Clinical Trial Details
— Status: Withdrawn
Administrative data
| NCT number |
NCT04263168 |
| Other study ID # |
6397-19-SMC |
| Secondary ID |
|
| Status |
Withdrawn |
| Phase |
N/A
|
| First received |
|
| Last updated |
|
| Start date |
March 1, 2020 |
| Est. completion date |
August 1, 2022 |
Study information
| Verified date |
October 2021 |
| Source |
Sheba Medical Center |
| Contact |
n/a |
| Is FDA regulated |
No |
| Health authority |
|
| Study type |
Interventional
|
Clinical Trial Summary
The diverse community of gut microbes commonly referred to as the 'gut microbiome', is
increasingly suggested to play significant roles in health and disease, and to affect even
distant non-GI organs by metabolite signaling. Type 2 diabetes mellitus (T2DM) patients
feature a distinct gut microbiome signature4, while modulating the gut microbiome by either
antibiotics or fecal microbial transplantation (FMT) is suggested to impact insulin
sensitivity. Originally designed to treat obesity, bariatric surgeries often induce a robust
and rapid weight-independent improvement in glucose homeostasis within days. Early diabetes
remission following bariatric surgery is hypothesized to be mediated by rapid alterations in
the gut microbiome and bile acids composition, however, the exact mechanism is yet to be
uncovered. Elucidating this mechanism is important as it may form the basis of a new
therapeutic modality in diabetes. The investigators intend to deeply characterize early
post-bariatric changes in the gut microbiome of diabetic patients, as well as their gut
mucosal transcriptome and metabolome, by using state-of-the-art experimental and
computational pipelines. Additionally, The investigators will utilize a unique mouse model of
bariatric surgery under germ-free conditions, developed at the Elinav lab, that allows us to
dissect the role of microbes in post-operative metabolic improvements.
Description:
Type 2 diabetes mellitus (T2DM) is one of the most prevalent and deadly conditions in the
21st century. T2DM is characterized by obesity and insulin resistance that leads to chronic
hyperglycemia, which even with best medical care is often uncontrolled, resulting in
life-threatening micro- and macrovascular complications.
The gut microbiota (i.e. the microbial population inhabiting the gut) has been extensively
linked to blood glucose levels and was shown to mediate insulin response in various settings,
including anti-diabetic pharmacotherapy. Moreover, fecal microbial transplantation (FMT) from
lean healthy donors improved insulin resistance in humans suffering from metabolic syndrome.
These pre-clinical and clinical evidence suggest that the gut microbiota has a mechanistic
role in insulin-resistance.
Bariatric surgeries were originally designed to treat obesity but were also retrospectively
found to ameliorate T2DM among other metabolic and non-metabolic disorders. Since obesity is
a significant risk factor for T2DM, it is not surprising that surgically-induced weight loss
which occurs within several months after surgery also improves insulin sensitivity. However,
a substantial share of patients experience an improvement in insulin resistance within days
after bariatric surgery, which clinically presents as normal glycemic values despite
decreased dosage of anti-diabetic medications in the first post-operative days. This
phenomenon of early diabetes remission after surgery precedes any weight-loss, therefore it
is weight-independent and it is far from being understood.
Several explanations were suggested to explain early post-bariatric surgery diabetes
remission, among which are acute caloric restriction, amplified incretins response, and rapid
alterations in bile acids composition; however, none of them accounts for such a drastic
improvement in glycemic control within such a short time frame.
Bariatric surgery rapidly alters the gut microbiome in a conserved fashion in both humans and
rodents. Although descriptive studies demonstrated a change in microbiome composition within
a few months after surgery, most studies didn't analyze microbiome in the first
post-operative weeks in which the improvement in diabetes takes place, and data so far
remains associative at best. Two independent studies exhibited improved metabolism following
FMT from post-bariatric surgery humans and mice donors
into germ-free (microbiota-devoid) mice recipients, however, no mechanism was suggested and
both studies used stool samples taken at a very late postoperative period, therefore no
conclusions could be made regarding early diabetic remission. Caloric restriction, incretins,
bile-acids, and the gut microbiome most probably "co-evolve" following surgery to exert
surgery's beneficial metabolic effect with no single factor solely responsible for the entire
effect.
Despite being highly effective in ameliorating obesity and obesity-related co-morbidities in
the short-term, bariatric surgeries are invasive, risky, and not always successful in the
long-term. Bariatric surgeries are thus far from being a perfect solution to obese diabetic
patients, but they do serve as an intriguing investigational-model in the context of glucose
metabolism. Hopefully, probing the mechanisms behind surgery's metabolic effect will
facilitate the development of safer treatments for diabetic patients.
