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Visando a microbiota intestinal como uma possível terapia para o diabetes

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Review Article
Targeting gut microbiota as a possible therapy
for diabetes
Canxia He, Yujuan Shan⁎, Wei Song
School of Food Science and Engineering, Harbin Institute of Technology, Harbin 150090, China
A R T I C L E I N F O
Abbreviations: Acc, acetyl-CoA carboxylas
glucagon-like peptide; GPR, G-protein coupl
chain fatty acid; SREBP-1c, sterol response e
⁎ Corresponding author. Tel.: +86 451 8628202
E-mail address: yujuan72@163.com (Y. Sh
http://dx.doi.org/10.1016/j.nutres.2015.03.002
0271-5317/© 2015 Elsevier Inc. All rights rese
A B S T R A C T
Article history:
Received 26 August 2014
Revised 26 February 2015
Accepted 9 March 2015
The incidence of diabetes has increased rapidly across the entire world in the last 2 decades.
Accumulating evidence suggests that gut microbiota contribute to the pathogenesis of
diabetes. Several studies have demonstrated that patients with diabetes are characterized
by a moderate degree of gut microbial dysbiosis. However, there are still substantial
controversies regarding altered composition of the gut microbiota and the underlying
mechanisms by which gut microbiota interact with the body’s metabolism. The purpose of
this review is to define the association between gut microbiota and diabetes. In doing so an
electronic search of studies published in English from January 2004 to the November 2014 in
the National Library of Medicine, including the original studies that addressed the effects of
gut microbiota on diabetes, energy metabolism, inflammation, the immune system, gut
permeability and insulin resistance, was performed. Herein, we discuss the possible
mechanisms by which the gut microbiota are involved in the development of diabetes,
including energy metabolism, inflammation, the innate immune system, and the bowel
function of the intestinal barrier. The compositional changes in the gut microbiota in type 2
and type 1 diabetes are also discussed. Moreover, we introduce the new findings of fecal
transplantation, and use of probiotics and prebiotics as new treatment strategies for
diabetes. Future research should be focused on defining the primary species of the gut
microbiota and their exact roles in diabetes, potentially increasing the possibility of fecal
transplants as a therapeutic strategy for diabetes.
© 2015 Elsevier Inc. All rights reserved.
Keywords:
Gut microbiota
Diabetes
Metabolism
Inflammation
Fecal transplant
1. Introduction
Diabetes mellitus (DM) is becoming a common problem across
the entire world. According to the latest information from the
International Diabetes Federation in 2013, there are 382 million
people now livingwith diabetes. And this number will rocket to
592 million by 2035 [1]. DM had caused 5.1 million deaths and
e; AMPK, adenosine 5′-mo
ed receptor; HbA1c, hemo
lement binding protein 1c
1; fax: +86 451 86282906.
an).
rved.
cost 548 billion USD in healthcare expenses at the end of 2013
[1]. In 2008, a national survey inChina revealed that 92.4million
adults had DM, and 148.2 million adults had pre-diabetes [2].
This high prevalence of DM in Chinamight cause more serious
diabetes-related burdens than in any other country. (See Table.)
It is known that both genetic and environmental factors
contribute to the pathogenesis of DM, particularly type 2
nophosphate (AMP)–activated protein kinase; GF, germ-free; GLP,
globin A1c; IL, interleukin; NOD, non-obese diabetic; SCFA, short
; TLR, Toll-like receptor.
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Table – Changes in the gut microbiota associated with diabetes
Disease Models Implicated microbiota Function changes with DM Reference
T2D 18 Male patients and
18 controls
Firmicutes↓ Clostridia↓ Associated with plasma glucose
positively and significantly.
12
T2D 345 Chinese patients
and controls
Clostridiales sp. SS3/4↓ Eubacterium rectale↓
Faecalibacterum prausnitzii↓ Roseburia intestinalis↓
Roseburia inulinivorans↓ Bacteroides caccae↑
Clostridium↑ Akkermansia muciniphila↑
Desulfovibrio sp. 3_1_syn3↑
Associated with membrane transport
of sugars, branched-chain amino acid
transport, methane metabolism,
xenobiotics degradation and metabolism,
sulphate reduction.
13
T2D 145 European women Lactobacillus↑ Clostridium↓ Associated with fasting glucose and
HbA1c,insulin, plasma triglycerides,
adiponectin and HDL.
14
T2D 50 Japanese Clostridium coccoides↓ Atopobium↓
Prevotella↓ Lactobacillus↑
15
T1D 4 Matched case–control
in Finland
Firmicutes↓ Bacteroidetes↑ 16
T1D 16 White children Clostridium↑ Bacteroides↑ Veillonella↑
Lactobacillus↓ Bifidobacterium↓
Blautia coccoides/Eubacterium rectale↓
Prevotella↓
Associated with the plasma glucose level
and HbA1c level.
17
362 N U T R I T I O N R E S E A R C H 3 5 ( 2 0 1 5 ) 3 6 1 – 3 6 7
diabetes (T2D) [3–5]. Recently, studies revealed that the gut
microbiota function as an important environmental factor in the
development of DM [6,7]. The human gut hosts trillions of
microorganisms, includingmore than 1014 bacteria belonging to
1000 species [8]. The genome size of this microbial organ,
collectively termed the microbiome, exceeds the size of the
human nuclear genome by 100-fold and provides humans with
additional biological and metabolic functions for maintaining
homeostasis in the body [9]. Numerous studies have shown that
the composition of the gut microbiota is altered in diabetic
groups. However, there are no consistent results regarding
which species are altered in diabetic patients. Moreover, the
detailed mechanisms linking the gut microbiota to diabetes
have not been well described. Therefore, we conducted an
electronic search of English articles from 2004 to 2014 inMedline
to clarify the possible relationship between gut microbiota and
diabetes. The MeSH search terms used were gut microbiota,
diabetes, metabolic diseases, energy metabolism, immune
system, inflammation, gut permeability, and fecal transplant.
In this review, we present data on the changes of the gut
microbiota both in type 1 diabetes (T1D) and in T2D, and
summarized the possible mechanisms through which the gut
microbiota interact with diabetes. Finally, we discussed the
very recent research regarding the effects of dietarymodulation
and fecal transplantation of intestinal microbiota as treatment
strategies for diabetes. All of these compelling lines of evidence
strongly suggest that gut microbiota might play a significant
role in the development and treatment for diabetes.
2. Gut microorganisms and DM
The gut microbiota in our body is part of a dynamic ecosystem,
and its composition is altered at the phylum and class levels by
environmental and host factors which jointly influence the gut
and far removed organs. Thus, the gut microbiota is linked to
several human diseases, such as obesity and diabetes [10,11].
Recently, numerous studies indicated a relationship between
the gut microbiota and T2D. In 2010, Larsen et al reported that
the ratios of Firmicutes to Clostridia species were attenuated in
T2D patients [12]. The ratio of Bacteroidetes to Firmicutes and the
ratio of the Bacteroides-Prevotella group to theC coccoides-E. rectale
group were positively and significantly correlated with plasma
glucose concentrations [12]. Qin et al found that Chinese T2D
patients exhibited a decline in butyrate-producing bacteria
(eg, Clostridiales sp. SS3/4, Eubacterium rectale, Faecalibacterium
prausnitzii, etc.) and an increase in several opportunistic patho-
gens (eg, Bacteroides caccae, Clostridium hathewayi, C ramosum,
C symbiosum and others) [13]. Moreover, the mucin-degrading
species Akkermansia muciniphila and sulfate-reducing species
Desulfovibrio sp. 3_1_syn3 weremore abundant in T2D samples
[13]. Although it is important to characterize the link between
gut microbiota and T2D, there are still some shortcomings that
should be noted. For example, the entire gut bacteria population
was not classified by age, gender, or drug treatment of subjects
tominimize the sources of variation. Researchwas completed in
Europe that examined the composition and function of gut
microbiota in a well-characterized population of 70-year-old
women [14]. In this T2D group, the abundances of 4 Lactobacillus
species were increased, whereas the abundances of 5 Clostridium
species were decreased compared to individuals without
diabetes. Lactobacillus species were positively correlated with
fasting glucose and glycosylated hemoglobin A1c (HbA1c).
However, Clostridium species were negatively correlated to
fasting glucose, HbA1c, insulin and plasma triglycerides [14]. In
an cohort of Japanese T2D patients, the numbers of Clostridium
coccoides, Atopobium, and Prevotella were decreased, while the
quantities of total Lactobacilluswere increased compared to those
that were not diabetic [15]. This high Lactobacillus level might
reflect the original numbers of bacteria in T2D patients because
no significant differences were found between the participants
who consumed yogurt and those who did not. Currently, the
reason for the high counts of Lactobacillus in T2D patients
remains unclear. Although these independent studies revealed
an association between T2D and the gut microbiota, some other
discrepancies should not be ignored. For example, neither
363N U T R I T I O N R E S E A R C H 3 5 ( 2 0 1 5 ) 3 6 1 – 3 6 7
Akkermansia in European women nor Lactobacillus in Chinese
people contribute to the compositions of gut microbiota in
T2D patients.
Altered compositions of gut microbiota have also been
observed in T1D patients. In a 4-matched case–control study in
Finland, the gut microbiota differed between the children who
werehealthyand thosewithautoimmunedisorders. The striking
differences included a reduced Firmicutes level and an increased
Bacteroidetes level in the children with autoimmune disorders.
Moreover, the high ratio of Firmicutes to Bacteroidetesmight be an
early diagnostic marker of pending autoimmunity problems
such as T1D [16]. However, in another case–control study that
included 16 Caucasian T1D children, the numbers of Clostridium,
Bacteroides and Veillonella were all significantly increased, while
the numbers of Lactobacillus, Bifidobacterium, Blautia coccoides/
Eubacterium rectale and Prevotella were all obviously decreased
compared to normal subjects [17]. Interestingly, this study
demonstrated that the decreased number of Bifidobacterium
and Lactobacillus, as well as the decreased ratio of Firmicutes to
Bacteroidetes were negatively and significantly associated with
the plasma glucose level, whereas the increased numbers of
Clostridium were positively and significantly linked to a higher
level of HbA1c in the T1D group, which is completely contradic-
tory to the findings in T2D patients [14,17].
These results suggest that there is some degree of gut
microbial dysbiosis in diabetes, although there are differences
in thealtered species. Thesedifferencesmight be attributable to
the different geographical locations, ages or gender makeup of
the populations or different food habits and analysis methods
used. Moreover, there are still some questions that remain
unresolved regarding the association between gut microbiota
and diabetes. For example, whether the alterations in the
gut microbiota in diabetes are the causes or the consequences
of the diabetic pathology. Hence, the interactions between
diabetes and gut microbiota are more intricate than what we
previously believed. Further studies are required to investigate
the roles of gut microbiota in diabetes.
3. Mechanisms by which Gut microbiota are
associated with DM
3.1. The role of gut microbiota in energy metabolism
Gut microbiota hydrolyze and ferment the dietary polysaccha-
rides to generate monosaccharides and short chain fatty acids
(SCFAs) that can be absorbed and utilized for energy by the host.
SCFAs, such as acetate, propionate, and butyrate, contribute
approximately 5% to 10% to human energy resources [18]. The
signaling actions of SCFAs are mediated by endogenous ligands
of G protein-coupled receptor 41 (GPR41) and GPR43, which
are particularly expressed in adipocytes and identified as
receptors of fatty acids [19,20]. Acetate preferentially activates
GPR43 in vitro, butyrate displays a potent effect on GPR41, and
propionate is selective for both GPR41 and GPR43 [21]. Impor-
tantly, the energy-regulating effects of GPR41 and GPR43 are
both microbiota-dependent. There are significant differences
in body weight between Gpr41/43-deficient mice and their
counterparts among conventionally raised or gut microbial-
colonizedmice. However, no evident differenceswere observed
between germ-free (GF) conditions and following treatment
with antibiotics [22,23].
Diabetes, particularly T2D, is associated with a cluster of
interrelated lipid metabolism abnormalities [24]. Compared
with GF mice, the levels of triglyceride in conventionalized
mice were increased in adipose tissues and liver, while
decreased in serum, suggesting the role of gut microbiota in
lipid metabolism [25,26]. The process in which fatty acids are
released from triglyceride-rich lipoproteins to the muscle and
heart is mediated by fasting-induced adipose factor [26,27].
The gut microbiota also dramatically increases the synthesis
of hepatic triglycerides. Carbohydrate response element
binding protein (ChREBP) and sterol response element binding
protein 1c (SREBP-1c) are both involved in lipogenesis due to
their independent effects on increasing glucose absorption
and insulin levels [19,28]. Unlike GF mice, the ChREBP and
SREBP-1c mRNAs are increased in mice that have been orally
gavaged with Bacteroides thetaiotaomicron strain VPI-5482 [29].
Also acetyl-CoA carboxylase and fatty acid synthase, 2 critical
transcriptional targets of ChREBP and SREBP-1c are signifi-
cantly elevated in the liver of conventionalized mice [29]. The
increased transactivations of ChREBP, SREBP-1c, acetyl-CoA
carboxylase, and fatty acid synthase are accompanied by a
statistically significant increase in liver triglyceride contents
[29]. Additionally, the adenosine 5′-monophosphate–activated
protein kinase (AMPK) is another key factor in the regulation of
lipid metabolism and insulin sensitivity [30]. In C57BL/6 J mice
with deficiencies of the gut microbiota, high fat diet-induced
obesity was prevented by enhancing the AMPK-mediated fatty
acid oxidation in the peripheral tissues [27]. Moreover, acetyl-
CoA carboxylase and carnitine palmitoyl transferase-1, the
downstream targets of phosphor-AMPK in fatty acid oxidation,
are both statistically increased [27].
3.2. Metabolic endotoxemia involved in the low-grade
inflammation of DM
Current views suggest that low-grade chronic systemic inflam-
mation contributes to the development of insulin resistance,
diabetes, and obesity [31,32]. The increased circulating concen-
tration of plasma lipopolysaccharide (LPS), which is defined as
metabolic endotoxemia, is a trigger factor for the maintenance
of a low-tone continuous inflammatory state in the host
responding to high-fat diets [33,34]. The decreased cecal
contents of Bifidobacterium spp upon high-fat diets are signifi-
cantly and negatively correlated with high portal plasma levels
of LPS [35]. The results from a population-based cohort
demonstrated that LPS is significantly associated with in-
creased risks for the incidence and prevalence of diabetes [36].
Moreover, a broad-spectrumantibiotic treatment (ampicillin and
neomycin) dramatically reduces themetabolic endotoxemia and
cecal contents of LPS in ob/ob mice, as well as the glucose
intolerance, inflammation and body weight [33]. Additionally,
antibiotic treatment significantly reduces the numbers of
Lactobacillus spp, Bifidobacteriumspp, and Bacteroides-Prevotella spp
in ob/ob mice [34].
Accumulating in vitro and in vivo evidence suggests that these
inflammatory responses initiated by LPS in the host are
mediated throughToll-like receptor (TLR)-2/-4–related pathways
[37–39]. The Toll-like receptor-4/cluster of differentiation-14
364 N U T R I T I O N R E S E A R C H 3 5 ( 2 0 1 5 ) 3 6 1 – 3 6 7
(CD14)/myeloid differentiation-2 pathway is induced by LPS in
response to high-fat diets and mediates the activation of
transcription factor nuclear factor κB, which ultimately results
in the secretion of pro-inflammatory cytokines such as tumor
necrosis factor-α, interleukin-1 (IL-1) and IL-6 [33,40]. Moreover,
TLR4 gene silencing with siRNA or pharmacologic blockade
suppresses the inflammation and insulin resistance triggered
by LPS [37,41]. TLR-2 recognizes the components of bacterial
cell walls and lipid-containing molecules and then transduces
inflammatory signaling by activating nuclear factor κB and
producing pro-inflammatory cytokines in cells [42]. Mice lacking
TLR-2 exhibit an increased insulin sensitivity and a faster
clearance of glucose that are accompanied by attenuated
expression of inflammatory cytokines [42–44].
3.3. Gut microbiota and gut permeability: a novel insight
into diabetes
Recent studies suggested that an altered bowel function of the
intestinal barrier contributes to the pathogenesis of metabolic
diseases such as diabetes [45,46]. The disruption of the
intestinal barrier in genetically obese mice enhances intestinal
mucosa permeability, leads to a profound and consistent
leakage of LPS into the portal blood circulation, which in turn
increases metabolic endotoxemia and inflammatory cytokine
levels [47]. After feeding mice with high-fat diets, the expres-
sions of the tight junction proteins zonula occludens-1 and
occludin are significantly reduced, resulting in a obvious
increase in intestinal permeability andmetabolic endotoxemia,
inflammation and metabolic disorders [34]. A further study
showed that the greater production of endogenous glucagon-
like peptide-2 (GLP-2) is associated with improved tight
junctions. GLP-2 is an intestinal meal-stimulated peptide
hormone that mediates the cleavage of proglucagon in the
intestinal endocrine L cells [48]. Prebiotic or GLP-2 pharmaco-
logical treatment induces GLP-2 production and improves tight
junctions, which ultimately decreases LPS levels in the plasma
and blunts the inflammatory state of ob/ob mice [49].
3.4. The immune system and diabetes
Recent studies have suggested that there is an interaction
between the intestinal microbiota and the immune system in
diabetes. T1D, a well-known autoimmune disease that is
characterized by lymphocytic infiltration or inflammation in
pancreatic islets, that is usually associated with infiltration of
innate immune cells. The cytokinesproducedby innate immune
cells in the gut could destroy β-cells through promoting β-cells
apoptosis and islet-specific T cells infiltration, suggesting the
linkage between intestinal microbiota and immune system in
T1D [50,51]. After treatment with a cocktail of antibiotics
(metronidazole, neomycin and polymyxin), non-obese diabetic
(NOD) pregnant mice exhibit significant alterations in the
peripheral composition of the T cell compartment and
alterations in their offspring including a higher frequency of
cluster of differentiation (CD3+CD8+) T cells in the mesenteric
lymph nodes. Additionally, lymphocytic infiltration into the
pancreatic islets is slightly lower in the offspring of NOD mice,
and there are changes in the clusters of gut microbiota [52].
Another result revealed that treatment with vancomycin
protects NOD mice from T1D in the early postnatal period and
increases the cluster of differentiation CD 4+ T cells. Moreover,
most of the gram-positive and -negative microbes are depleted
with the exception of Akkermansia muciniphila [53]. The in-
creased population of Akkermansia muciniphila induces Foxp3
regulatory T cells in visceral adipose tissues and significantly
enhances glucose tolerance, and these effects suggest that the
modulation of the immune system by Akkermansia muciniphila
might be a potential treatment for diabetes [54].
T2D has been traditionally known as a solely metabolic
disease, however, recent studies have suggested the associa-
tionbetween immune systemand thepathogenesis of T2D. The
obesity-related chronic inflammation and β-cells stress induced
by gluco-and lipotoxicity could activate both innate and
adaptive immunity in T2D [55]. The local or generalized
immune responses stimulate TLRs and nucleotide-binding
oligomerization domain (NOD) receptors, and promote the
production of cytokines such as IL-1β which destroy β-cells
[55–57]. But more detailed effects of gut microbiota and the
immune system on diabetes warrant further studies.
The innate immune system could be activated by TLR,
which induces dendritic cell maturation and inflammatory
cytokine secretion, also generates favorable conditions for the
activation of naïve T-cells [58]. TLR-5, a component of innate
immune system that was expressed in intestinal mucosa,
plays an important role in the development of metabolic
syndromes [58]. TLR-5–deficient mice exhibit hyperphagia
and develop metabolic diseases such as hyperlipidemia,
hypertension, insulin resistance and obesity. After transplan-
tation of the gut microbiota from TLR5-deficient mice to their
wide-type GF counterparts, the increased levels of pro-
inflammatory cytokines and features of metabolic diseases,
such as insulin resistance and obesity, have been observed
in the recipients [59]. The elevated inflammatory mediators
in diabetes induce oxidative and endoplasmic reticulum
stress in pancreatic islet β-cells, which then influences
insulin sensitivity and glucose homeostasis [60]. These data
suggest that the interaction between the innate immune
system and the intestinal microbiota collectively contributes
to the development of metabolic syndrome. However, the
underlying mechanisms remain poorly understood and no
consistent results have been concluded. For example, 2 recent
studies revealed that deficiency of TLR5 in mice has no
relationship with changes in the composition of the gut
microbiota and metabolic syndromes such as obesity and
intestinal inflammation [61,62].
4. Novel therapeutic strategies targeting gut
microbiota for diabetes
Experimental and clinical studies have shown that targeting
gut microbiota might be an effective strategy to prevent and
manage diabetes [63,64]. Diet is one of the main factors that
influences the composition of gut microbiota. Prebiotic,
defined as a nonviable food component that confers a health
benefit to modulate the composition of gut microbiota in the
host, are mainly inulin, fructo-oligosaccharides and galacto-
oligosaccharides and lactulose [65]. The therapeutic effects of
prebiotics on metabolic diseases have been confirmed by a
365N U T R I T I O N R E S E A R C H 3 5 ( 2 0 1 5 ) 3 6 1 – 3 6 7
clinical trial. Six obese volunteers with T2D and/or hyperten-
sion were fed on a strict vegetarian diet for one month, the
metabolic parameters such as body weight, the levels of
triglycerides and HbA1c were significantly reduced, and the
levels of fasting glucose and postprandial glucose were also
improved. Such a strict vegetarian diet led to compositional
changes of the gut microbiota, for example, a reduced ratio of
Firmicutes to Bacteroidetes and an increase in the species of
Bacteroides fragilis and Clostridium, which decreased intestinal
inflammation and SCFA levels [66]. Another area of therapeutic
interest is probiotics, which are the live microorganisms either
in the form of food or supplement. After consuming probiotic
yogurt (Lactobacillus acidophilus La5 and Bifidobacterium lactis
Bb12) for 6 weeks at the dose of 300 g/d, fasting blood glucose
and HbA1c were significantly decreased in T2D patients. The
antioxidant levels such as the serum malondialdehyde were
also significantly decreased.In mice, the antidiabetic effect
of probiotics was demonstrated by feeding with probiotics
containing Lactobacillus acidophilus and Lactobacillus casei [67].
Recently, fecal transplant as a therapeutic strategy has
attracted more attention. Vrieze et al investigated the effects of
transferring the intestinalmicrobiota from lean subjects tomale
recipients with metabolic syndrome [68]. Six weeks after the
infusion of the gut microbiota, the insulin sensitivity of the
recipients and the levels of butyrate-producing intestinal
microbiota were both significantly increased [68]. The effects of
the transfer of gut microbiota on diabetes in mice were
subsequently further discussed. After the transfer of bacteria
Figure – Possible pathways linking gut microbiota and diabetes. T
microbiota influence the development of diabetes are summarized
immune system have been considered to be the keymechanisms
diabetes. The gut microbiota regulates energy metabolism through
SREBP-1c, AMPK, and fasting-induced adipose factor pathways. Ad
enhances intestinal mucosa permeability, which are followed by a
development of insulin resistance and diabetes. The innate immu
and TLR-5 in the intestinal mucosa, which have also been linked t
from MyD88-deficient NOD mice, insulitis and the onset of
diabetes were significantly improved. Moreover, after the oral
transfer of fecal bacteria over 3weeks, the compositionof the gut
microbiota were stably altered, mainly in terms of increases in
LachnospiraceaeandClostridiaceae anddecreases in Lactobacillaceae
[69]. These results indicate that the oral administration of gut
microbiota represents a possible therapeutic intervention for
improving insulin sensitivity in diabetes. However, the safety of
fecal microbiota transplantation should be noted because
potential adverse effects have also been reported. For example,
2 patients died in a study involving 18 patients who underwent
bacterial transplantations to treat recurrent Clostridium. difficile
colitis [70]. More clinical data and critical discussions of fecal
microbiota transplantation protocols are required to prove
whether this approach is beneficial for diabetic patients overall.
Moreover,muchmore attention should be paid to the safety and
composition of donor microbiota.
5. Summary and future research
The human gut hosts trillions of microorganisms, which are
collectively termed the “microbiome” and provide us with
genetic and metabolic attributes pertinent to the maintenance
of our homeostasis. Recent studies have revealed an important
role of gutmicrobiota in the development of diabetes. However,
the available data in this field remain limited, and the relevant
scientific work has only just begun.Moreover, it is worth noting
he variety of independent mechanisms through which the gut
. Energy metabolism, inflammation, gut permeability and the
through which the gut microbiota regulate the development of
various pathways including the SCFA-GPR41/43, ChREBP/
ditionally, high-fat food promotes the plasma levels of LPS and
n inflammatory response in the host that contributes to the
ne system has been linked to diabetes through T lymphocytes
o inflammation, insulin sensitivity and glucose homeostasis.
366 N U T R I T I O N R E S E A R C H 3 5 ( 2 0 1 5 ) 3 6 1 – 3 6 7
that the available data are heterogeneous in nature and include
examinations of different populations or rodent models and
various types of food. In addition, similar to all systematic
reviews, the findings in this review depend on other factors,
such as the nature of the search strategy. Therefore, the limited
availability and complexity of the relevant research in this area
are limitationsof this review. In summary,we conclude that the
gutmicrobiota influence thedevelopment of diabetes through a
variety of independent mechanisms (Figure). Although com-
pelling evidence support the concept that gut microbiota are
potentially a new therapy target for diabetes, more research is
needed to elucidate the associations between the microbiota
and diabetes.
Future research should address the following issues: (1) a
thorough characterization of the main subspecies of gut micro-
biota that contribute to the incidence or development of diabetes,
and the exact role of the individual’s gut microorganisms in the
pathogenesis of diabetes. (2) Detailed interactions between the
host and the gut bacteria is needed. (3) Additionalwell-controlled
clinical studies with the gut microbiota should be done to
confirm safety in the patient.
Acknowledgment
This work was supported by the Fundamental Research Funds
for the Central Universities (Grant No. HIT. IBRSEM.201335).
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	Targeting gut microbiota as a possible therapy for�diabetes
	1. Introduction
	2. Gut microorganisms and DM
	3. Mechanisms by which Gut microbiota are associated with DM
	3.1. The role of gut microbiota in energy metabolism
	3.2. Metabolic endotoxemia involved in the low-grade �inflammation of DM
	3.3. Gut microbiota and gut permeability: a novel insight into diabetes
	3.4. The immune system and diabetes
	4. Novel therapeutic strategies targeting gut microbiota for diabetes
	5. Summary and future research
	Acknowledgment
	References

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