EDITORIALS
Constipation and the Microbiome: Lumen Versus Mucosa!
See “Relationship between microbiota of the
colonic mucosa vs feces and symptoms, colonic
transit, and methane production in female
patients with chronic constipation,” by
Parthasarathy G, Chen J, Chen X, et al, on
page 367.
C hronic constipation is a highly prevalent disorder
worldwide and, although often dismissed as a mere
nuisance, can result in a significant impairment in quality of
life and impose considerable costs to the individual, as well
as to society at large.1 Several endocrine, neurologic, and
other nongastrointestinal disorders, as well as a long list of
commonly prescribed drugs, may result in so-called sec-
ondary constipation; in many instances, however, an
obvious cause is not evident, this clinical entity is referred to
as chronic idiopathic constipation (CIC; frequently referred
to simply as chronic constipation). CIC is now defined not on
the basis of a mere reduction in stool frequency, but rather
on the presence of a symptom complex that includes a
number of symptoms that convey a sufferers’ difficulty with
the act of defecation (eg, straining, hard stools, a sense of
incomplete evacuation).2 By definition, pain is not a prom-
inent feature in CIC and this symptom has been used to
differentiate CIC from what many would regard as its very
close relative; constipation-predominant irritable bowel
syndrome (IBS-C).2 Clinical experience and a number of
clinical studies suggest that this convenient separation
between CIC and IBS-C may not be so easy or appropriate.3
These shifts in phenotype, which have resulted in a
considerable expansion of the concept of constipation, have
necessitated that we revisit its pathophysiology and
certainly demand that we expand our horizon beyond that
of colonic inertia as the sole determinant of defecation-
related symptomatology. First came the proposal that CIC
could be conveniently split into 3 distinct phenotypes (slow
transit constipation, defecatory dysfunction, and IBS-C) on
the basis of simple tests of colon transit and anorectal/
pelvic floor function.4 Intellectually, neat; yes, but clinically
unhelpful because symptoms proved poorly predictive of
physiologic dysfunction and overlap, not just in patient de-
mographics and symptomatology, but also in colon transit
time, anorectal manometric parameters and pelvic floor
function between these groups seemed to be the rule rather
than the exception.3,5 More detailed studies of colonic
physiology and morphology have unearthed some surpris-
ing findings in constipated subjects and illustrated the likely
heterogeneity and intrinsic complexity of the disorder: high-
resolution manometry revealed disordered rather than
reduced motor activity6 and studies of colonic ultrastruc-
ture loss of interstitial cells of Cajal and not loss of muscle
layers,7 for example. Lingering in the background and
Gastroenterology 2016;150:300–314
occasionally bubbling toward the surface has been the
suggestion that the answer might lie in the lumen and
changes there might influence enteric neuromuscular
function.
The role of gut bacteria in the digestion of dietary fiber
was well-documented >80 years ago8 and the impacts of
fiber–microbiome interactions on stool habit, colon transit,
and stool weight elegantly detailed many decades ago.9
Other luminal factors (all modulated by the microbiota),
such as short chain fatty acids10,11 and bile acids,12 can in-
fluence colonic motility and secretion. Based on these
physiologic effects, a deficiency of bile acids or an excess of
certain short chain fatty acids could be seen to contribute to
the pathophysiology of constipation. Indeed, some evidence
exists to suggest a role for both of these factors in the
pathophysiology of constipation.13,14 Furthermore, the
physiologic effects of bile acids on the colon have most
recently been translated into therapy through the use of an
ileal bile acid transporter inhibitor, elobixibat, in chronic
idiopathic constipation.15 Certain gaseous products of bac-
terial fermentation have also been associated with con-
stipation. Methane, produced by Archaea through the
reduction of carbon dioxide using hydrogen (produced by
bacterial fermentation of undigested or poorly digested
carbohydrates) as the electron donor has been linked to
both CIC and IBS-C.16 Methaninobrevibacter smithii is the
dominant methanogen in the human gut and certain in-
dividuals (approximately one-third of the US population)
preferentially excrete methane, rather than hydrogen, when
administered a nonabsorbable carbohydrate such as lactu-
lose.17 Although the interpretation of hydrogen breath test
results in IBS remain controversial, there is a reasonable
consensus that preferential excretion of methane on a lac-
tulose breath hydrogen test is predictive of the IBS-C sub-
type and has also been linked with CIC18; more problematic
has been converting this observation into a therapeutic
strategy.
Taking these somewhat disparate pieces of information
together, one can begin to visualize a scenario whereby
dietary constituents and the colonic microbiota interact to
generate biologically active molecules that influence gut
motility and secretion and could play a fundamental role in
the pathogenesis of constipation (Figure 1). These consid-
erations are not of theoretical interest alone; we already
know that a number of strategies, ranging from dietary
fiber, to lactulose and polyethylene glycol, which have
proven effective in the management of chronic constipation,
alter the microbiome and its metabolism and that, in certain
circumstances, they may owe their efficacy to these
effects.19,20
What then do we know of the colonic microbiota and its
metabolic activity in constipation? In contrast to IBS where
several studies are extant, remarkably few studies using
modern molecular methods have explored this question in
 EDITORIALS

Figure 1. Interactions be-

tween diet, the microbiota
and colonic physiology in
the pathogenesis of con-
stipation. (1) Bile acids
entering the colon are
deconjugated and stimu-
late both motility and
secretion; a deficiency of
bile acids could promote
constipation. (2) Dietary fi-
ber and other poorly
absorbed carbohydrates
are metabolized to pro-
duce short chain fatty
acids, which promote net
fluid absorption and may
also enhance motility. In
individuals with a
methanogenic microbiota,
methane is produced,
which has been shown to
slow transit. (3) Changes in
the mucosal or juxtamu-
cosal microbiota could
promote constipation by
enhancing absorption.
Red arrows indicate im-
pacts of products of in-
teractions between the
colonic microbiota and
luminal contents on
colonic functions (luminal
pH, mucosal absorption/
secretion, colonic motility).
Dashed arrows indicate
effects that are proposed
but not necessarily uni-
versally accepted.

CIC, despite its prevalence and impact.21 Changes had been
demonstrated in culture-based studies, but it was unclear
whether such alterations in bacterial species that were
observed were a cause or a consequence of constipation.22
More recent studies using techniques that permit the defi-
nition of the entire microbiota have also demonstrated
changes in CIC; whether such changes reflected the effects
of constipation per se or the confounding effects of altered
fiber or fat intake was unclear.14,23 Furthermore, these
studies based their observations exclusively on an exami-
nation of the fecal microbiota; a bacterial population that
may differ substantially from that which lives in much more
intimate contact with the host, namely, the juxta-mucosal
microbiota. The study reported by Parthasarathy et al in
this issue of Gastroenterology, which set out to examine
relationships between the fecal and mucosal microbiota,
colonic transit, bacterial metabolism and diet is, therefore,
welcomed.24
Twenty-five females with constipation (15 CIC, 6 IBS-C,
6 mixed type IBS) and 25 gender-matched but slightly
younger healthy controls provided both fecal samples and
sigmoid biopsies for microbial analysis, had their dietary
intake assessed, and underwent a lactulose breath
hydrogen test as well as scintigraphic assessment of gastric
emptying and small bowel and colonic transit. Somewhat
surprisingly, given all that has been said above about
luminal factors, these investigators found that it was the
mucosal and not the luminal (ie, fecal) microbiota that
emerged as predictive of constipation; an association that
proved independent of colon transit, diet, age, and body
mass index. In contrast, and again somewhat counterintu-
itively, changes in the fecal microbiota were associated

301
EDITORIALS
with colonic transit but not with constipation. In inter-
preting results in relation to transit, it must be noted that
hard stools can result from altered motility, which may or
may not be associated with slow transit and only 14 of the
25 constipated patients actually had slow transit. Transit
correlated with calorie and fiber intake and the association
between microbiota and transit was lost after adjustment
for diet and other factors. Finally, and again surprisingly,
although methane production was associated with the
composition of the fecal microbiota, it was not linked to
either constipation or colonic transit.
A major strength of this study was its inclusion of an
assessment of dietary intake, which revealed that consti-
pated individuals reported consuming fewer total calories,
as well as lesser amounts of protein, fat, and fiber, factors
that could certainly influence the microbiota and transit.
Whether such dietary habits among those with constipation
reflect an adaptive response or play a primary role in
pathogenesis is, of course, unclear. Single-point-in-time
(cross-sectional) studies such as this can provide
intriguing findings but are limited in their ability to assign
causation; incriminating the microbiota, whether mucosal or
luminal, in the etiology of constipation would require diet-
controlled, longitudinal studies preferably including an
intervention that restored the microbiota to normal,
normalized transit, or relieved constipation. In this manner,
one can begin to dissect out relations between and the
relative contributions of diet, transit and the microbiota to
symptoms; are microbiota changes state or trait? In contrast
with animal studies, where potentially confounding factors
can be so readily manipulated or even eliminated, differ-
entiating between cause and effect has been a major limi-
tation of many studies of the microbiota in man in health
and disease. For example, a reduction in microbiota di-
versity seems to be a nonspecific effect of diarrhea and is
ubiquitous among diarrheal disease regard less of etiology25
and, of particular relevance to constipation, a recent study
in healthy volunteers demonstrated correlations between
the microbiota and stool consistency, as assessed by the
Bristol Stool Scale.26 Part of this correlation may reflect
microbial growth potential, because those able to grow
rapidly are more likely to survive under conditions of rapid
transit than those only capable of slow growth.
The findings of Parthasarathy et al24 again reveal the
complexity of relationships between colonic motility (as
assessed by colon transit in their study) and constipation;
recent revelations from high-resolution colonic manometry
suggest that disordered rather than hypomotility may be the
dominant motor pattern in constipation.6 Accordingly, the
prominent retrograde cyclic contractions described by
Dinning et al,6 which account for 97% of the increase in
cyclical patterns after eating, could be seen to promote
constipation by enhancing water absorption to produce
hard stools without invoking a delay in transit. Could an
altered mucosal microbiota, as described by Parthasarathy
et al, exert its effects also through a modulation of net
fluid fluxes? Explorations of bacterial function, through
metagenomics, and metabolic products, should throw
considerable light on how bacterial species might promote
302
constipation. In the meantime, Parthasarathy et al have
reminded us of the challenges and pitfalls that confront
those who attempt to study the microbiome in a functional
disorder, have highlighted the complexity of diet, transit and
microbiota relationships in health26 and in constipation and
have generated novel hypotheses that many will be eager
to test.
EAMONN M. M. QUIGLEY
Division of Gastroenterology and Hepatology
Lynda K. and David M. Underwood Center for Digestive Disorders
Houston Methodist Hospital and Weill Cornell Medical College
Houston, Texas
ROBIN C. SPILLER
Nottingham Digestive Diseases Biomedical Research Centre
University of Nottingham
Queens Medical Centre
Nottingham, UK
References
1. Suares NC, Ford AC. Prevalence of, and risk factors for,
chronic idiopathic constipation in the community: sys-
tematic review and meta-analysis. Am J Gastroenterol
2011;106:1582–1591.
2. Longstreth GF, Thompson WG, Chey WD, et al. Func-
tional bowel disorders. Gastroenterology 2006;130:
1480–1491.
3. Quigley EM. Editorial: differentiating chronic idiopathic
constipation from constipation-predominant irritable
bowel syndrome–possible and important? Aliment
Pharmacol Ther 2015;41:1299.
4. Hinton JM, Lennard-Jones JE. Constipation: defini-
tion and classification. Postgrad Med J 1968;44:
720–723.
5. Zarate N, Knowles CH, Newell M, et al. In patients with
slow transit constipation, the pattern of colonic transit
delay does not differentiate between those with and
without impaired rectal evacuation. Am J Gastroenterol
2008;103:427–434.
6. Dinning PG, Wiklendt L, Maslen L, et al. Colonic motor
abnormalities in slow transit constipation defined by high
resolution, fibre-optic manometry. Neurogastroenterol
Motil 2015;27:379–388.
7. Bassotti G, Villanacci V, Creţoiu D, et al. Cellular and
molecular basis of chronic constipation: taking the
functional/idiopathic label out. World J Gastroenterol
2013;19:4099–4105.
8. Mangold E. The digestion and utilisation of crude fibre.
Nutr Abstr Rev 1934;3:647–656.
9. Cummings JH. Dietary fibre. Gut 1973;14:69–81.
10. Yajima T. Contractile effect of short-chain fatty acids on
the isolated colon of the rat. J Physiol 1985;368:
667–678.
11. Binder HJ, Mehta P. Short-chain fatty acids stimulate
active sodium and chloride absorption in vitro in the rat
distal colon. Gastroenterology 1989;96:989–996.
12. Mekhjian HS, Phillips SF, Hofmann AF. Colonic secretion
of water and electrolytes induced by bile acids: perfusion
studies in man. J Clin Invest 1971;50:1569–1577.

13. Abrahamsson H, Ostlund-Lindqvist AM, Nilsson R, et al.
Altered bile acid metabolism in patients with
constipation-predominant irritable bowel syndrome and
functional constipation. Scand J Gastroenterol 2008;
43:1483–1488.
14. Kang DW, DiBaise JK, Ilhan ZE, et al. Gut microbial and
short-chain fatty acid profiles in adults with chronic
constipation before and after treatment with lubipro-
stone. Anaerobe 2015;33:33–41.
15. Chey WD, Camilleri M, Chang L, et al. A randomized
placebo-controlled phase IIb trial of a3309, a bile acid
transporter inhibitor, for chronic idiopathic constipation.
Am J Gastroenterol 2011;106:1803–1812.
16. Triantafyllou K, Chang C, Pimentel M. Methanogens,
methane and gastrointestinal motility. J Neurogastroenterol
Motil 2014;20:31–40.
17. Pimentel M, Lin HC, Enayati P, et al. Methane, a gas
produced by enteric bacteria, slows intestinal transit
and augments small intestinal contractile activity. Am
J Physiol Gastrointest Liver Physiol 2006;290:
G1089–G1095.
18. Kunkel D, Basseri RJ, Makhani MD, et al. Methane on
breath testing is associated with constipation: a sys-
tematic review and meta-analysis. Dig Dis Sci 2011;
56:1612–1618.
19. Vanhoutte T, De Preter V, De Brandt E, et al. Molecular
monitoring of the fecal microbiota of healthy human
subjects during administration of lactulose and Saccha-
romyces boulardii. Appl Environ Microbiol 2006;
72:5990–5997.
20. Jalanka J, Salonen A, Salojärvi J, et al. Effects of bowel
cleansing on the intestinal microbiota. Gut 2015;
64:1562–1568.
No Polyp Left Behind: Defining Bowel Preparation Adequacy to
Avoid Missed Polyps
See “Quantification of adequate bowel
preparation for screening or surveillance
colonoscopy in men,” by Clark BT, Protiva P,
Nagar A, et al, on page 396.
A major goal of colorectal cancer (CRC) screening
with colonoscopy is to minimize CRC incidence, and
this is accomplished by identifying and completely resecting
adenomas.1,2 In recent years, considerable attention has
been focused on the adenoma detection rate (ADR) as a
measure of the quality of colonoscopy.3 Higher ADRs are
associated with lower rates of interval CRC,4 which are
defined as CRC diagnosed after a prior colonoscopy but
before the next scheduled screening or surveillance colo-
noscopy. This is partly because endoscopists with a high
ADR seem less likely to “miss” adenomas during colonos-
copy. Endoscopists also intuitively understand that subop-
timal bowel preparation obscures some colonic mucosa and
EDITORIALS
21. Quigley EM. The enteric microbiota in the pathogenesis
and management of constipation. Best Pract Res Clin
Gastroenterol 2011;25:119–126.
22. Khalif IL, Quigley EM, Konovitch EA, et al. Alterations in
the colonic flora and intestinal permeability and evidence
of immune activation in chronic constipation. Dig Liver
Dis 2005;37:838–849.
23. Zhu L, Liu W, Alkhouri R, et al. Structural changes in the
gut microbiome of constipated patients. Physiol Geno-
mics 2014;46:679–686.
24. Parthasarathy G, Chen J, Chen X, et al. Relationship
between microbiota of the colonic mucosa vs feces and
symptoms, colonic transit, and methane production in
female patients with chronic constipation. Gastroenter-
ology 2016;150:367–379.
25. Shanahan F, Quigley EM. Manipulation of the microbiota
for treatment of IBS and IBD-challenges and contro-
versies. Gastroenterology 2014;146:1554–1563.
26. Vandeputte D, Falony G, Vieira-Silva S, et al. Stool
consistency is strongly associated with gut microbiota
richness and composition, enterotypes and bacterial
growth rates. Gut 2015 Jun 11 [Epub ahead of print].
Reprint requests
Address requests for reprints to: Eamonn M. M. Quigley, MD, FRCP, FACP,
MACG, FRCPI, 6550 Fannin Street, SM 1001, Houston, Texas 77030. e-mail:
equigley@tmhs.org.
Conflicts of interest
The authors disclose no conflicts.
Most current article
© 2016 by the AGA Institute
0016-5085/$36.00
http://dx.doi.org/10.1053/j.gastro.2015.12.023
increases the risk of “missing” an adenoma.5,6 So, when
bowel preparation is suboptimal, endoscopists are more
likely to vary from guidelines and recommend shorter
follow-up intervals for fear of missing important neo-
plasia.6–8 Current guidelines state that the bowel prepara-
tion should be reported to be “adequate” if it allows
visualization of polyps >5 mm.5 Up until now, this concept
has been poorly defined, leading to substantial variability in
endoscopists’ interpretation of what constitutes an
“adequate” bowel preparation and its impact on recom-
mendations for timing of future screening or surveillance
colonoscopy.8–10 Therefore, endoscopists need a quantifi-
able, validated, and reproducible guide to determine when
bowel cleansing is good enough. The findings of a new study
address this.
In this issue of Gastroenterology, Clark et al11 report on
their tandem colonoscopy study to assess the impact of
bowel cleansing on missing adenomas >5 mm. Study pa-
tients were average-risk, 50- to 75-year-old veterans un-
dergoing colonoscopy for CRC screening or colon polyp
303