Stomach, probiotics and inflammation in the upper GI tract

Richard H Hunt

FRCP, FRCPC, MACG, AGAF

Professor Emeritus,

Division of Gastroenterology

1

Quebec City

28th - 29th OCT 2015

Presenter Disclosure

I have no potential or perceived conflict of interest

I have no relationships with commercial interests which are relevant to my presentation

Outline of talk

Historical introduction – acid, bacteria and the stomach

Helicobacter pylori and the gastric microbiome

Gastric and esophageal microbiome and inflammation

Why did a bacteria (H. pylori) of the normal gastric microbiome become a serious pathogen?

Consider Lactobacillus as a candidate for influencing the behavior of H. pylori infection

Understanding the implications of Lactobacillus, the stomach and H. pylori for disease treatment and prevention

Future perspective with the potential for gastric probiotics

Gastric Acid - Evolutionary Advantage

Gastric acid present ~ 420 000 000 years ago

with evolution of jawed, active vertebrates

(Gnathostomata) and adaptive immunity

Present in all higher vertebrates: Fish (sharks

and rays), amphibians, reptiles, birds and

mammals

Evolutionary selection of species

maintaining gastric luminal pH 0.8-2.0

Coupled with pepsinogen secretion

Vital part of host defences – surface area of

gut ~200 Sq m vs skin ~2 Sq m

Acidity of the stomach contents

van Helmont (1622), Réaumur (1752), Reuss (1762),

Spalanzzani, Scopolli (1777), Young (1803) all referred to

chemical / acidic nature of gastric content

William Prout (1823) - Royal Society

of London “On the nature of acid and

saline matters usually existing in the

stomach of animals”

… stomach contains hydrochloric

acid

Notion that the “acidic stomach is

void of living organisms”

The stomach as a non-sterile niche

Bottcher G / Letulle M (1875), Klebs C (1881), Bizzozero G

(1893), Salomon H (1896), Krienitz W (1906), Edkins JS (1921),

Doenges JL (1938), Freedberg AS / Barron L (1940), Gorham

FD (1940) … reported bacteria in gastric mucosa

Jaworski W (1899) reported spiral-shaped and

other bacteria in human gastric washings

Milton-Thompson GJ et al (1982) studied intra-

gastric acidity, bacteria nitrite and N-nitroso

compounds before, during and after cimetidine

Warren JR & Marshall B (1983) identified

Helicobacter pylori infection of gastric mucosa

later implicated as causative agent for peptic ulcer

disease – NOBEL PRIZE in Medicine (2005)

Helicobacter spp NOT the only organisms colonizing stomach!??

Microscopy of the gastric juice - 1899

Ll

Jaworsky W Handbook of Gastric Diseases

Wydawnictwa Dzie Lekarskich Polskich 1899;30-47

Bacteria

There is a tendency to regard all micro-organisms as harmful and to equate bacteria with germs

Nothing could be further from the truth, the number of non-pathogenic species far exceeds the pathogenic, and we now know that these are essential for the existence of life on earth

Helicobacter pylori: A Global Infection, A Global Problem

The twists and turns of fate

http://www.economist.com/ story_id=11959214

“H. pylori has a reputation for causing ulcers and

cancer. Hunting it to extinction, however, may be

a mistake”

bbbbbbbbbbbbbbbbbbbbbbbbbbbbbbbbbbbbbbbbbbbbbbbbbbbbbbbb

“H. pylori has a reputation for causing ulcers and cancer. Hunting it to extinction, however, may be a

mistake” Martin Blaser has already linked the disappearance of the

bug with increased levels of obesity and with the rise of cancer of the oesophagus; last month they added asthma to the list

H. pylori helps to regulate stomach-acid levels in a way that is usually helpful to both itself and its host

A future in which doctors run routine checks on babies’ genes to find out their susceptibilities, and then colonise those babies’ stomachs with the strain or strains that are best for them?

Blaser MJ, 21st August 2008. www.economist.com

H. pylori infection, host response and clinical outcomes

Tissue response (inflammation)

Atrophic

gastritis

Hyperacidity Antigenic

stimulation

GERD and

sequelae

B-cell

lymphoma

Duodenal

ulcer

Distal

gastric cancer

Odds ratio

Primary

phenomenon

Secondary

phenomenon

Clinical

outcome

2 – 8 3 – 6 6 – 50 0.2 – 0.6

Blaser, J Infect Dis 1999;179:1523

? Mechanism

H. pylori the mucosa – the “inflammatory” response as a modulator of gastric physiology

Epithelium

Cytotoxin

IL8

PMN

TNFa

IL1b IL8

PMN

LPS

Bacterialsurfaceproteins

IL1bTNF aIL8

Inflammatorymediators

PGsLTs

Acid secretion

IL1b

TNF a

somatostatingastrin

DG

? PAIN

Mono

Mono

IL8

Submucosa

Epithelium

B cell IgGIgA

T cell – Th1 vs Th2

Clinical expressions of H. pylori infection

No atrophy

DU

H. pylori

+

Host factors

H+H+

No clinical

disease

Gastrin+ Gastrin-Atrophy

Gastric Ca

After McColl and El-Omar, 2000

H+

Somatostatin

ENS

EC cell

G cellD cell

Gastrin

Histamine

Physiology of acid secretion

ACHPACAP

GRPCGRP

GalaninCCKPYY

SPGhrelin

OpioidsVIP

BombesinNeurotensin

TRHAmylin

SecretinAdrenomedulin

EGF bFGFPDGFVEGF

H. pylori H. pylori

LPS Bacterial

products

TNF-α

IL-1β

IFN-γ

IL-2

PGE2

PGE2

PGE2

PGE2

PGE2

PGE2

PGE2

IL-2

IFN-γ

IL-1β

TNF-α

T

M

L

M

M

L

L

TTT

Inflammation

Gastric microbiome Stomach supports bacterial community with hundreds of

phylotypes

Microbial density 101-103 CFU/g

However, together with esophagus and duodenum least colonised of GI tract

Luminal pH is pH 1-2 but mucus layer forms 2 sub-layers ( pH)

Dynamic relationship with acid secretory status, especially with respect to swallowed or ingested bacteria (transient passage rather than colonisation)

Streptococcus, Lactobacillus, Bacteroides spp, Veillonella, Corynebacterium, Neisseria spp.

8 human studies using Sanger sequencing, community fingerprinting and Phylochip report Proteobacteria, Firmicutes, Bacteroidetes, Actinobacteria, Fusobacteria

Hunt RH, Gut 2015, Oct;64(10):1650-68. Epub ,2015, Sep 4

Gastric microbiome H. pylori dominant spp. in stomach (72-99% sequence readouts)

In absence of H. pylori most abundant are Firmicutes, Bacteroidetes, Actinobacteria and analysis consistently notes Streptococus spp - probably originating in oral or nasal cavities

Hypochlorhydria associated with higher gastric nitrite levels and gastric cancer resulting from nitrate reducing bacteria

Antisecretory treatment increases nitrate reducing bacteria and reduces antioxidant effects of Vit C

Colonisation dynamics influenced by H. pylori but not fully understood – increase in bacterial counts in presence of gastritis facilitating H. pylori to outcompete.

H. pylori may be present at extremely low levels in patients negative to conventional tests

Hunt RH, Gut 2015. Oct;64(10):1650-68. Epub, 2015, Sep 4

Epithelial damage

Pathogenesis of Esophageal Mucosal

Inflammation (GERD)

Gastroesophageal reflux

Acid/Bile/Pepsin

Alteration of Esophageal

MICROBIOTA

Neutrophil

Activation

ROS & NO

Release

New

Yang L, Gastroenterology 2009 Aug;137(2):588-97. Epub 2009 Apr 23

Host phenotype and microbiome types

in the distal esophagus

Type 1 Streptococcus genus

Type 2 Gram- anaerobes / microaerophiles

Normal

Esophagus

Esophagitis Barrett

Esophagus

Esophagus inflammation and intestinal metaplasia (BE) are associated with

global alteration of the microbiome

Yang L, Gastroenterology. 2009 Aug;137(2):588-97

Microbial colonization of the upper gastrointestinal tract in patients with BE

Macfarlane S , et al. Clin Infect Dis. 2007;45(1):29-38

Total number of bacteria and yeasts isolated from aspirate specimens and

esophageal mucosal samples from 7 control subjects and 7 patients with BE

•Both aspirate and biopsy

samples from patients with

Barrett’s Esophagus contained

complex populations of bacteria

•Uniquely, high levels of

Campylobacter species (which

have been linked to enteritis,

periodontal infections, and

tumor formation in animals),

found in 4 of 7 patients with BE

vs in none of the control

subjects

Mutual evolution of humans and

Helicobacter spp

Linz, B., et al. 2007. Nature. 445:915-918

Atherton JC & Blaser MJ. 2009. J. Clin. Invest.119:2475–2487

Humans and Helicobacter genus originate

from East Africa some 58,000 years ago

As humans colonized new geographical

environments, so Helicobacters also evolved

multiple mechanisms to colonize the gastric

environment e.g. spiral shape, flagella, acid

adaptation by utilizing urea, avoidance of

immune response of the host

This resulted in enormous genetic diversity of

H. pylori and the adaptation to its niche leading

to world wide expansion of the species

Helicobacter pylori

Genetic diversity in H. pylori decreases with geographic distance from East Africa, the birthplace of modern humans

Research indicates H. pylori spread from East Africa ~ 58,000 years ago

Modern humans were already infected with H. pylori before migrations out of Africa and bacterium has been associated with humans ever since

So WHY did H. pylori become associated with significant disease only 150 years ago?

Linz B, Balloux F, Moodley Y, et al. Nature 2007;445 (7130): 915-8

Gastric and duodenal ulcers are

“modern diseases”

Gastric ulcers (GU) and duodenal ulcers

(DU) were almost unknown about 150

years ago in UK and USA

The rise in the incidence of peptic ulcers in

these countries dates to ~1850 for GU and

around 1900 for DU

Records indicate that dyspepsia was the

predominant upper GI disease since ~1750

and the end of 18th century in UK and USA

respectively

Baron JH, Sonnenberg A. 2002, Gut 50(4):568-70

Baron JH, et al. 2006, Aliment Pharmacol & Thera. 24(5):821-9, 2006

Baron JH, Sonnenberg A. 2009, Gastroenterology.104(12):2893-6, 2009

Microscopy of the gastric juice - 1899

Ll

Jaworsky W Handbook of Gastric Diseases

Wydawnictwa Dzie³ Lekarskich Polskich 1899;30-47

Lactobacillus colonises the human stomach

Lactobacillus species colonize the human gastric mucosa

Found in the stomachs of most mammals and primates, thus

suggesting it is normal microbiota

Some strains of Lactobacillus, like H. pylori, have a urease

mechanism

Bernhardt H. Medizin Mikrobiol Parasitol 1974;226(4):479-90

Valeur N et al. Appl & Environ Microbiol 2004;70(2):1176-81

Roos S et al. Int J Systematic & Evolution Microbiol 2005;55(Pt 1):77-82,

Saeed A and Heczko Folia Medica Cracoviensia 2007;48(1-4):99-111

Ryan KA et al. Lett Appl Microbiol 2008b;47(4):269-74

Hakalehto E et al. Isrn Gastroenterol Print 2011;109183

Delgado S et al. Microbial Ecology 2013;65(3):763-72

Moreau MC,. Infection & Immunity 1976;13(1):9-15

Suzuki K. Applied & Environmental Microbiology 1979;37(3):379-82

Helicobacter spp not the only organisms

able to colonize gastric mucosa …

Lactobacilli are rod shaped, microaerophilic, gram-positive,

acidophilic bacteria and the hallmark of their metabolism is conversion

of sugars into lactic acid, consequently acidifying their environment

Lacobacilli have been present for thousands of years

in our diet through consumption of raw milk, cheese and

sour-pickled vegetables. Pasteurization and modern

pickling and preservation techniques dramatically

reduced Lactobacilli consumption in the diet

Lactobacilli are able to acclimatize in low pH environments and thus

to colonize human gastric mucosa

Valeur N et al 2004, Roos S et al 2005, Bik EM et al 2006

Saeed A et al 2007, Ryan KA et al, 2008

Lactobacilli inhibit growth of Helicobacter by producing

lactic acid (bacteriocidal) and other factors, compete for

gastric urease and down-regulate the virulence of

Helicobacters

Helicobacter spp and Lactobacillus spp have likely

coexisted in the stomach throughout human evolution and

have served as a good example of self-regulating bacterial

co-existence

Lactobacilli and Helicobacters both evolved and mutually

co-adapted their biology with resultant commensal or

perhaps even symbiotic benefits for the host

Lactobacilli and Helicobacter pylori: Gastric

microbiota occupy the same ecological niche

Low co-existence of Lactobacillus spp andH. pylori in symptomatic patients

Bacterial diversity of the stomach is now acknowledged

Gastric biopsies from 427 patients with GI symptoms and standard culture for H. pylori and Lactobacillus

6.1% of samples found coexistence of Lactobacillus spp and H. pylori.

H. pylori was uniquely present in 42.6% while Lactobacillus spp was found in 19.4% and significantly increased with age (p=0.005)

Chronic non-atrophic gastritis present in patients not colonised with Lactobacillus spp while both chronic atrophic and non-atrophic gastritis was similar in those with Lactobacillus spp (p <0.001)

Garcia A et al Rev Esp Enferm Dig 2012;104:473-478

Acidification of the gastric mucosa causes

an immediate inhibition of gastrin and thus

reduction of gastric acid secretion

Phenomenon well documented by the work of

John Walsh and colleagues in the 1970s and

1980s

Fordtran JS, Walsh JH. J Clin Invest. 1973 Mar;52(3):645-57

Walsh JH, Grossman MI. N Engl J Med. 1975 Jun 19;292(25):1324-34

Walsh JH, Grossman MI. N Engl J Med. 1975 Jun 26;292(26):1377-84

Feldman M et al. Gastroenterology. 1980 Aug;79(2):294-8

Peterson WL et al. Gastroenterology. 1986 Dec;91(6):1390-5

Mogard MH et al. Gastroenterology. 1987 Jul;93(1):63-8

Effect of acid and gastrin

Concept of how Lactobacilli modulate acid secretion

Lactobacilli

Gastrin

G cell

Ammonia

Base pH

Lactic

Acid pH

HCl

G cell

Gastrin

HCl

NEUTRALIZATION

Lactic acid

Gastrin

Gastric acid

Ammonia

Gastrin

Gastric acid

Lactobacillus Helicobacter

pylori

The intragastric balance between

Lactobacilli and Helicobacter pylori

In culture, Lactobacilli can produce lactate / lactic

acid (0.25M – 0.50M), which can modulate H.

pylori and gastric physiology based on an

equimolar balance, especially in proximity to the

alkaline microenvironment associated with

Helicobacter and to the near neutral pH at the

surface of the gastric epithelium

Effects of Lactobacillus: Lactic acid

and gastrin

Lactic acid produced by Lactobacilli has been shown

to inhibit the growth of Helicobacter pylori at

concentrations of 1 and 3%

A concentration of 0.45% (50 mM) lactic acid

decreased the cytoplasmic pH of H. pylori to 5.52

preventing spontaneous growth

(personal communication from George Sachs 2010)

Bhatia SJ,. Journal of Clinical Microbiology 27(10):2328-30, 1989

Midolo PD. Journal of Applied Bacteriology 79(4):475-9, 1995

Effect of lactic acid on H. pylori

Linsalata M,et al. Current Pharmaceutical Design 2010; 16(7):847-53

Lam EK, et al. European Journal of Pharmacology2007;565(1-3):171-9

Lam EK, et al.. Life Sciences 2007; 80(23):2128-36

Russo F, et al. Nutrition & Cancer 2007;59(1):106-14

Lactobacillus rhamnosus improved gastric mucosal integrity

and enhanced gastric ulcer healing in a rat model and

showed anti-proliferative and pro-apoptotic actions on human

gastric cancer cells

Lactobacillus gasseri prevented acute gastric lesions and

antral ulcers and accelerated the healing of chronic gastric

ulcer in a rat model

Uchida M,. Bioscience, Biotechnology & Biochemistry 2010;74(9):1891-4

Uchida M, Journal of Pharmacological Sciences 2004;96(1):84-90,

Other gastric effects of Lactobacillus

Supportive evidence for gastrin effects comes from a human

study in Finland, where probiotic treatment decreased serum

gastrin-17 in Helicobacter pylori infected patients

Myllyluoma E. et al. Digestive & Liver Disease 39(6):516-23, 2007

Probiotic VSL#3 accelerates GU healing by stimulating VEGF

VSL#3 (mixture of 8 probiotic bacteria Lactobacillus, Bifidobacteria, Streptococcus spp.)

Heals acetic acid induced gastric ulcer in rat model

Mechanism of healing explored by gene expression of several pro-inflammatory cytokines, protein and expression of stomach mucin-Muc-Sac, IL-10, COX-2 and growth factors

Only expression and protein production of VEGF was increased (X332) on day 7

Predictably healing in anumals with VEGF neutralizing antibody showed significantly delayed healing

Dharmani P et al. PLoS ONE 2015;8:e58671

Antibacterial effects of acid-resistant strain of Lactobacillus johnsonii 1088

Lactobacillus johnsonii 1088 shown to be a uniquely acid resistant bacteria

It also has a strong antibacterial activity including activity against H. pylori

It also inhibits gastrin-induced acid secretion in germ free-mice

This Lactobacillus species possesses properties which could be of benefit in managing H. pylori infection and also GERD

Aiba et al. Microbiology Open 2015;4:465-474

Acid-resistant strains of Lactobacillus

Viability of Lactobacillus johnsonii No. 1088 and other lactobacilli at pH 1.0 (A), 1.5 (B),

and 2.0 (C). Growing bacteria diluted at a density ~107 CFU/mL in acidic buffer and

incubated at 37C up to 120 min. Living bacterial counts made at various time points.

Aiba et al. Microbiology Open 2015;4:465-474

Antibacterial effects of acid-resistant strain of Lactobacillus johnsonii 1088

Aiba et al. Microbiology Open 2015;4:465-474

Anti-inflammatory properties of gastric derived Lactobacillus on H. pylori

In a rodent model Lactobacillus plantarum XB7, L salivarius B101, L rhamnosus B103 derived from a gastric source suppressed IL8 production and IL8-mRNA expression in H. pylori-induced AGS cells without influencing H. pylori growth

Lactobacillus plantarum XB7 also delayed detection and colonization of H. pylori in rat stomachs and attenuated gastric inflammation and improved histology. Administration of LP XB7 correlated with suppression of TNF-α

Thiraworawong T et al Helicobacter 2014;19:144-55

Reduction in H. pylori load in humans with non-viable Lactobacillus reuteri

Study sought to reduce Helicobacter pylori load by selective bacterial interaction

Lactobacillus reuteri DSM17648 identified among more than 700 wild type strains as a selective binder to H. pylori under in-vivo gastric conditions.

Specific co-aggregation between Lact. reuteri DSM17648 and different different H. pylori strains and serotypes and H. heilmanii but not Campylobacter jejunii or other pathogens

Proof of concept study in H. pylori infected, otherwise healthy adults, confirmed reduction in bacterial load assessed by UBT

Holz C et al Probiotics & Antimicrob. Prot 2015;7:91-100

Lactobacillus limits the growth of H. pylori

Lactobacilli in clinical trials showed that co-administration

aids eradication of H. pylori infection or limits related disease

or symptoms

Sun YQ, et al. Helicobacter 8(2):149-57, 2003

Gotteland M,. Alimentary Pharmacology & Therapeutics 23(8):1077-86, 2006

Vilaichone RK et al. Journal of the Medical Association of Thailand 85 Suppl 1:S79 84, 2002

Michetti P, et al. Digestion 60(3):203-9, 1999

Coconnier MH, Applied & Environmental Microbiology 64(11):4573-80, 1998

Boyanova L. Letters in Applied Microbiology 48(5):579-84, 2009

Ryan KA,et al.. Journal of Antimicrobial Chemotherapy 61(4):831-4, 2008

Andrzejewska E, Szkaradkiewicz A. Medycyna Doswiadczalna i Mikrobiologia 59(1):59-64, 2007

Imase K, Journal of the Japanese Association for Infectious Diseases 81(4):387-93, 2007

Hamilton-Miller JM. International Journal of Antimicrobial Agents 22(4):360-6, 2003

Zou J, Helicobacter 14(5):97-107, 2009

Gotteland M,. Alimentary Pharmacology & Therapeutics 23(8):1077-86, 2006

Johnson-Henry KC,. Digestive Diseases & Sciences 49(7-8):1095-102, 2004

Felley C, Best Practice & Research in Clinical Gastroenterology 17(5):785-91, 2003

Canducci F, et al. Digestive & Liver Disease 34 Suppl 2:S81-3, 2002

Role of Lactobacillus in treatment

of H. pylori infection

The effect of supplemental probiotics on

H. pylori eradication rates: Results of

meta-analyses 4 meta-analyses performed 2007-2009 studied 8-14 RCTs and

showed ~ 10% (5-15%) improvement on Hp eradication rates

Included studies were characterized by heterogeneity of

probiotic species used and their combinations (Lactobacilli,

Bifidobacterium, Sacharomyces, Bacillus, Clostridium, yoghurt

of unknown composition or preparation containing multivitamin

cocktail)

Also variable dose and duration of treatment

Not all studies used UBT for evaluating Hp eradication

Sachdeva, A et al. European J Gastroenterol & Hepatol.21(1):45-53, 2009

Zou, J et al. Helicobacter.14(5):97-107, 2009

Lesbros-Pantoflickova , D et al. Journal of Nutrition.137(3 Suppl 2):812S-8S, 2007

Tonh, JL et al. Alimentary Pharmacology & Therapeutics. 25:155-68, 2007

Effect of probiotics supplementation

on H. pylori eradication rates

and side effects: A meta-analyses Thirty-three RCTs involving 4459 patients met inclusion

criteria in which 20 trials also assessed side effects

Pooled eradication rate in probiotic group was significantly

higher than in controls (ITT analysis RR 1.122 95% CI 1.086-

1.159; PP analysis RR 1.114 95% CI 1.070-1.159)

Sub-group analysis confirmed this finding for only 4 strains

Lact acidophilus, Lact Casei DN-114001, Lact gasseri, Bifido

infantis 2036, and for relatively ineffective antibiotic therapy

Significant reduction in Side Effects but confirmed only for

non-blinded trials

Dang Y et al. PLoS ONE 2014;9:e111030

Probiotics for H. pylori eradication therapy: Not ready for prime time

Editorial reviewed results of RCTs and meta-analyses to date

8 meta-analyses – all except 2 show a consistent, statistically significant increase in eradication rates and reduced side effects from antibiotic treatment

Recent study (Zheng 2013) showed increased eradication rates but no benefits on side effects. Authors explained their divergent results on their more ‘rigorous methodology’

Heterogeneity of probiotics and strains likely primary reason

No studies with newer non-bismuth quadruple therapies

More robust and consistent results needed before global acceptance - with high quality strength of evidence - GRADE

Molina-Infante J, Gisbert JP Rev Esp Enserm Dig. 2013;105(8):441-444

Zheng X et al. Rev Esp Enferm Dig 2013;105:445-53

Some 100-150 years ago intragastric acidity was measurably less

than today, partly reflecting the smaller body mass index (BMI) of

people of the time, resulting in a lower parietal cell mass and

secretory capacity of the stomach

This would favor H. pylori and other bacteria including Lactobacilli

providing opportunity for H. pylori to colonize corpus and the antrum

resulting in pangastritis

Marks IN,. Scandinavian J Gastroenterol - Suppl 1992;7-13

Kinoshita Y. Gut , 1997;41(4):452-8

Sipponen P, Gastroenterol Clin North America 2000;29(3):579-92, v-vi

Atherton JC, JCI 2009;119(9):2475-87

Could Lactobacillus have been key tomaintaining gastric homeostasis?Changes in gastric secretion over time

Prevalence of Lactobacillus spp has diminished over past century -

changes in diet and environment outpaced evolutionary adaptation.

Has this contributed to the explosion of acid related diseases in the

1900s? Loss of Lactobacilli from the diet began ~1850 preceding rise

in PUD, GERD etc.

Plausible that generation and preservation of cytotoxic and

pathogenic genes by H. pylori could have been prevented or

modulated by the coexistence of Lactobacillus.

Co-colonization of Lactobacillus and H. pylori permits

horizontal gene transfer through conjugation, transduction,

and transformation

Horizontal gene transfer to Lactobacilli may have acted as

a “genetic sink”, allowing the transfer of pathogenic

plasmids or genes acquired by H. pylori to Lactobacilli

Ryan KA. Journal of Medical Microbiology 2009;58(Pt 8):996-1005

Mater DD,. J Molecular Microbiology & Biotechnology 2008;14(1-3):123-7

Nicolas P, BMC Evolutionary Biology 2007;7:141

Makarova K, et al. Proc Nat Acad Sciences of the USA 2006;103(42):15611-6

Relationship between Lactobacillus and H. pylori

Environmental changes with and after

the industrial revolution

Population shifts from rural to city environments

Huge change in diet with increased energy requirements –

increase in salt, meat and CHO intake

Antiseptics introduced

Modern food preparation – preservation, prolonged shelf-

life - canning introduced in 1810

Vinegar pickling replaced lactic acid pickling (sauerkraut)

Pasteurization of milk described in 1864 and introduced

widely by 1910

Antibiotics introduced in middle of the 20th Century

Changing Incidence of Upper GI Diseasesand H. pylori Infection

after Blaser, J Infect Dis 1999; 179: 1523

1900 1930 1950 1970 1990 2000

Years

Relative incidence of event

10

0

2

4

6

8

Duodenal ulcer

Gastric ulcer

Gastric cancer

H. pylori colonization

Reflux esophagitis

Barrett’s esophagitis

Adenocarcinoma

of the esophagus

Suggested revised time line for changes in

the effects of a changing gastric microbiome

Conclusions, future studies and directions

Lactobacillus was likely in the stomach 150 years ago and can

colonize the stomach

Lactobacilli modulate acid physiology of the stomach through

gastrin

Lactobacilli modulate H. pylori and other gut bacteria and

reduce inflammation

Future in vivo studies in animal models and in humans will

determine inhibitory / modulatory actions of Lactobacilli or their

products on acid physiology in health and disease

This in part could explain much about Helicobacter pylori and

its role as a pathogen or as a member of the normal gastric

microbiome

The new concept of gastric probiotics could

have a beneficial impact on acid related

diseases such as: peptic ulcer, gastritis,

dyspepsia and reflux disease

“Discovery consists of

seeing what everybody has

seen and thinking what

nobody has thought”

Albert Szent Györgyi

1937 Nobel Laureate

Ireneusz (Rene) Padol PhD

Research Associate

Thanks to my friend and colleague

Rene Padol

Thank you for your attention

A place for probiotics in UGI Disease

deserves more active research!