Gases

Ali Rezaie, MD, MSc, FRCPC

Assistant Professor

Division of Gastroenterology and Hepatology

Cedars-Sinai

Objectives

• Basics of gas production by microbiome

• Clinical implications of breath gas measurement

• How does breath gas measurement help us

advance our knowledge on microbiome?

Gases

• Hippocrates: Aroma of human breath can provide clues to diagnosis

• Avicenna of Persia described the change in breath smell and sweet taste of urine as prognosticating factor

Canon of Medicine.1025 AD

Gases

• Antoine Lavosier

discovered O2 and H2 in

1772

– Found CO2 in exhaled

breath: “Respiration is

combustion”

Opuscules physiques et chimiques. 1774

Intestinal Gas-The Basics

• On average healthy subjects have ~100 cc of

intestinal gas (range 30-200 cc)

• 99% of intestinal gas is composed of odorless

O2, H2

, N2, CO2

and CH4

• <1% include other gases such as H2S, indole,

skatole and NH3

Levitt M. NEJM. 1971

Intestinal Gas-The Basics

• Intestinal gas is eliminated via four mechanisms

– Belching

– Diffusion

– Bacterial consumption

– Flatus

Levitt M. NEJM. 1971

Intestinal Gas-The Basics

• Intestinal gas derives from four sources

– Swallowed air and air mixed with food

– Chemical reactions (e.g. H+ + HCO3- H2O+CO2)

– Diffusion of gases from blood stream

– Bacterial metabolism (CO2+4H2O CH4+2H2O)

Levitt M. NEJM. 1971

CH4 and H2 Exclusive Biomarkers of

Gut Microbiome

• Source of CH4 and H2 in the breath in the

intestinal gas is from the bacterial metabolism

– Germ free rats

– Infants in the first day of life

Levitt M. Gastroenterology.1970

Bacterial

fermentation of

carbohydrates

H2

CO2

Methanogens: CH4

Sulfate reducers: H2S

Nitrate reducers: NH4

Acetogens: CH3COO-

Simplified Pathways of Gas Production

by Microbiome

Yang et al.Front Microbiol. 2016

Diagnosis of SIBO

• Gold standard:

Concentration of bacteria

in the jejunum is more

than 103 CFU/ml using

small bowel aspiration

Rezaie A et al. North American consensus. DDW 2016

Greiner AK et al. Am J of Physiology 2014

What Are the Symptoms of SIBO?

• Abdominal distention

• Bloating

• Early satiety

• Dyspepsia

• Nausea

• Abdominal discomfort

• Fatigue

• Post-prandial “Brain fog”

Rezaie A, Pimentel M, Rao SS. Curr Gastro Report. 2016

Greiner AK et al. Am J of Physiology 2014

What Are the Symptoms of SIBO?

• Diarrhea (Hydrogen-predominant SIBO)

• Constipation (Methane-predominant SIBO)

• Weight loss

• Rarely: Vitamin B12 and iron deficiency

Rezaie A et al. Curr Gastroenterol Report 2016

Causes of SIBO

SIBO is not a primary disease

Small bowel dysmotility: Connective tissue diseases, anti-vinculin/anti-CdtB

antibodies, diabetes

Post-surgical: Gastric bypass, ileocecal resection

Medication: Narcotics, anticholinergics and anti-diarrheals

Lack gastric acid secretion: PPIs, autoimmune gastritis and gastrectomy

Rezaie A et al. Curr Gastroenterol Report 2016

Diagnosis of SIBO

• Current gold standard: Small bowel aspiration

– Invasive

– Costly

– Time-consuming

• Breath testing:

– Non-invasive

– Inexpensive

Rezaie A et al. Curr Gastroenterol Report 2016

Jacobs et al. APT 2013

Basic Principles of

Breath Test

• Lactulose and

glucose are the most

common substrates

for diagnosis of SIBO

CH4

H2

CH4

H2

Blood stream

Food

Depending on the type of

excessive bacteria, H2

and/or CH4 gases are

produced

Glucose

Lactulose

Rezaie A et al. North American Consensus statement on Breath testing. 2016

0 15 30 45 60 75 90 105 120 135 150 165 180

H2 8 12 9 11 16 14 12 16 17 12 18 25 29

CH4 1 1 2 0 1 2 1 1 1 1 2 1 1

0

20

40

60

80

BR

EA

TH

HY

DR

OG

EN

AN

D M

ET

HA

NE

C

ON

CE

NT

RA

TIO

N (

PP

M)

Normal Breath Test

Rezaie A et al. Curr

Gastroenterol Report 2016

Positive test: Rise of hydrogen by

20 ppm within 90 minutes

Rezaie A et al. Curr

Gastroenterol Report 2016

Small intestinal bacterial overgrowth

(Hydrogen producing bacteria)

0 15 30 45 60 75 90 105 120 135 150 165 180

H2 8 3 9 11 9 4 12 12 8 6 9 2 10

CH4 42 45 49 52 41 47 43 44 46 44 43 47 39

0

20

40

60

80

BR

EA

TH

HY

DR

OG

EN

AN

D M

ET

HA

NE

C

ON

CE

NT

RA

TIO

N (

PP

M)

Small intestinal bacterial overgrowth (Methane producing bacteria)

Positive test: Methane level ≥10 ppm

0 15 30 45 60 75 90 105 120 135 150 165 180

H2 2 2 2 1 2 1 2 2 2 2 2 2 2

CH4 0 0 0 0 0 0 0 0 0 0 0 0 0

0

20

40

60

80B

RE

AT

H H

YD

RO

GE

N A

ND

ME

TH

AN

E

CO

NC

EN

TR

AT

ION

(P

PM

)

Small intestinal bacterial overgrowth

(H2S producing bacteria)

Rezaie A et al. Curr

Gastroenterol Report

2016

SIBO

Excessive methane production

or flat-line

Hydrogen-predominant SIBO

without excessive methane production

Combine broad spectrum

antibiotic with neomycin 500 mg PO

BID for 14 days

Broad spectrum antibiotic

(amoxicillin, ciprofloxacin, trimethoprim-

sulfamethoxazole or rifaximin)

for 14 days

Consider alternative

antibiotics or elemental diet Clinical Response

No

Yes

Recurrence - Educate patient about the risk of recurrence

- Adopt a strategy for maintenance of remission

Maintenance of

remission

Consid

er

elim

inatio

n o

r m

odific

ation o

f th

e u

nd

erl

yin

g c

ause o

f S

IBO

Induction of Remission

Re

za

ie A

, P

ime

nte

l M

, R

ao

SS

. C

urr

Ga

str

oente

rol R

ep

ort

20

16

Ø

*

• Rifaximin 400mg TID vs. tetracycline 333mg TID in SIBO patients

• Significant improving in Rifaximin arm for diarrhea, fatigue and borborygmi

Di Stefano et al. APT 2000

Rifaximin-SIBO

Ø

*

P<0.01 • TARGET 1 & 2 RCTs (n= 1,258)

• Rifaximin 550 mg PO TID for 14 days vs placebo

Pimentel M et al. NEJM. 2011

Rifaximin-Single course for IBS-D

P<0.01

Ø

*

P<0.01

Lembo A, Pimentel M et al. Gastroenterology. 2016

Rifaximin-Repeat therapy for IBS-D (TARGET 3)

P<0.01 • N = 2,579

• No statistically significant AEs between placebo and Rifaximin

• One case of C diff in the observation phase while patient being treated for UTI

• No change in MICs

n=1,891

Rezaie A et al. ACG 2015

Fasting

methane

level

(ppm)

Sensitivity

(95% CI)

Specificity

(95% CI)

PPV

(95% CI)

NPV

(95% CI) +LR -LR

≥5 96.1

(95.1-96.9)

99.7

(99.6-99.8)

98.5

(97.8-99.0)

99.3

(99.1-99.4) 353 0.04

Accuracy of a single fasting measurement of methane as

compared to 2–hour lactulose breath testing (gold standard)

Rezaie A et al. ACG 2015

n=12,183

Prevalence of Excessive Methane

Producers Increases by Age

Chang B, Pimentel M, Rezaie A. Gastroenterology. 2015. S-729

21 yo female with refractory clostridium difficile colitis

Fecal microbiota transplantation in July 2014

Eradication of Cdiff but severe distention, fatigue

and constipation

W/U Neg

No response to Antidepressants, low

FODMAPs, peppermint, OTC laxatives, linaclotide,

lubiprostone and prucalopride

Found to have methane-predominant bacterial

overgrowth in Oct 2015

Perfect response to Rifaximin and neomycin

FMT donor was found to be an excessive methane producer!

Chang B and Rezaie A. AJG 2016 (in press)

Ø

* P <0.01 Ø P <0.001

* *

Rezaie A, Pimentel M, McGovern D. DDW 2016

• Methanogenesis is significantly suppressed in

IBD patients; however, if present it is associated

with severe constipation

• A flatline breath test is more prevalent in CD

which may suggest excessive H2S production

Rezaie A, Pimentel M, McGovern D. DDW 2016

Conclusion

• Exhaled breath gases are non-invasive, inexpensive

and accessible alternatives to assess gut

microbiome in research and clinical practice

– Diagnosis of SIBO and carbohydrate malabsorption

– Tailored microbiome-directed therapy and diet

– Dynamism of microbiome

– Variability in metabolic behavior of gut microbiome

– Differences in microbiome in various diseases

Acknowledgments

• Dr. Mark Pimentel

• Dr. Ruchi Mathur

• Dr. Niki Pichetshote

• Dr. Gillian Barlow, Shari Chua,

Walter Morales, Stacey Weissman,

Emily Marsh