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Nom original: modif cell nitestinale ap chir baria 2017 pharma.pdf
Titre: Intestinal adaptations following bariatric surgery: towards the identification of new pharmacological targets for obesity-related metabolic diseases
Auteur: Lara Ribeiro-Parenti

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Available online at www.sciencedirect.com

ScienceDirect
Intestinal adaptations following bariatric surgery:
towards the identification of new pharmacological
targets for obesity-related metabolic diseases
Lara Ribeiro-Parenti1, Jean-Baptiste Cavin1,2 and
Maude Le Gall1
Although the gastrointestinal tract is the primary target of
bariatric surgery, its contributions to the metabolic changes
observed after surgery are still underestimated. Changes in the
number of incretin-producing cells could result in the modified
hormonal response seen after surgery. Additionally, the rate of
absorption and consumption of glucose could contribute to the
ameliorated glycaemia. Moreover, decreased intestinal
permeability could prevent endotoxemia.Recently, numerous
studies have focused on intestinal adaptation following
bariatric surgeries. These studies bring new insight into the
different roles the GI tract plays in the metabolic outcomes of
bariatric surgery and open new avenues for therapeutic
treatments.
Addresses
1
Inserm UMR 1149, UFR de Me´decine Paris Diderot, Universite´ Paris
Diderot, Sorbonne Paris Cite´, DHU Unity APHP, F-75890 Paris, France
2
Department of Physiology and Pharmacology, Hotchkiss Brain
Institute, University of Calgary, Alberta, T2N4N1 Calgary, Canada
Corresponding author: Le Gall, Maude (Maude.le-gall@inserm.fr)

Current Opinion in Pharmacology 2017, 37:29–34
This review comes from a themed issue on Endocrine and metabolic
diseases
Edited by Gavin Bewick
For a complete overview see the Issue and the Editorial
Available online 17th August 2017
http://dx.doi.org/10.1016/j.coph.2017.08.002
1471-4892/ã 2017 Elsevier Ltd. All rights reserved.

emptying, carbohydrate digestion, and glucose absorption
during and between meals. Meanwhile, alteration of the
GI barrier function is increasingly recognized as a key
player in metabolic disease development through endotoxemia. The point of this review is to illustrate how the
adaptation of the GI tract may play important roles in the
metabolic changes induced by bariatric surgeries and how
this adaptation could be targeted by new pharmacological
drugs delivered per os to bypass the surgery.
Bariatric surgery

The most commonly performed bariatric surgeries worldwide are sleeve gastrectomy and Roux-en-Y gastric
bypass (RYGB) (Figure 1). Sleeve gastrectomy consists
of the resection of three quarters of the stomach, removing the fundus and part of the gastric body. Although it
does not physically rearrange the intestinal tract, it modifies the intestinal luminal content by accelerating gastric
emptying and decreasing stomach secretory activity. The
bypass procedure, on the other hand, profoundly modifies
the intestinal tract. In addition to the creation of a small
gastric pouch, the chyme is directly discharged from the
stomach into a more distal part of the jejunum; thereby,
bypassing the duodenum and a large part of the jejunum.
RYGB is thus considered to be malabsorptive although
the intestine rapidly adapts and compensates for this
malabsorption [1]. Historically, bariatric surgeries were
designed to promote weight loss however their benefits
on obesity comorbidities are far beyond and even independent of weight loss [2].
Enteroendocrine cells after bariatric surgery

Introduction
The main gastro-intestinal (GI) functions (i.e. absorption,
secretion and its barrier) can be modulated according to
environmental factors, food composition, and metabolic
state, they have even been shown to be altered by
bariatric surgeries. For instance, the GI tract is the largest
endocrine organ of the body and produces a set of
hormones, including incretins that regulate the release
of insulin. Alterations in incretin secretions after bariatric
surgeries are well characterized but their origins are still a
matter of debate. In addition, the GI tract plays a direct
role in glucose homeostasis by modulating gastric
www.sciencedirect.com

Modulation of gut hormone secretion is a pivotal aspect
underlying the beneficial metabolic effects of bariatric
surgeries. Hormonal changes are numerous after surgery,
and depend on the type of GI reconstruction [3,4].
Exacerbated GLP-1 secretion is notably suspected to
contribute to most metabolic improvements observed
after bariatric surgery, regardless of weight loss [5].
The origin of the modified hormonal secretions is still
highly debated. The two main overlapping hypotheses
propose that altered nutrient flow, either by duodenal
exclusion or by accelerated hindgut delivery of nutrients
(also called the ‘foregut’ and ‘hindgut’ hypotheses), are
responsible for the altered hormonal response. They
could drive the success of not only RYGB [6], but also
of VSG as gastric emptying rates are very rapid after this
Current Opinion in Pharmacology 2017, 37:29–34

30 Endocrine and metabolic diseases

Figure 1

(a)

(b)

Current Opinion in Pharmacology

(a) For vertical sleeve gastrectomy approximately 75% of the stomach is removed leaving a sleeve-shaped stomach with a capacity ranging from
about 60 to 150 cc. (b) For RYGB, the stomach is divided into a small pouch ( 30 ml), the small intestine is divided 50 cm from the pylorus, and
the distal limb of the small intestine (Roux or alimentary limb) is directly connected to the gastric pouch. The gastric remnant and isolated 50 cm
of small intestine (‘biliopancreatic limb’) is connected to the jejunum 150 cm distal to the gastrojejunal anastomosis. The small intestine distal to
the anastomosis is called the common limb.

procedure, possibly resulting in a similar distal nutrient
exposure as RYGB [7,8].
An additional hypothesis is that a modification of the
number, the location or the sensitivity of enteroendocrine
cells could contribute to the modified hormonal response.
Accordingly, the intestinal adaptation following RYGB is
characterized by a hypertrophy of the Roux limb associated with local increase in the number of several enteroendocrine cells, including CCK-producing, GLP-1-producing, GIP-producing and PYY-producing cells [9–
13,14 ]. Enteroendocrine cell distribution has also been
examined in rats after VSG in two recent reports but
showed conflicting results. In the first study, Mumphrey
et al. reported that GLP-1 cell numbers remained constant three month after VSG surgery [15]. Yet, in the
second study, the number and density of GLP-1 cells
were found to increase 14 days after surgery [14 ].
However, we must note that a change in the number
or density of a specific enteroendocrine cell type is not
necessarily associated with a change in plasma concentrations of the corresponding produced hormones. A recent
study identified two different responses in mice fed a
high-fat diet [16 ]: some maintained normal blood glucose levels and others developed hyperglycemia and
insulin resistance with the same weight gain. The former
had an L-cell density and number comparable to mice
under control diet but an increase in GLP-1 secretion
during a glucose tolerance test. On the contrary, the latter
mice displayed an increase in the number of GLP-1Current Opinion in Pharmacology 2017, 37:29–34

producing cells but secreted less GLP-1 during the glucose tolerance test suggesting a functional alteration of
these cells. In that case, the increase of L-cell numbers
probably constitutes an attempt to compensate for their
functional alteration [17 ,16 ].
These observations raise the question of the existence of
additional signals influencing enteroendocrine cell function beyond nutrients such as glucose or fatty acids that
are known to stimulate hormone production [18,19].
Specific microbiota for instance may be at play. Some
pharmacological treatments today consist in using hormone mimetics as GLP1 receptor agonists or DDPIV
inhibitors that are largely used in patients with type
2 diabetes. GLP-1 receptor agonists appear to lower blood
glucose to a greater extent and promote more weight loss
than DPP-4 inhibitors, which are weight neutral [20] but
GLP-1 receptor agonists are administered by subcutaneous injections, which could potentially reduce compliance among patients. An interesting idea would be to
target the endogenous secretion of GLP1 per
os. Currently, measuring enteroendocrine cells’ sensitivity to nutrients remain a challenge; nevertheless, there is
promise in the development of enteroids from human
biopsies for evaluating nutrient sensitivity [21,22].
Intestinal glucose consumption and metabolism

Recent evidence illustrated an association between
hyperplasia of the alimentary Roux limb after RYGB
and a reprogramming of glucose metabolism in intestinal
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Positive impact of gut adaptations after bariatric surgery Ribeiro-Parenti, Cavin and Le Gall 31

cells of this limb, which effectively increased intestinal
glucose consumption [14 ,23]. Analysis of PET-CT
scans showed an increased [18F]-FDG uptake in the
intestine associated with a 30% decrease of [18F]-FDG
signal in the blood of RYGB rats compared to sham
animals [23]; a similar phenomenon was reported in
humans [14 ]. The remodelled intestine could thus
increase whole body glucose disposal and contribute to
the glucose lowering effect of derivative bariatric procedures [14 ,24] but not vertical sleeve gastrectomy
[15,14 ]. A recent study challenged this hypothesis;
using a murine model of duodenal-jejunal bypass
(DJB), the authors explored the specific contribution of
the biliary limb versus alimentary limb to weight loss and
glucose tolerance. They demonstrated that shortening
the biliary limb, without changing the length of the
common limb, dampens weight loss and amelioration
of oral glucose tolerance [25]. Conversely, a similar shortening of the alimentary limb had no effect on weight loss.
Still, in this study the direct effect of each limb on glucose
tolerance cannot be distinguished from their effect on
weight loss.
Could we imagine mimicking the increased intestinal
glucose utilization after surgery by a pharmacological
treatment? Metformin, one of the most commonly used
diabetes medications, has been shown, a long time ago, to
increase intestinal metabolism of blood glucose in rats
[26]. Increasing numbers of studies show that this intestinal utilization of glucose contributes to metformin’s
ability to lower blood glucose in humans [27 ,28–31]. It
would be important to know whether the increased
intestinal utilization of glucose triggered by metformin
or RYGB rely on the same molecular and metabolic
mechanisms to determine whether metformin could be
delivered to replace or to complement RYGB surgery, if
not we could expect a potentiation of these effects in the
remodelled hyperplasic intestine of RYGB patients.
Indeed, faced with the progressive relapse of type 2 diabetes in patients having undergone bariatric surgeries, the
question whether or not to maintain patients on metformin after bariatric interventions is highly debated.
Intestinal transport of alimentary glucose

The GI tract plays a direct role in controlling the appearance of alimentary glucose in the blood (postprandial
hyperglycemia) by modulating dynamic meal delivery
from the stomach to the intestine, carbohydrate digestion
and glucose absorption.
In a recent study using a minipig RYGB model, Baud et al.
proposed that alimentary glucose transport was damped
in the alimentary limb, despite intact expression of the
sodium-glucose cotransporter-1 (SGLT1) [32]. Addition
of bile acids increased alimentary limb glucose uptake,
through a SGLT1 inhibitor (phlorizin)-sensitive mechanism [32]. The authors suggest that bile acid is a source of
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sodium that modulates glucose homeostasis partly by
altering sodium glucose intestinal cotransport. While bile
acids are important in the metabolic improvement after
bariatric surgeries [33 ], these observations contradict
numerous earlier studies [34,35,8,14 ,23]. In addition,
throughout the study, a direct comparison with sham
minipigs is lacking, which impairs the proper analysis
of the data. It is thus unclear how intestinal glucose
transport is really modified after RYGB or VSG in vivo
and in humans.
A recent study measured GI retention and presumably
metabolism of ingested glucose in obese subjects before
and after RYGB [36 ]. Using a mixed meal containing
labelled [6,6-2H2]glucose, the authors demonstrated
that GI retention — and presumably metabolism — of
ingested glucose is increased (albeit insignificantly) after
RYGB surgery. Thus, intestinal retention and consumption of alimentary glucose may not provide a large contribution to the postprandial improvement in glycemic
control.
The idea of pharmacologically modulating glucose
absorption by the intestine is not new and acarbose,
voglibose and miglitol, are glucosidase inhibitors commonly used as antidiabetic drugs, efficient as primary
intention, but their side effects (abdominal pain and
diarrhoea) call for new drugs to be developed [37].
Intestinal permeability after bariatric surgery

All intestinal epithelial cells are connected by tight junctions, adherence junctions and desmosomes to form a
physical barrier preventing the passage of toxins, antigens
and microorganisms from the intestinal lumen into the
body. In addition, secretory goblet and Paneth cells
scattered within the enterocytes are devoted to innate
immune defence by producing and secreting mucins and
antimicrobial peptides respectively. Intestinal permeability is thus reflected by the relative properties of the
epithelium structure and the complex composition of
mucus. Obesity and consumption of western diet are
associated with increased intestinal permeability favouring the entry of bacterial products, such as LPS, from the
lumen to the circulation, a key event in the development
of a chronic inflammatory state and insulin resistance [38].
Surprisingly, despite growing interest in gut microbiota
and endotoxemia in obesity and after bariatric surgery
[39–42,43 ], only a few studies have evaluated the
changes in intestinal permeability after bariatric surgery
[44–47]. One of them, using lactulose-mannitol ratio tests,
show no significant differences when comparing global
intestinal permeability in obese patients before and
6 months after RYGB [44]. Another study measured
the expression of tight junction proteins and the transepithelial resistance (TER) in jejunal biopsies obtained
from patients before and after surgery [45]. The authors
reported an increase in claudin3 and claudin4 expression
Current Opinion in Pharmacology 2017, 37:29–34

32 Endocrine and metabolic diseases

after RYGB, associated with an increase in TER. These
results suggest a decreased paracellular permeability after
RYGB that could eventually contribute to decreased LPS
translocation. However, this study only addressed the
adaptation of the RYGB-remodelled jejunum where only
few bacteria are present and changes in epithelial permeability of the distal parts of the small intestine and
colon remain to be explored. Another study, using a
mouse model of sleeve gastrectomy, reported a decrease
in jejunal permeability after 4weeks and an increase in
colonic permeability associated with an increase in LPS
translocation in the plasma [47]. This observation contradicts a human study, which reported that LPS levels are
diminished after sleeve surgeries [46]. However, in the
murine study, animals were maintained on a high fat diet
after surgery and changes in nutrient composition, in
particular fat content, may play a role in the ameliorated
intestinal barrier function.
In addition, changes in gut microbiota after bariatric
surgery in human or murine models and their relation
to improved metabolic state have been largely illustrated
[39–42,43 ]. Faecal transplantation, which significantly
alters gut microbiota composition and associated phenotype, represents one of the most promising tools for GI
and metabolic disorders [48].
Alternatively, the bacteria specie Akkermansia muciniphila
by itself can improve obesity associated metabolic conditions [49]. Recently, a specific A. muciniphila product
(Amuc_1100) has been shown to mimic part of the effects
of the living organism and could thus be a therapeutic tool
in the management of the obesity [50 ].
Could bariatric surgery help to design new therapeutic
targets to improve intestinal permeability? GLP-2, an
enterohormone co-secreted with GLP-1, has been
reported to be increased in patients after bariatric surgery
[9,51] and was shown in mice to improve barrier function
and reduce metabolic endotoxemia [52]. The pharmacological GLP-2 analogue Teduglutide is already used in
patients suffering from short bowel syndrome in order to
increase intestinal growth and to improve intestinal function [53]. The use of teduglutide as a treatment to prevent
endotoxemia in obese patients merits further
investigations.

Conclusion
The three main functions of the GI tract — nutrient
absorption, endocrine secretion and barrier integrity —
are modified by bariatric surgery. Each of these modifications seem to contribute to the beneficial effects of the
procedures. Recent research and drug development programmes offer the potential of new opportunities to
mimic some of the effects of surgery, but no single drug
is able to equal the surgical intervention. Although the
most promising recent development is a monomeric
Current Opinion in Pharmacology 2017, 37:29–34

GLP1/GIP/glucagon triagonist [54 ,55]. Whether using
a combination/cocktail of drugs will be safe, appropriate
for long-term use and less constraining than the surgery
itself remains to be evaluated.

Funding
This work was supported by Inserm, University Paris
Diderot. LRP received funding from the Fondation pour
la Recherche Me´dicale, JBC received funding from Afero
and the Prix Claude Roze´, MLG received funding from
Socie´te´ Francophone du Diabe`te, SFNEP and Institut
Benjamin Delessert.

Conflict of interest statement
Nothing declared.

Acknowledgements
We thanks all Bado’s team members and especially A. Bado for advice and
constant support. We are grateful to Dr Lionel Arnaud for drawing Figure 1,
and to Nicholas Nguyen for English editing.

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