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Best Practice & Research Clinical Endocrinology & Metabolism 35 (2021) 101507
Contents lists available at ScienceDirect
Best Practice & Research Clinical
Endocrinology & Metabolism
journal homepage: www.elsevier .com/locate/beem
6
Gut microbiome, prebiotics, intestinal
permeability and diabetes complications
Matthew Snelson, PhD, Research Fellow a, *,
Cassandra de Pasquale, Medical Student a,
Elif I. Ekinci, MBBS , PhD, Academic Endocrinologist, Associate
Professor b, c, Melinda T. Coughlan, PhD, Associate Professor a, d
a Department of Diabetes, Central Clinical School, Alfred Medical Research and Education Precinct, Monash
University, Melbourne, Victoria, Australia
b Department of Endocrinology, Austin Health, Australia
c Department of Medicine Austin Health, Melbourne Medical School, The University of Melbourne, Australia
d Baker Heart and Diabetes Institute, Melbourne, Australia
a r t i c l e i n f o
Article history:
Available online 17 February 2021
Keywords:
diabetes
diabetic kidney disease
prebiotics
short chain fatty acids
intestinal permeability
* Corresponding author. Department of Diabetes,
E-mail address: matthew.snelson@monash.edu
https://doi.org/10.1016/j.beem.2021.101507
1521-690X/© 2021 Elsevier Ltd. All rights reserved
Diabetes is a metabolic condition. The composition of the gut
microbiota is altered in diabetes with reduced levels of short chain
fatty acids (SCFA) producers, notably butyrate. Butyrate is associ-
ated with a number of beneficial effects including promoting the
integrity of the gastrointestinal barrier. Diabetes may lead to an
increase in the permeability of the gut barrier, which is thought to
contribute to systemic inflammation and worsen the microvas-
cular complications of diabetes. Prebiotics, non-digestible carbo-
hydrates, are fermented by the colonic microbiota leading to the
production of a range of metabolites including SCFAs. Thus, pre-
biotics represent a dietary approach to increase levels of micro-
bially produced SCFAs and improve intestinal permeability in
diabetes. Whether prebiotics can lead to a reduction in the risk of
developing diabetes complications in individuals with type 2
diabetes needs to be explored.
© 2021 Elsevier Ltd. All rights reserved.
Level 5, Alfred Centre, 99 Commercial Road, Melbourne 3004, VIC, Australia.
(M. Snelson).
.
mailto:matthew.snelson@monash.edu
http://crossmark.crossref.org/dialog/?doi=10.1016/j.beem.2021.101507&domain=pdf
www.sciencedirect.com/science/journal/1521690X
http://www.elsevier.com/locate/beem
https://doi.org/10.1016/j.beem.2021.101507
https://doi.org/10.1016/j.beem.2021.101507
Abbreviations
GLP-1 glucagon-like peptide-1
GLP-2 glucagon-like peptide-2
HDL high-density lipoprotein
ITF inulin-type fructans
LAL limulus amebocyte lysate
LBP lipopolysaccharide binding protein
LPS lipopolysaccharide
RDS rapidly digestive starch
RS resistant starch
SCFA short chain fatty acids
SDS slowly digestive starch
T1DM type 1 diabetes mellitus
T2DM type 2 diabetes mellitus
TLR4 toll-like receptor-4
Tregs regulatory T cells
ZO-1 zonula occludens-1
M. Snelson, C. de Pasquale, E.I. Ekinci et al. Best Practice & Research Clinical Endocrinology & Metabolism 35 (2021) 101507
Introduction
The human gut contains an important microbial ecosystem, where there is a symbiotic relationship
between the microbes and host. Each human has an individual ecosystem. Research has shown that
humans share a ‘core’ microbiota, which is roughly one-third of species in the gut. Whilst the
remaining two-thirds of species can vary between individuals [1]. This individuality is influenced by a
range of factors. Intrinsic factors include intestinal motility, pH, antibacterial proteins and mucus while
extrinsic factors include medications and diet [2e4]. Initial estimates indicated that bacterial cells
outnumbered human cells 10:1, however more recent estimates indicate that these numbers are closer
to parity [5]. Despite this, the microbial genomic content far outweighs the human genomic content,
contributing ~150 fold more genetic material [1]. The bacteria that inhabit the intestinal tract have
been shown to play amajor role in human health. In particular, the gutmicrobiota appears to play a role
in several chronic diseases such as diabetes, inflammatory bowel disease and diabetic kidney disease
[6]. Critically, the gut microbiota is easily modifiable by dietary intervention, signifying that diet may
represent a potential therapeutic opportunity.
An abnormal gut microbiota profile is associated with metabolic abnormalities such as obesity [7]
and insulin resistance [8] and impaired intestinal permeability [9]. Increased intestinal permeability is
a causal factor of systemic inflammation. This chronic low-grade inflammatory state is a characteristic
of diabetes and its complications, such as diabetic kidney disease [10]. Prebiotics, such as resistant
starches, escape digestion in the small intestine and are available in the large intestine for fermentation
to produce a number of metabolites including short chain fatty acids (SCFAs) [11]. These SCFAs are
known to improve glucose metabolism and maintain the integrity of the intestinal barrier [12]. Thus,
prebiotics may alter the gut microbiota, improve intestinal permeability and limit the downstream
diabetic complications.
Altered gut microbiota in diabetes
Diversity
One of the most commonly assessed measures of the microbiota is diversity, although it should be
noted that there are many different statistical methods for assessing microbial diversity. One central
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M. Snelson, C. de Pasquale, E.I. Ekinci et al. Best Practice & Research Clinical Endocrinology & Metabolism 35 (2021) 101507
postulate of recent microbiota theory is that a lack of microbial diversity is associated with adverse
chronic health outcomes [13]. Reductions in microbial diversity have been observed to occur in more
developed countries, and associated with increased antibiotics use, a higher proportion of caesarean
births, reduced breastfeeding, and aWestern style processed food diet [13,14]. A study investigating the
microbiome of a previously uncontacted Yanomami Amerindian tribe, found much greater microbial
diversity compared with a population in the USA [15], providing further evidence that the modern
lifestyle is associated with decreases in microbial diversity.
In relation to diabetes, numerous human and animal studies have provided evidence that there is an
alteration of the gut microbiota during diabetes. Several human studies have linked lower gut mi-
crobial diversity with diabetes [16,17] and insulin resistance [8,18]. Similarly, animal studies have
illustrated that a model of diabetes associated with obesity is associated with a reduction in microbial
diversity, as observed in both ob/ob [19] and db/db [20] mice. However, not all studies have identified
an association between diabetes and lowered microbial diversity. In one large study in 345 Chinese
participants, no differences were found in terms of fecal microbial diversity between control and T2DM
participants [21]. Similarly a study comparing patients without diabetes, with pre-diabetes and T2DM
found no change between groups in regards to Shannon diversity metrics, however did note increases
in specific taxa, notably Collinsella and Enterobacteriaceae, in the T2DM group compared with the
other groups [22]. Whilst there are several studies demonstrating that diabetes is associated with
reduced microbial diversity, other studies do not support such an association and it is likely the
relationship between the microbiome and diabetes is more complicated.
Firmicutes/Bacteroidetes ratio
The bacterial component of the gut microbiota in humans and mice are dominated by the Firmi-
cutes and Bacteroidetes phyla, which typically contributes ~90% of the bacterial consortium. The third
most prevalent phylum is Actinobacteria, which is predominantly the genus bifidobacterium. With
much smaller numbers of the remaining bacterial phyla, such as Proteobacteria.It has been reported
that African children have greater proportion of Bacteroidetes and a reduction in Firmicutes compared
with European children, leading to the hypothesis that the Western lifestyle is associated with an
increase in Firmicutes, at the expense of Bacteroidetes [23]. This has led to several other findings that
have supported the notion that the ratio between these two phyla, the Firmicutes and the Bacter-
oidetes, plays an important role in health outcomes.
It has been reported that the gutmicrobiota in peoplewith diabetes and/or obesity is changed at the
phyla level, with several studies observing a relative expansion in the proportions of Firmicutes phyla
and a reduction in the Bacteroidetes phyla, commonly assessed as the Firmicutes/Bacteroidetes ratio
[21]. One of the first papers to report this finding observed an increase in Firmicutes to Bacteroidetes
ratio, though it should be noted this study compared only 12 obese participants with five lean par-
ticipants [19]. Multiple other human studies soon provided supporting evidence for the Firmicutes/
Bacteroidetes ratio being altered in conditions of diabetes or obesity [24]. However not all studies have
observed this association, with Larsen et al. [16] observing in a cohort of 36 males, half of whom had
T2DM, that diabetes was associated with a decrease in the proportion of Firmicutes and a decrease in
the Firmicutes/Bacteroidetes ratio. Another study in obese patients observed a decrease in the Fir-
micutes/Bacteroidetes ratio in overweight people compared with lean controls [25].
There is compelling evidence that the microbiome is altered in the context of diabetes and
furthermore there is evidence from preclinical fecal microbiota transfer studies that the gut microbiota
may influence the development of diabetes and its complications. Vrieze et al. [8] transplanted the
fecal microbiota from lean to obese humans and showed an improvement in insulin sensitivity after 6
weeks. The causal role of the microbiota in obesity was further demonstrated by Ridaura et al. [26]
where microbe-free mice were transplanted with microbiota from either lean or obese human co-
twins. Results showed that those transplanted with lean microbiota were less inclined to increase
body fat or weight through an increase in capacity to breakdown and ferment polysaccharides. This
provides compelling evidence as to why altering the microbiome in diabetes, via interventions such as
diet, represent promising therapeutic avenue.
3
M. Snelson, C. de Pasquale, E.I. Ekinci et al. Best Practice & Research Clinical Endocrinology & Metabolism 35 (2021) 101507
Intestinal permeability
The intestinal mucosal barrier is the layer of intestinal epithelium and mucous layer that protects
the human body from the luminal contents of the gut. An important component of its integrity is the
tight junction proteins located between the epithelial cells, which bind the cells close together. In
particular, these tight junction proteins play a role in paracellular permeability, regulating the size of
which macromolecules are able to cross the intestinal barrier [27]. The intestinal barrier has two main
functions, firstly to selectively absorb nutrients from the diet and secondly, to protect the circulation
from harmful microbes and toxins [28]. Intestinal permeability refers to the leakiness of the gut,
specifically what can cross over the barrier from the intestinal lumen into the circulation. When the
barrier is impaired or weakened there is increased intestinal permeability. This means that certain
molecules can evade the protective regulations of the barrier, exposing the circulation to pathogenic
microorganisms, inflammatory mediators and uremic toxins. This topic has become a wide area of
research as a disrupted barrier can lead to and perpetuate disease.
Intestinal permeability in diabetes
Several mouse studies have assessed the gut permeability in vivo using the Dextran FITC assay and
observed that therewas increased gut permeability to this molecule in the diabetic ob/obmousemodel
[29,30]. Furthermore, this increased gut permeability in this mouse model of T2DM was abrogated by
mechanisms which target the microbiota, such as prebiotics [30] or antibiotic treatment [29]. In
particular this increase in intestinal permeability has been implicated as a precursor to chronic low-
grade inflammation, due to an increased translocation of bacterial endotoxin into the circulation.
Multiple human studies have shown that endotoxin levels are increased in both T1DM and T2DM
[31e34]. A 2017 meta-analysis of studies found that fasting lipopolysaccharide (LPS) levels were
elevated 235% and 64% in T1DM and T2DM patients, respectively, compared to non-diabetic control
participants [35]. In the FINRISK97 cohort, serum endotoxin levels were predictive of T2DM devel-
opment during the ten year follow up [34]. Furthermore, patients with T2DM have been shown to have
higher postprandial endotoxin excursions following a high fat diet meal [33]. These chronic low-level
increases in endotoxin are additional insults which contribute to chronic low-grade inflammation seen
in diabetes.
It should be noted that endotoxin has traditionally been measured using the limulus amebocyte
lysate (LAL) Assay; and increasingly there have been concerns about the accuracy of this method when
used in the range of measuring for metabolic endotoxaemia (as opposed to the levels of endotoxin that
would be detectable during sepsis), and that alternative markers such as lipopolysaccharide binding
protein (LBP) may be more reliable for assessing metabolic endotoxaemia [36]. LBP binds LPS in the
circulation, which facilitates immune cell signalling via the CD14:TLR4:MD2 pathway. There is also
evidence that LBP can transfer LPS to lipoproteins, notably high-density lipoprotein (HDL), which
neutralises LPS. Cross sectional studies have demonstrated that increased LBP levels are present in
participants with T2DM [37e39]. LBP levels correlate with glycated haemoglobin and are inversely
correlated with insulin sensitivity in patients with T2DM and glucose intolerance [38]. However, a five-
year nested case-control study of 3510 individuals found that LBP levels were not able to predict the
development of T2DM [40]. LBP is noted to be markedly increased with obesity [38,39,41] and a four-
month weight loss intervention in obese subjects resulted in reduced LBP concentrations which
correlated with the change in BMI [38]. Whilst LBP appears closely related with T2DM, it is unclear the
extent to which obesity may be a confounder in this relationship.
Glucose is toxic to intestinal epithelial barrier function
Leptin is a hormone that plays a role in appetite regulation and consequently, its dysfunction has
been related to obesity and thus diabetes [42]. In vitro, leptin has been shown to modulate expression
of tight junction proteins [43], suggesting that it may play a critical role in intestinal permeability in
metabolic diseases. A study by Thaiss et al. [44] investigated the cause of an abnormal barrier in db/db
mice, which have a leptin receptor gene mutation, and showed abnormal barrier function through
4
M. Snelson, C. de Pasquale, E.I. Ekinci et al. Best Practice & Research Clinical Endocrinology & Metabolism 35 (2021) 101507
abrogated gene expression of tight junction proteins. However, additional experiments revealed that,
neither leptin deficiency nor obesity alone impacted the intestinal barrier dysfunction, but rather
hyperglycaemia [44]. The results indicated that hyperglycaemia is directly toxic to epithelial cells by
altering tight junction integrity. This finding is supported by several human studies in T2DM patients,
which showed that blood glucose levels positively correlatedwith intestinal permeability, measured by
circulating endotoxin levels [32,45]. Additionally, a small subgroup (n ¼ 11) of patients in the study by
Al-attas et al. [32] had serum LPS measured before and after commencing the anti-diabeticmedication
rosiglitazone; treatment with the glucose lowering medication resulted in a 13.5% reduction in plasma
LPS in these patients. In addition, consumption of a high sugar diet inmice facilitates degradation of the
mucus barrier via expansion of mucus-degrading colonic bacteria [46]. These findings collectively
provide evidence that it may be the hyperglycaemia per se in diabetes that is a contributing factor to the
increased intestinal permeability observed with diabetes (Fig. 1).
Intestinal permeability and diabetic complications
The pathogenesis of the complications of diabetes, including diabetic cardiomyopathy, nephropa-
thy, neuropathy and diabetic retinopathy are multifaceted. As discussed above, the condition of dia-
betes is associated with increased intestinal permeability leading to bacterial translocation and
systemic inflammation. This increased inflammation may be another mechanism contributing to the
progression of the complications of diabetes [47]. For example, diabetic nephropathy is a well-
established contributor to end-stage renal disease, a condition which is associated with worsened
intestinal permeability and inflammation [48]. Thus, therapies which limit disruption of the gut barrier
and limit systemic inflammation may have an important role to play in limiting the progression of
diabetic complications.
Intestinal permeability modulation by the microbiota
An altered gut microbiota, as is present in diabetes, appears to also be a major stimulus for an
impaired mucosal barrier [9]. Increased permeability is associated with decreased levels of glucagon-
like peptide-2 (GLP-2) which play a vital role in the tight junction barrier, through regulating the tight
junction proteins zonula occludens-1 (ZO-1), occludin and claudin-1 [49]. Additionally, microbial
perturbations in diabetes are associated with elevated levels of toxic metabolites such as LPS in the
systemic circulation [9]. Increased intestinal permeability allows LPS to access the circulation and incite
inflammation. LPS interacts with toll-like receptor-4 (TLR4) receptors to activate a proinflammatory
cascade through the release of cytokines, adhesion molecules and reactive oxygen species [50]. This
ultimately results in a state of metabolic endotoxaemia, a state present in T2DM, which is characterised
by insulin resistance, oxidative stress and chronic low-grade inflammation [51].
Prebiotics
Diet heavily influences gut microbiota as these microorganisms obtain their energy from food,
particularly non-digestible carbohydrates. Non-digestible carbohydrates are known colloquially as
dietary fibres and the recommended intake is 25e30 g per day, while the average Australian fails to
reach this target consuming roughly 20 g per day [52]. These non-digestible substances can be clas-
sified as prebiotics and their role as a prebiotic is to promote beneficial bacterial species and conse-
quently one of their fermentation products, short-chain fatty acids (SCFAs). Prebiotics were first
defined in 1995 by Glen Gibson and Marcel Roberfroid as “a non-digestible food ingredient that
beneficially affects the host by selectively stimulating the growth and/or activity of one or a limited
number of bacteria in the colon, and thus improves host health” [53]. This narrow definition focussed
mainly on the beneficial bacteria Lactobacilli and Bifidobacteria, leading to two types of prebiotics;
inulin-type fructans (ITFs) and galacto-oligosaccharides [54]. ITFs and galactooligosaccharides are
linear chains of fructose or galactose molecules (with a terminal glucose in the case of gal-
actooligosaccharides), respectively, connected with b(2-1) glycosidic bonds, which whilst resistance to
human digestion [55]. These bonds are able to be broken by b-fructanoside and b-galactoside enzymes
5
Fig. 1. Disruption of the intestinal barrier during diabetes. During diabetes, there is a relative reduction in the abundance of butyrate producing bacteria and concomitant decrease in microbial
product of short chain fatty acids (SCFAs). This reduction in SCFAs contributes to a reduced integrity of the gastrointestinal barrier. Additionally, glucose itself is inhibitory to the tight junction
proteins between epithelial cells in the intestinal barrier. This decrease in barrier integrity permits the translocation of lipopolysaccharide (LPS), leading to the activation of inflammatory
signalling pathways. Created with BioRender.com.
M
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M. Snelson, C. de Pasquale, E.I. Ekinci et al. Best Practice & Research Clinical Endocrinology & Metabolism 35 (2021) 101507
which are prevalent in bacterium such as Bifidobacterium [56]. ITFs are the most commonly studied
prebiotic in humans [56], and show a demonstrated bifidogenic effect in T2DM [57].
However, it is widely accepted that other bacteria are important and not only dietary fibres or
carbohydrates as such should be classified as prebiotics. Thus in 2016, a modified definition was
decided upon by the International Scientific Association for Probiotics and Prebiotics (ISAPP), declaring
that a prebiotic is “a substrate that is selectively utilized by host microorganisms conferring health
benefit” [53]. Ultimately prebiotics have three requirements: they cannot be broken down by the
human intestinal enzymes, they can be fermented by intestinal microbiota and they improve the host’s
health. Due to the updated definition, more substrates are now accepted as prebiotics including non-
carbohydrates, such as polyphenols [54]. One increasingly utilised prebiotic is resistant starch, which
retains many of the cooking properties of regular starch and can be easily substituted in food
production.
Resistant starch
Starch is a polysaccharide, produced by plants for energy storage. There are two main structural
components to starch, the amylose which is a linear chain and the amylopectin which is a branched
glucose chain [58]. Starches cannot be absorbed in the small intestine without first being digested into
glucose molecules. Alpha-amylases are digestive enzymes that cleave the glucosidic bonds to depo-
lymerise starch. Starch is classified by this digestion time and can be grouped into rapidly digestive
starch (RDS), slowly digestive starch (SDS) and resistant starch (RS) [59]. RDS are the most commonly
consumed starchy foods in Western countries, with diets high in white bread, cakes and noodles [11].
This has multiple health implications as it causes rapid and high levels of blood glucose postprandially
which leads to an increase in the body’s demand for insulin. Resistant starchwas first described in 1982
by Englyst and others, upon the discovery of starches that were not digested in the small intestine [60].
There are five types of RS; RS1 is physically inaccessible starch which can be found in bread made with
whole or coarsely ground kernels of grains and pasta made from durum wheat. It is surrounded by a
protein matrix and cell wall material which is what makes it physically inaccessible. RS2 is granular
starch which makes it resistant to digestive enzymes, preventing enzymatic hydrolysis to glucose
molecules. It can be found in uncooked potato starch, green banana starch and high-amylose maize
starch. It is important to note that cooking foods with RS2 often results in starch gelatinisation to
become RDS. Retrograded starch is type 3. It occurs in foods that have been cooked and then cooled to
create a structure which is resistant to enzymatic hydrolysis. RS4 is chemically modified to make it
more resistant to enzymatic hydrolysis. This is achieved by adding chemical derivatives or cross-linking
to change the structure of the starch. RS5 is alsomodified and is a result of starch interacting with lipids
which prevent granule swelling during gelatinisation and enzyme hydrolysis [11]. As RS avoids
digestion in the small intestine, it can pass throughto the colonwhere it is available to be fermented by
gut microbes. A by-product of the microbial fermentation of RS is the production of SCFAs and other
microbial metabolites, which can have positive benefits on health. Thus, RS has been a widely studied
topic of research to see how its role as a prebiotic can be used in treating or preventing disease.
Prebiotics and diabetes
A common question in regard to prebiotics affecting intestinal permeability in diabetes, is whether
the dietary intervention is having an effect on the diabetes itself. As previously discussed, diabetes is
associated with increased intestinal permeability, and it has been recently demonstrated that high
glucose levels are themselves detrimental to gastrointestinal barrier integrity [44]. Thus, it is important
to examine the effects that prebiotics have on diabetes itself. Many prebiotics are also non-viscous
dietary fibres, and dietary fibre intake of all types has been demonstrated to improve glycaemic
control [61]. There have been a number of studies that have utilised prebiotic interventions in diabetes
and observed improvements in parameters such as insulin resistance [56]. A meta-analysis of 33
randomised control trials that utilised ITFs observed reductions in fasting blood glucose (FBG), fasting
insulin levels and HOMA-IR in conditions of prediabetes or T2DM [55]. Similar results were seen in a
meta-analysis of trials that utilised inulin specifically in T2DM [62]. A recent meta-analysis of 22 trials
7
M. Snelson, C. de Pasquale, E.I. Ekinci et al. Best Practice & Research Clinical Endocrinology & Metabolism 35 (2021) 101507
that utilised resistant starch type 2 (RS2) observed that resistant starchwas associatedwith a reduction
in body weight in T2DM and a trend towards a reduction in HbA1c (p ¼ 0.07), however no significant
effects of resistant starch supplementationwas observed on insulin resistance (as measured by HOMA-
IR), FBG, LDL, HDL, total cholesterol or triacylglycerol concentrations [63]. This limited effect may in
part be due to the relatively short duration of many of the trials included in this meta-analysis, with 13
of the including trials having a duration of 6 weeks or less. It has been suggested that prebiotic sup-
plementation may require at least 6e8 weeks to have an observable effect on metabolic parameters
[56]. A meta-analysis investigating the effects of inulin supplementation did a duration subgroup
analysis and observed that inulin supplementation was associated with reductions in HOMA-IR and
FBG only in the subgroup of 8 weeks or greater, with HbA1c reduced regardless of duration subgroup
[62].
Gut microbial metabolites as modifiers of intestinal permeability
Short chain fatty acids (SCFAs)
Non digestible carbohydrates, including prebiotics, get fermented in the large intestine, leading to
the production of short-chain fatty acids (SCFAs). SCFAs are carboxylic acids consisting of two to six
carbons of which acetate (C2), propionate (C3) and butyrate (C4) are most abundant [64]. Butyrate is
predominately utilised by colonocytes, whilst propionate and acetate are absorbed through the portal
vein. Propionate is metabolised by hepatocytes, while a proportion of acetate is released from the liver
and is the primary SCFA present in the systemic circulation [64]. The microbiota has a clear role in the
production of SCFAs, withmice treatedwith antibiotics to deplete the microbiome having a far reduced
SCFA production [65]. Prebiotics are a well-established dietary intervention for increasing microbial
production of SCFAs.
The use of dietary prebiotics to increase SCFA production may be particularly relevant in diabetes.
This is because several studies have reported that there are decreases in the proportion of butyrate-
producing species in individuals with diabetes [8,17,21,66]. In an elegant study by Ridaura et al. [26],
the faeces of twins discordant for obesity were transferred into germ-free mice; those mice receiving
faeces from the lean twin had greater amounts of the SCFAs propionate and butyrate compared with
the obese twin. These findings are relevant as there is evidence that SCFAs, particularly butyrate,
enhance tight junction assembly to improve intestinal barrier integrity [67e69]. Thus, interventions
such as prebiotics which increase the production of SCFA, particularly butyrate, are important for
maintenance of the gut barrier [56].
Multiple animal studies have shown that an infusion of SCFAs can increase GLP-2 levels, which lead
to maintain tight junction integrity [70e72]. Similarly, to GLP-1, SCFAs stimulate the endocrine L cells
to release GLP-2 [73]. SCFAs may also reduce systemic inflammation through the activation regulatory
T cells (Tregs). Tregs are lymphocytes whose role are to suppress or regulate cells in the immune
system. As such Tregs have anti-inflammatory effects and have a major role in preventing autoimmune
conditions, allergies, and asthma [74]. Studies have shown that in patients with T2DM there is a
reduction in serum Treg levels compared to healthy individuals [75,76]. Additionally, these studies
indicated that T2DM patients with nephropathy had lower Treg levels than those without renal injury.
Furthermore, the mean Treg level was inversely related to the urine albumin: creatinine ratio and
therefore kidney damage. Eller et al. [77] further demonstrated this association in a study that
demonstrated depleting Treg levels in db/db mice resulted in worsening insulin resistance and albu-
minuria. Additionally, the same study showed that supplementing db/db mice with Tregs, led to a
significant improvement in insulin sensitivity and kidney injury compared to control mice. Prebiotic
supplementation may stimulate the production of Tregs through its enhancement of butyrate pro-
duction. Butyrate acts on GPR109a, which is present on colonic immune cells. Activation of GPR109a on
macrophages and dendritic cells promotes the production of IL-10 which further induces the differ-
entiation of Tregs [78]. GPR109a stimulation also results in the suppression of proinflammatory me-
diators such as TNF-a and IL-6 [79]. Murine studies have shown that prebiotic supplementation is
8
M. Snelson, C. de Pasquale, E.I. Ekinci et al. Best Practice & Research Clinical Endocrinology & Metabolism 35 (2021) 101507
associated with increased levels of Tregs in mice with colitis and inflammatory bowel disease [80,81].
Increased microbial SCFA production may be one mechanism by which prebiotic supplementation
assists in improving intestinal barrier integrity (Fig. 2).
Protein fermentation products
The microbiota is also a source of metabolites that are produced by protein fermentation; these
include ammonia, phenol, p-cresol, indole, hydrogen sulphide and brain-chain fatty acids (BCFAs) [82].
Fig. 2. Dietary prebiotics improve intestinal barrier integrity. Fermentation of prebiotic fibres by the commensal microbiota leads
to the production of short chain fatty acids (SCFAs). SCFAs bind to enteroendocrine L cells, producing GLP-2, which enhances in-
testinal tight junction integrity. The SCFA butyrate is able to bind to dendritic cells via receptor GPR109a, leading to the production of
IL-10 which promotes activation of anti-inflammatory T regulatory cells. Created with BioRender.com.
9
http://BioRender.com
M. Snelson, C. de Pasquale, E.I. Ekinci et al. Best Practice & Research Clinical Endocrinology & Metabolism 35 (2021) 101507
Increased ammonia degrades intestinal tight junction proteins [83e85] and prebiotic interventions
have been shown to decrease cecal ammonia concentrations [86]. P-cresol and indole are produced
from fermentation of the amino acids tyrosine and tryptophan respectively, and once absorbed and
sulphated in the liver to the uremic retention solutes, p-cresol sulphate and indoxyl sulphate [64]. High
levels of p-cresol sulphate and indoxyl sulphate are extremely toxic and can lead to insulin resistance
[87], activation of the renin-angiotensin-aldosterone system[88], impaired endothelial function [89]
and renal tubulointerstitial fibrosis [90]. As uremic toxins contribute to renal inflammation, apoptosis,
and fibrosis, they may be a cause of progression to diabetic kidney disease and most likely worsens the
disease [91].
Another fate of bacterial metabolism of tyrosine is the production of phenols [92]. Evidence from
in vitro studies utilising intestinal cell lines has indicated that phenol increases paracellular perme-
ability [93,94], suggesting that there may be a negative effect on gut barrier integrity. However, these
metabolites are present in the colon at far lower concentrations than used in in vitro experiments,
which would be more simulating of exposure to environmental contamination [82]. With the excep-
tion of ammonia, there is limited data regarding the effect of protein fermentation products on
epithelial barrier integrity.
Summary
There is compelling evidence that the microbiome is altered in diabetes. Whilst there are in-
consistencies between studies regarding the role of microbial diversity or phylum level changes with
diabetes, there is a noted reduction seen in butyrate producers and subsequent SCFA levels in diabetes.
Concurrently, diabetes is associated with increased intestinal permeability, and recently it has been
demonstrated that glucose itself directly alters integrity of the intestinal barrier. These alterations in
intestinal permeability permit the translocation of material from the intestinal lumen, such as lipo-
polysaccharide, into the circulation and subsequent activation of pro-inflammatory pathways, which
may contribute to the progression of diabetic complications. Prebiotics are dietary components that are
fermented by the colonic microbiota leading to the production of SCFAs and enhancement of gastro-
intestinal barrier integrity. Thus, prebiotics offer a promising avenue to counteract the changes to the
microbiota, SCFA production and intestinal permeability observed in diabetes. Dietary prebiotic sup-
plementation represents a safe, well tolerated and inexpensive therapeutic avenue. It is possible that
supplementation with prebiotics could act as an adjunct therapy for diabetes complications.
Practice points
- The gut microbiota is altered in diabetes, with a noticeable reduction in short chain fatty acids
(SCFA) producers, particularly butyrate producers.
- In diabetes, there is an increase in intestinal permeability.
- Butyrate promotes integrity of the intestinal barrier. Prebiotics are fermented by the gut
microbiota to produce SCFAs.
Research agenda
- The evidence regarding increased permeability of the gut barrier during diabetes is largely
built upon the LAL assay which may not be that accurate for assessing metabolic endotox-
aemia. Future studies should utilise alternative markers of intestinal permeability.
10
M. Snelson, C. de Pasquale, E.I. Ekinci et al. Best Practice & Research Clinical Endocrinology & Metabolism 35 (2021) 101507
Acknowledgement
EIE is supported by the Sir Edward Weary Dunlop Foundation. EIE’s research is supported by
funding from the National Health and Medical Research Council (NHMRC) of Australia, Medical
Research Future Fund. EIE’s institute receives funding fromNovo Nordisk, Gilead, Bayer, Eli Lilly, Sanofi,
Boehringer for unrelated research.
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	Gut microbiome, prebiotics, intestinal permeability and diabetes complications
	Introduction
	Altered gut microbiota in diabetes
	Diversity
	Firmicutes/Bacteroidetes ratio
	Intestinal permeability
	Intestinal permeability in diabetes
	Glucose is toxic to intestinal epithelial barrier function
	Intestinal permeability and diabetic complications
	Intestinal permeability modulation by the microbiota
	Prebiotics
	Resistant starch
	Prebiotics and diabetes
	Gut microbial metabolites as modifiers of intestinal permeability
	Short chain fatty acids (SCFAs)
	Protein fermentation products
	Summary
	Acknowledgement
	References

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