Prof Peter 145 main thursday - Living FODMAP Free · Core concept intensity stimuli intensity ... diet induces abdominal pain Healthy controls IBS * ... Prof Peter 145 main thursday

THE SCIENCE BEHIND FODMAPs

Peter Gibson

FODMAPs Fermentable Oligo- Di- & Mono-

saccharides And Polyols

Theory: Act by distending the intestinal

lumen via being:

� Osmotically active� Osmotically active

� Small molecules

� Trapped in the lumen �� ↑ luminal water volume

� Osmotic effect related to molecular size

� fructose = ~0.5 lactose (lactulose) = ~0.25 FOS

� Rapidly fermented

� �� gas ��↑ luminal volume

Enteric

nervous

system

Controller of most GI

functions - secretion,

motility, blood flow,

mucosal growth

“Normal”

low

“Abnormal”

high

Food

Luminal

distension

Core concept

low

intensity

stimuli

high

intensity

stimuli

• Little effect on motility

• Few conscious messages

• Alter motility

• Pain, discomfort, awareness

750

1000

To

tal o

utp

ut

(g)

p=0.01

• 4-day randomised cross-over dietary study

• Diets differed in FODMAP content by ~10 g/day

• Daytime ileostomy output measured

0

250

500

To

tal o

utp

ut

(g)

High FODMAP Low FODMAP

22%

Wilcoxon signed rank testBarrett et al APT 2010

FODMAP recovery

High FODMAP

Low FODMAP

Gra

ms

(g)

10

*

* p<0.05 Wilcoxon signed rank test

0

Gra

ms

(g)

5

*

Barrett et al APT 2010

Correlation of water and FODMAP recovery

600

800

Wate

r co

nte

nt

dayti

me o

utp

ut

(ml)

r = 0.7223

p=0.018

0 5 10 15 20 25

0

200

400

FODMAPs recovered

Wate

r co

nte

nt

dayti

me o

utp

ut

(ml)

Spearman's correlationBarrett et al APT 2010

Liquid volume in

small intestinal

lumen:

mannitol vs glucose

Marciani et al Gastroenterology 2010

↑ colonic water: Dose-dependence of effect on faecal volume in response to lactulose/FOS

�� lactulose�� FOS

Volume with lactulose = 2 x volume with FOS

2 sugars 4 sugars

Clausen et al DDS 1998

2 sugars 4 sugars

Luminal

FODMAPs in terminal ileumFODMAPs in terminal ileum

Increased water Increased water

delivery delivery (osmotic)(osmotic)

Bacterial Bacterial

fermentation fermentation ColonColon

Bloating Luminal

distension

Propulsive motor

activity

Luminal retention

of Na & H2O

Bloating

Pain/discomfort

FODMAPs are rapidly fermentable

� In vitro - fecal slurries:� Rapid fermentation of FODMAPs

� Lactulose = fructose = lactose = FOS >sorbitol > GOS

Clausen et al Dig Dis Sci 1998

� Fermentability of carbohydrates dependent � Fermentability of carbohydrates dependent upon chain length� e.g., in vivo - breath hydrogen production:

� 4.7 ppm/h………Resistant starch

� 19.1 ppm/h………Inulin

� 26.6 ppm/h………Lactulose

Brighenti et al Ital J Gastro 1995

20

25

30

35

Hy

dro

ge

n P

rod

uc

tio

n / p

pm

Diet A Low

FODMAP

Diet B High

FODMAP

Typical effect of FODMAP intake on

hydrogen production during the day

0

5

10

15

20

1 2 3 4 5 6 7 8 9 10 11 12 13 14

Time / hours

Hy

dro

ge

n P

rod

uc

tio

n / p

pm

Ong et al J Gastro Hepatol In press

AUC breath gas production over 12 h in

15 healthy volunteers

400.00

200.00

Hy

dro

gen

AU

C

p<0.001* H2 CH4

High FODMAP DietLow FODMAP diet

200.00

0.00

Hy

dro

gen

AU

C

FODMAP content of diet

Low High

AUC breath gas production over 12 h in

15 healthy volunteers

400.00

200.00

Hy

dro

gen

AU

C

350.00

300.00

250.00

200.00

Me

tha

ne

AU

C

p<0.001* p=0.025*H2 CH4

High FODMAP DietLow FODMAP diet

200.00

0.00

Hy

dro

gen

AU

C

High FODMAP DietLow FODMAP Diet

150.00

100.00

50.00

0.00M

eth

an

e A

UC

FODMAP content of diet

Low High HighLow

Gas

(H2, CO2, CH4)

Short-chain fatty

acids

Luminal

FODMAPs in terminal ileumFODMAPs in terminal ileum

Increased water Increased water

delivery delivery (osmotic)(osmotic)

Bacterial Bacterial

fermentation fermentation ColonColon

Bloating

Promote Na &

H2O absorption

Luminal

distension

Propulsive motor

activity

Luminal retention

of Na & H2O

Bloating

Pain/discomfort

Dose-dependence of effect on fecal volume in

response to lactulose/FOS



Luminal retention

of Na & H2O

Promote Na &

H2O absorption

Opposing forces of FODMAP

disposal in colon

Diarrhea Desiccation

� Dose of FODMAPs� Efficiency of fructose & lactose absorption

� Efficiency of fermentation� Motility responses to distension/butyrate

� Epithelial function/dysfunction

Wide individual variation of fecal volume in

response to lactulose/FOS



Small intestine

FODMAPs

Large intestineMode of action of FODMAPs

gas production

water deliveryLuminal distension

Altered motility

Pain, bloating, distension, constipation &/or diarrhoea

2 days’ (blinded) high FODMAP

diet induces abdominal pain

Healthy controls IBS

*

* p<0.05 Mann-Whitney U

& Wilcoxon signed ranks testsOng et al JGH 2010

Healthy controls IBS

*

2 days’ (blinded) high FODMAP

diet induces bloating

*

* p<0.05 Mann-Whitney U &

Wilcoxon signed ranks testsOng et al JGH 2010

0

50

100

150

200

250

300

350

400

450

0 5 10 15 20

Total bowel symptom score

Bre

ath

hy

dro

ge

n (

AU

C) Breath hydrogen vs

total symptom score

r=0.467

p=0.012

-50

0

50

100

150

200

250

300

350

0 5 10 15 20

Total bowel symptom score

Bre

ath

me

tha

ne

(A

UC

)

Breath methane vs

total symptom score

r=-0.434

p=0.021

Ong et al JGH 2010

Ch

an

ge

s in

VA

S s

core

(m

m)

35

40

45

50

100

Effect of 10 g sorbitol or mannitol on symptoms4 h changes in overall abdo symptoms in IBS (n=20)

p=0.03

p=0.05, Wilcoxon sign-rank test

Malabsorption (BH2T) 60% 20% 0%C

ha

ng

es

in V

AS s

core

(m

m)

0

5

10

15

20

25

30

Sorbitol GlucoseMannitol

Yao et al AGW 2011

Liquid volume in

small intestinal

lumen:

mannitol vs glucose

Marciani et al Gastroenterology 2010

Is benefit of low FODMAP diet only a

placebo effect? – ‘rechallenge’Randomised placebo-controlled 4-arm cross-over

trial of reintroduction of fructose/fructans

25 patients with IBS (12 IBS-D)

� 23-60 y; 4 men� 23-60 y; 4 men

� Fructose malabsorption (breath test)

� Durable response to low FODMAP diet

(at least 3 months)

� Well controlled symptomsShepherd et al, Clin Gast Hep 2008

11oo endend--pointpoint

% % symptoms not adequately controlledsymptoms not adequately controlled

P < 0.001

Shepherd et al Clin Gastro Hepatol 2008

Median overall symptom score Median overall symptom score

in relation to dosein relation to dose

Median scores onVAS

p<0.001, cf glucose

p<0.001, across groups

p<0.001, Fisher’s exact

Fisher’s exact

*Median scores onVAS

p<0.001, cf glucose

Shepherd et al, Clin Gast Hep 2008

Rechallenge RCT

� Improvement with low FODMAP diet was

not a placebo effect

� Involved not just fructose but fructans� Involved not just fructose but fructans

� Fructose & fructans have additive effects

= supporting the FODMAP concept

FODMAP content of food

� By combination of enzymatic and HPLC

techniques, content of wide variety of

Australian foods now known

Muir et al JAFC 2007 & 2009; Biesierkierski et al JHND 2011Muir et al JAFC 2007 & 2009; Biesierkierski et al JHND 2011

� Tables of ‘safe’ and ‘unsafe’ foods

continuing to be updated → beware old lists on the internet!

Oligosaccharide content

7.1g*

3.0g

1.3g

1.2g

33.0g

10.6g

7.1g*

9.6g‡


7.1g*

3.0g

1.3g

1.2g

33.0g

10.6g

7.1g*

* Barrett FFQ, data unpublished, upper range of daily oligosaccharide intake

9.6g‡


7.1g*

3.0g

1.3g

1.2g

33.0g

10.6g

7.1g*

* Barrett FFQ, data unpublished, upper range of daily oligosaccharide intake‡ Barrett et al. Aliment Pharmacol Ther 2010

9.6g‡


7.1g*

3.0g

1.3g

1.2g

33.0g

10.6g

7.1g*


9.6g‡


7.1g*

3.0g

1.3g

1.2g

33.0g

10.6g

7.1g*


9.6g‡

Do IBS patients consume more

FODMAPs than non-IBS?

� Not known, but now have a validated Food

Frequency Questionnaire (‘Monash CNAQ’)

Barrett & Gibson JADA 2011Barrett & Gibson JADA 2011

� Fructose & lactose malabsorption occurs at

similar frequency in IBS as for healthy

population Barrett et al APT 2010

Unanswered questions

� Long-term safety� Nutritional adequacy of the diet

� Effect on microbiota (reduction of natural prebiotics)

� Effect on colorectal carcinogenesis

� Effect on physiology of the bowel� e.g., does it change visceral hypersensitivity?

� Mechanism of action in � Induction of fatigue Ong et al JGH 2010

� Increasing gastro-oesophageal reflux Piche et al GE 2003

The science behind FODMAPs

� FODMAPs distend the intestinal lumen

� Retain water via osmotic effects

� Induce increased gas production → favours higher volume H2 vs methanehigher volume H2 vs methane

� FODMAPs induce symptoms when present in

food most likely via luminal distension with

water and gas

� Many questions still to be answered

� Senior Dietitians

� Sue Shepherd

� Jane Muir

� Jaci Barrett

� Dietitians/PhD students

� Emma Halmos

� Jessica Biesierkierski

� Gastroenterology Fellows

� Richard Gearry

� Peter Irving

� Sally James

� Debbie Nathan

� Melissa Haines

� Evan Newnham� Jessica Biesierkierski

� CK Yao

� Scientists

� Nia Rosella

� Rosemary Rose

� Kelly Liels

� Evan Newnham

� Catherine Croagh

� Daniel van Langenberg

� Honours students

� Derrick Ong

� Shayleen Mitchell

Prof Peter 145 main thursday - Living FODMAP Free · Core concept intensity stimuli intensity ... diet induces abdominal pain Healthy controls IBS * ... Prof Peter 145 main thursday

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