Short Chain Fatty Acid Metabolism in COPD

Short-chain fatty acids (SCFAs) are straight or branched-chain fatty acids produced by the
intestinal microbiota mainly through fermentation of undigested carbohydrates, but also
through degradation of dietary and endogenous proteins. With a share of 90 to 95 %, acetate
(C2), propionate (C3), and butyrate (C4) are the most common SCFAs in the colon (3). The
molar ratios of acetate to propionate to butyrate are on average approximately 60:20:20
throughout the whole colon. Several human studies tried to determine the in situ production
of SCFAs by measuring their content in feces (5-8). But fecal SCFA concentrations do not
accurately represent the concentrations in more proximal regions of the colon, because
colonocytes absorb more than 95 % of SCFAs to use them as an energy source. Further, the
measurement of plasma SCFA concentrations is inaccurate because SCFA plasma levels are low
due to high metabolism in colonocytes and liver. Thus, stable isotope studies are needed to
examine the colonic production and metabolic fate of SCFAs in healthy and diseased subjects.

SCFAs seem to have anti-inflammatory and immune modulating effects. In COPD an enhanced
pulmonary inflammatory response causes a combination of small airways disease (e.g.,
obstructive bronchiolitis) and/or a destruction of lung parenchyma (emphysema). This leads to
a progressive and persistent airflow limitation. Smoking and the exposure to polluted air are
main risk factors causing COPD. In a mouse model, a diet rich in whey proteins attenuated
emphysema through the suppression of respiratory inflammation. This might have been related
to a high colonic SCFA concentration due to the diet. Young et al. proposed that in smokers
SCFAs might mitigate both the innate-mediated systemic inflammation controlled by the liver
and the inflammatory responses in the lung.

Moreover, Nielsen et al. found that gastrointestinal diseases are significantly more
prevalent in COPD patients (15 %) than in patients with other diseases (9%). This might have
an influence on the SCFA production in the colon. Gastrointestinal problems may also be
assessed through the usage of validated questionnaires.

Inclusion criteria COPD subjects:

- Ability to walk, sit down and stand up independently

- Age 45 years - 100 years

- Ability to lie in supine or elevated position for 1.5 hours

- Diagnosis of moderate to very severe chronic airflow limitation and compliant to the
following criteria: FEV1 < 70% of reference FEV1

- Clinically stable condition and not suffering from a respiratory tract infection or
exacerbation of their disease (defined as a combination of increased cough, sputum
purulence, shortness of breath, systemic symptoms such as fever, and a decrease in
FEV1 > 10% compared with values when clinically stable in the preceding year) at least
4 weeks prior to the first test day

- Shortness of breath on exertion

- Willingness and ability to comply with the protocol

Inclusion criteria control subjects:

- Healthy male or female according to the investigator's or appointed staff's judgment

- Ability to walk, sit down and stand up independently

- Age 45 years - 100 years

- Ability to lay in supine or elevated position for 1.5 hours

- No diagnosis of COPD

- Willingness and ability to comply with the protocol

Exclusion Criteria all subjects:

- Any condition that may interfere with the definition 'healthy subject' according to
the investigator's judgment (healthy subjects only)

- Subjects 86 years and older that fail to get physician eligibility confirmation

- Insulin dependent diabetes mellitus

- Established diagnosis of malignancy

- History of untreated metabolic diseases including hepatic or renal disorder

- Presence of acute illness or metabolically unstable chronic illness

- Presence of fever within the last 3 days

- Any other condition according to the PI or nurse that was found during the screening
visit, that would interfere with the study or safety of the patient

- Use of protein or amino acid containing nutritional supplements within 5 days of first
study day

- Use of short course of oral corticosteroids within 4 weeks preceding first study day

- Failure to give informed consent or Investigator's uncertainty about the willingness
or ability of the subject to comply with the protocol requirements

- (Possible) pregnancy

- Already enrolled in another clinical trial and that clinical trial interferes with
participating in this study

When during the period from enrollment to the test day any condition causing the subject to
not meet inclusion criteria or to meet exclusion criteria, the subject will be excluded
from the study.