The Butyrate-Producing Microbiome in Murine Models of Insulin Resistance: Time for Translational Research
Authored by
Craig Beam
Introduction
Significant among the 21st century's
global health challenges is the growing prevalence of obesity and
insulin resistance, particularly type 2 diabetes mellitus (T2DM) [1-3].
Type 2 diabetes mellitus is characterized by obesity and insulin
resistance and is associated with cardiovascular disease, renal disease,
neuropathy, nonalcoholic fatty liver disease, blindness and malignancy,
making it a significant global cause of morbidity and mortality [2,3]
Research increasingly indicates that obesity, metabolic derangement and
T2DM could be interrelated through the gut Microbiome, as studies have
found that obese individuals possess a Microbiome that diverges
significantly from that found in lean individuals [1].
The gut Microbiome refers to the ecosystem of
>1014 bacteria that reside in the human gastrointestinal tract in a
symbiotic relationship with the human host [2,3]. It is well documented
that the gut Microbiome plays a role in host health by synthesizing
vitamins and altering bile acid solubility. The Microbiome also
contributes to daily caloric intake via the breakdown of insoluble
dietary components into the short chain fatty acids (SCFA) acetate,
propionate and butyrate. Without the gut Microbiome, these dietary
elements would be indigestible by the human enterocyte [2].
Additionally, the Microbiome influences disease states -deviations from
normal gut flora impact numerous inflammatory and metabolic conditions
such as inflammatory bowel disease, irritable bowel syndrome,
nonalcoholic fatty liver disease, T2DM and obesity [1-4].
Current hypotheses regarding mechanisms of
Microbiome impact on obesity and insulin resistance include enhanced
absorption of nutrients, enhanced SCFA production and lipogenesis,
decreased activity of fasting-induced adipose factor, increased
inflammation and intestinal permeability and altered bile acid
circulation [2]. The focus of much research in recent years has been the
SCFA butyrate and its relationship to obesity and T2DM. A preliminary
search of PubMed reveals that the number of papers published on
"butyrate and obesity" or "butyrate and diabetes" has almost doubled in
the last decade. Specific research that focuses on the role of SCFAs in
obesity and T2DM indicates that butyrate may promote insulin sensitivity
in peripheral tissues, contribute to glucose homeostasis and may even
prevent and treat diet-induced insulin resistance in obesity [1,5].
However, the majority of studies have been performed in rodents and
there is still a great deal of knowledge to be elucidated on the
subject of human gut Microbiome interactions with
obesity and T2DM, as well as the impact of specific SFCAs and microbial
products on insulin resistance and glucose tolerance [2].
The obese Microbiome exhibits decreased bacterial
species diversity and altered species -to-species ratios, both of which
are associated with increased insulin resistance. Specifically, in
T2DM, the populations of the phyla Firmicutes is increased, while
Bacteroides is decreased [3]. Studies indicate, albeit with varying
levels of certainty, that these derangements in bacterial ratios
correlate with decreased numbers of butyrate-producing bacteria and
increased numbers of Lactobacillus, a Firmicute. Butyrate then appears
significant in the relationship between insulin resistance and the
Microbiome. In fact, insulin-resistant individuals treated with
vancomycin were noted to have a decrease in the number of
butyrate-producing gut microbiota and an associated increase in insulin
resistance. Additionally, fecal transfer of lean individuals into obese
recipients results in increased insulin sensitivity and increased
numbers of butyrate- producing bacteria in the Microbiome of obese
recipients[4].
Studies in mice have attempted to characterize
the impact of butyrate on insulin resistance and obesity, however such
studies are lacking in humans. A study of mice that underwent Roux-en-Y
gastric bypass (RYGB) indicates that the microbiome of post-RYGB mice is
modified compared to that found in the native gut. Indeed, diabetic
mice that received a fecal transplant
from the gut of post-RYGB mice were noted to have
weight loss, improved glucose and lipid metabolism, and an increase in
butyrate-producing organisms in their gut microbiota [3]. This data, in
conjunction with a study by [5] continues to lend significance to
butyrate's role in modulating insulin sensitivity. In this study, obese
mice received dietary supplementation with butyrate and were noted to
have increased insulin sensitivity and decreased body fat content. In
addition, mice receiving a high fat diet supplemented with butyrate did
not develop insulin resistance and obesity. In comparison with mice not
receiving butyrate supplementation, these mice had decreased adiposity,
increased energy expenditure, and increased fatty acid oxidation [5]
This indicates that dietary supplementation with butyrate can prevent
insulin resistance in susceptible animals and halt further development
of obesity in already obese mice [5].
Although some promising research has been
conducted to untangle the mechanistic relationships between obesity,
insulin resistance, and the function of the gut Microbiome in mice,
there is a dearth of information on these subjects in humans. In order
to more fully investigate etiology and treatments for T2DM, obesity and
insulin resistance, research on the Microbiome and its role in these
conditions needs to shift its focus into human subjects. Future studies
could investigate the effect of dietary supplementation with butyrate in
humans, as well as attempt to characterize the mechanism of action of
SCFAs in inducing insulin-sensitivity, should that be a benefit of human
butyrate supplementation. Moreover, studies could investigate the
impact of diet upon the gut microbiome and attempt to characterize the
relationship between changes in diet and changes in microbial
populations. Mechanistic studies could characterize the most
representative places in the gastrointestinal tract from which
to sample the Microbiome, and still other studies could
investigate the role of individual species as opposed to the "cocktail"
of the entire Microbiome in inducing insulin sensitivity.
We look forward to developments in translational research in the relationship between the gut Microbiome and obesity and T2DM.
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