modif cell nitestinale ap chir baria 2017 pharma.pdf

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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

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
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