side effects in probiotic supplementation were lesser than to without probiotics (24.7% vs 38.5%, OR 0.44)

Tong – APT 2007

Most of the trials reported lower incidences of diarrhoea (6.0% vs 16.1%, OR 0.34) in probiotic group

Tong – APT 2007

I probioIci sono sempre sicuri?

Gut Barrier disfunction

Intestinal permeability (Leaky gut)

Villus/crypt tight junctions in health

Intes;nal lumen

Villus cells

Tight junc;ons

Crypt cells Tight junc;ons

Hollander D et al. Scand J Gastroenterol, 1992

Villus/crypt tight junctions in health

Villus/crypt tight junctions in disease

Intes;nal lumen

Villus cells

Leaky ;ght junc;ons

Crypt cells Tight junc;ons

Hollander D et al. Scand J Gastroenterol, 1992

Villus/crypt tight junctions in disease

§  Burns and trauma §  Major vascular surgery §  Sepsis §  MOF §  Renal failure §  Diabetes mellitus §  Joint disease §  Autoimmune diseases §  Psychiatric pathologies §  Heart and lung diseases

§  Coeliac disease §  IBD/IBS §  Food allergy §  Acute gastroenteritis §  Radiation enteritis §  Intestinal by-pass §  Intestinal obstruction §  Peritonitis §  Wipple’s disease §  Liver Diseases

DISEASES RELATED TO BARRIER DEFECTS

GASTROINTESTINAL EXTRAINTESTINAL

§  298 patients with predicted severe acute pancreatitis

§  Multispecies probiotic preparation (Lactobacillus acidophilus, Lactobacillus casei, Lactobacillus salivarius, Lactococcus lactis, Bifidobacterium bifidum, and Bifidobacterium lactis) bid/28 days

§  Infectious complications: 30% probiotics VS 28% placebo (RR 1.06, 95% CI 0.75–1.51)

§  Deaths: 16% probiotics VS 6% placebo (RR 2.53, 95% CI 1.22–5.25)

§  Bowel ischaemia (pts): 9 probiotics VS 0 placebo (p=0.004)

Besselink – Lancet 209

Enache-Angoulvant et al. – Clin Infect Dis 2005

§  92 cases of Saccharomyces invasive infection

§  S. boulardii accounted for 51.3% of fungemias

§  Saccharomyces invasive infection is clinically indistinguishable from an invasive candidiasis

§  S. cerevisiae clinical isolates exhibited low susceptibility to amphotericin B and azole derivatives

Bittersweet Saccharomyces boulardii

Esistono altri Ipi di modulazione di gut microbiota?






How to (re)modulate gut microbiota?

Prebiotic Dietary indigestible ingredient which selectively stimulates growth and activity of one or multiple microbial species Probiotic Non pathogenetic microorganisms that, when ingested, excert a positive influence on host by altering his microbial balance Symbiotic Mix of probiotics and prebiotics that increase survival of the probiotic, making immediately available its substrate for fermentation

BIOTHERAPY (I)

Postbiotic A metabolic byproduct generated by a probiotic micro-organism that influences the host’s biology Functional food Any modified food or food ingredient that provides a health benefit beyond that ascribed to any specific nutrient/nutrients it contains. It must remains a food and demonstrates its effect in amounts normally expected to be consumed in the diet. Any food that contains probiotics or prebiotics is a functional food. Example of a functional food: live-culture yogurt that contains probiotic bacteria, prebiotics and other dietary nutrients

BIOTHERAPY (I)

Ramirez-Farias C Br J Nutr 2009

Inulin and F. prausnitzi ü  Analysis of faecal microbiota composition of human

volunteers after ingestion of inulin (10 g/d) for a 16-d VS control period

ü  Significant increase of Faecalibacterium prausnitzii (from 10 to 15% during inulin intake, P=0.019)

..how to feed NEXT GENERATION PROBIOTICS?

1. Faecalibacterium Prausnitzii 2. Akkermansia Muciniphila 3. Eubacterium halii 4. …

DOMINIUM PROKARIOTA

REGNUM BACTERIA

PHYLUM FIRMICUTES

CLASSE CLOSTRIDIA

ORDO CLOSTRIDIALES

FAMILIA CLOSTRIDIACEAE

SPECIES FAECALIBACTERIUM

SUBSPECIES FAECALIBACTERIUM PRAUSNITZII

Faecalibacterium prausnitzii

Ø  Gram positive, anaerobic bacterium. Among the most abundant anaerobic bacteria in the human gut microbiota, with a proportion of around 5% of total bacteria in faeces Ø  It produces SCFA, particularly Butyrate, primary energy source for intestinal epithelial cells and crucial for maintenance of barrier integrity Ø  It has a strong anti-inflammatory effect both in vitro and in vivo

Cao Y, Gastroenterol Res Pract. 2014 Duncan, Appl Environ Microbiol, 2002

Faecalibacterium prausnitzii

ü  11 studies included ü  Significantly lower F. prausnitzii

counts in IBD patients versus controls

Reduction of F. prausnitzii links to dysbiosis of gut microbiota in IBD

patients, especially CD patients with ileal involvement

Cao, Gastroenterol Res. Pract 2014

DOMINIUM PROKARIOTA

REGNUM BACTERIA

PHYLUM VERRUCOMICROBIA

CLASSE VERRUCOMICROBIAE

ORDO VERRUCOMICROBIALES

FAMILIA VERRUCOMICROBIACEAE

SPECIES AKKERMANSIA

SUBSPECIES AKKERMANSIA MUCINIPHILA

Akkermansia muciniphila

Akkermansia muciniphila

ü  Gram-negative bacterium, mucin-degrading bacteria that resides in the mucus layer ü  Its genome contains numerous candidate mucinase-encoding genes ü  A. muciniphila produces several proteins involved in the different steps of mucin degradation

Tilg, GUT 2014 Everard, PNAS 2013 Van Passel MW, Plos One 2011 Derrien M, Appl Environ Microbiol. 2008 Collado MC, Appl Environ Microbiol. 2011

ü Akkermansia muciniphila decreased in obese and was inversely correlated with body weight in rodents and humans

ü Akkermansia muciniphila treatment improved metabolic parameters in obese mice models

ü  A. muciniphila treatment reversed fat gain, serum LPS levels, gut barrier function and insulin resistance by increasing endocannabinoids and gut peptides ü  Metformin and RYGB surgery increased the abundance of Akkermansia muciniphila






How (re)modulate gut microbiota?

FECAL MICROBIOTA TRANSPLANTATION

v  Oral probiotic doses are typically 3–4 orders of magnitude lower than the 100 trillion native micro-organisms contained within the colon

v  Fecal microbiota transplantation is the transfer of gut microbiota from a healthy donor to introduce or re-establish a stable microbial community in the gut

v Previously known as “fecal bacteriotherapy”

v  First FMT reported in fourth century China (Ge Hong)

Borody – Nat Rev Gastro 2011 Aroniadis – Curr Opin Gastro 2013

FECAL MICROBIOTA TRANSPLANTATION and C. DIFFICILE INFECTION


v  Premise of FMT is to repair or replace the disrupted native microbiota

v  1958 First report of FMT for CDI

v  2013 First guidelines of FMT for CDI

v  Good standardization of technique over the last years

FECAL MICROBIOTA TRANSPLANTATION and C. DIFFICILE INFECTION

v  Until 1989 enema was the most common technique

v Alternative methods carried out over the years: Ø Nasogastric/Nasoduodenal tube Ø Gastroscopy Ø Colonoscopy Ø Self-administered enemas

v Colonoscopic approach is favored over fecal enema (reaching of entire colon)


Route of administration

FMT and CDI: the evidences

Kassam – AJG 2013

v  11 studies, 273 CDI patients treated with FMT, no RCTs

v  No statistically significant heterogeneity between studies (Cochran Q test P = 0.13, I 2 = 33.7 % )

v No difference in clinical outcomes between anonymous vs. patient selected donors

v No reported adverse events

v Follow-up: weeks to years


Kassam – AJG 2013

v Clinical resolution in 245 pts (UPR 89.7 % ; WPR 89.1 % (95 % CI 84 to 93 % ))

v Lower GI FMT delivery led to a trend towards higher clinical resolution rates than the upper GI route

UPR: unweighted pooled resolution rates WPR: weighted pooled resolution rates

Microbial transplantation and Clostridium Difficile

Van Nood – NEJM 2013

v  After enrollment of 43 pts the study was stopped (interim analysis)

v  CDI Resolution (pts) Ø Infusion group: 13/16 (81%) after the first infusion (2/3 after a second infusion

Ø Vancomycin group: 4/13 (31%)

Ø Vanco + bowel lavage: 3/13 (23%)

P<0.001 (both comparisons with infusion group)

RESULTS


Cammarota et al – JCG 2014

v 20 full-text case series, 15 case reports, and 1 RCT

v A total of 536 patients were treated

v 467 (87%) patients experienced resolution of diarrhea


Cammarota et al – JCG 2014

v Diarrhea resolution rates varied

according to the site of infusion

Ø  81% in the stomach Ø  86% in the duodenum/jejunum Ø  93% in the cecum/ascending colon Ø  84% in the distal colon

v No severe adverse events were

reported

Borody – Nat Rev Gastro 2011

FECAL MICROBIOTA TRANSPLANTATION

Emerging application and future dreams

v  OBESITY and METABOLIC SYNDROME

v  IBD v  IBS

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