Type 1 Diabetes Mellitus

is Related to Gut Dysbiosis

Yasmin Barakat, Seunghee Lee, Jessica Lehrke

Abstract
Type 1 diabetes mellitus (T1DM) is a chronic illness that affects people worldwide,
typically beginning in childhood. The exact cause is unknown, but studies have shown that
children diagnosed with T1DM have significant differences in gut microbiota compared with
healthy children. The purpose of this review is to begin narrowing the scope of influential
bacteria and determine if manipulating the gut microbiota could halt the pathogenesis of T1DM.
The MNCAT database was searched using the terms Type 1 Diabetes, gut microbiota. Studies
published in English between 2010 and 2015 in peer-reviewed journals were used, eight of them
included in this review. All of the studies found evidence in support of a correlation between gut
dysbiosis and T1DM. The studies using human subjects found a positive correlation between
levels of gastrointestinal Bacteroidetes and risk for T1DM, while risk for T1DM was negatively
correlated with levels of Bifidobacterium and overall bacterial diversity. The animal studies
support this theory as well, showing that certain bacterial species may protective against T1DM
and that infection by pathogenic bacteria that create gut disturbances can induce the disease. This
evidence reveals the potential for T1DM prevention through gut microbiota manipulation. The
implementation of further study is limited by ethical standards, as microbiota manipulation
would require testing on human subjects. More research is needed using various bacteria in order
to determine which species and ratios of species can protect against T1DM.
Introduction
Type 1 diabetes mellitus (T1DM), also known as juvenile diabetes or insulin-dependent
diabetes, is a chronic condition characterized by the lack of insulin production from the pancreas.
T1DM is commonly diagnosed in children and young adults, and it is believed that its onset
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occurs when 80% or more of the pancreatic beta cells have been destroyed by the immune
system, causing an inability to secrete insulin.1 The incidence of T1DM has been increasing in
children and young adults at a rate of 3% to 4% per year.2 The exact cause of T1DM is yet
unknown, and both genetic susceptibility and environmental conditions are likely to play a role.
However, the increasing incidence of the disease points toward changing environmental
circumstances as a strongly correlating factor.
Many studies have shown a correlation between T1DM and gut dysbiosis. Most research
has focused on case-control studies in human subjects, observing fecal microbial composition in
stools, and have shown that gut microbiomes of patients with or at the onset of T1DM differs
from healthy controls.3-7 Across the five human studies reviewed, the strongest correlations were
found in the measured levels of Bifidobacterium and Bacteroidetes, as well as overall bacterial
diversity.3-7 Three of the five studies looked at Bifidobacterium and found lower levels in those
with T1DM or beta cell autoimmunity when compared with healthy controls.3-5 Four of the five
studies looked at Bacteroidetes and found higher levels in those with T1DM or beta cell
autoimmunity when compared with controls.3, 5-7 Additionally, four of the five studies analyzed
overall microbial diversity and found less diversity in those with T1DM or beta cell
autoimmunity when compared with controls.4-7 Other similarities were found across studies that
will be discussed later in this review.
In addition to the five human case studies, three case control studies using mice were
reviewed.8-10 All three used different methods to manipulate gut microbiota in order to
determine the role of different types of bacteria in the T1DM pathophysiology. One administered
antibiotics, another infected the mice with a pathogenic bacteria, and the third administered a

bacteria that is common in the human gastrointestinal tract.8-10 These animal studies found
dysbiosis to be correlated with T1DM.
Gut dysbiosis can be caused by a variety of stimuli. We know that gut microbiota can be
affected by many environmental factors, including mode of birth delivery, breast feeding or lack
thereof, antibiotic medications, diet (related to prebiotics) and daily activities during which a
person may be exposed to either pathogenic or nonpathogenic bacteria. It is also known that a
healthy gut microbiota contributes to immune system function. In particular, certain probiotics
such as Lactobacillus and Bifidobacteria, commonly found in the human GI tract as well as in
common food products like yogurt, have been shown to have a health benefit on the host.11 We
see this pattern repeated in some of the studies reviewed below.3-5
After completing this review, it is clear that gut dysbiosis is related to Type 1 Diabetes
Mellitus. What needs to be found are the exact strains of bacteria, or rather the ratio of bacteria,
that have protective or adverse effects as related to T1DM pathophysiology. This will take
additional research to determine how to manipulate the gut microbiome as a means of
prevention. This review lays out the common correlations found across T1DM bacterial studies,
and narrows the scope of bacterial targets for future research to Bifidobacterium, Bacteroidetes,
and overall gut microbiome diversity.
Review
Five out of the eight studies reviewed were case-control studies focused mainly on child
subjects who had T1DM or beta-cell autoimmunity compared with healthy individuals of
approximately the same ages. Beta cells typically produce and secrete insulin when signaled to
do so by an increase in blood glucose levels. Without enough insulin, blood glucose levels
remain high in the body. In T1DM, the beta cells do not produce enough insulin. This is due to
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the loss of beta cells.12 Autoimmunity is the most prevalent effector mechanism of T1DM, but it
is not the primary cause. Some studies show that genetics play a huge role in the trigger of
T1DM, however, other studies suggest that enteroviruses trigger T1DM, and some
microorganisms show protective effects.13
Murri et al3 examined 16 children with T1DM and compared them to 16 healthy controls.
Using a real-time quantitative polymerase chain reaction (qPCR) method, results showed a
significant decrease in Lactobacillus levels in the fecal composition of the study group. Reduced
numbers of Lactobacillus and Bifidobacterium were associated with higher levels of plasma
glucose, which is usually observed in diabetic patients.3 Similarly, this study found elevated
amounts of Clostridium in T1DM individuals, which also positively correlated with the levels of
plasma glucose in T1DM individuals.3 Results also showed lower levels of Eubacterium Rectale
and higher levels of Bacteroidetes in T1DM study groups.3 Bacteroides, a genus of the phylum
Bacteroidetes, is one of the bacteria that could be passed from the mother to the child during
vaginal birth, and thus, it becomes part of the human flora.15
Soyucen et al4 used a larger sample size of 70 and found slightly different results. Like
Murri et al,3 Soyucen et al4 found a decrease in Bifidobacterium in eight T1DM patients and one
control. However, no significant differences in Lactobacillus were found.4 Overall, the study
found that microbial diversity was reduced in study groups, but elevated in controls.4 The study
was limited by the use of selective and non-selective media to measure bacterial cultures, as the
outcome probably would have been more accurate if they had used a more accurate technique
such as qPCR, as Murri et al3 did.
In a third human study by de Goffau et al,6 28 individuals with T1DM were compared to
27 individuals without T1DM. Microbiota composition was determined by DNA analysis. The
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study found that members of Clostridium clusters IV and XIVa were increased in healthy
controls. However, controls older than 2.9 years had an increased fraction of butyrate-producing
species within the Clostridium clusters IV and XIVa than what was observed in diabetic
children. Butyrate, a short-chain fatty acid (SCFA) produced by fermentation of fiber (prebiotics)
by bacteria in the gut, provides more than 70% of the fuel for colonic epithelial cells.2 Among
other things, SCFAs enhance sodium and water absorption, colonic blood flow, colonic epithelial
cell proliferation, and metabolic energy production.2 Due to this relationship, dietary
interventions aimed at achieving or maintaining optimal butyrate production levels may
measurably reduce the risk of developing T1DM. The results of the de Goffau et al6 study
supported this hypothesis, especially in kids with high-risk Human Leukocyte Antigen (HLA)
genotypes. Supporting the results of Murri et al,3 the healthy controls of de Goffau et al6 showed
an increase of Lactobacilli in their sample, in particular, Lactobacillus Plantarum, and
Bacteroidetes levels were increased in T1DM groups. The study also showed that T1DM
individuals older than 2.9 years had increased microbial diversity.6
While the de Goffau et al6 study has some interesting findings, it has some weaknesses.
Two T1DM children did not have paired controls, whereas, in every study observed every T1DM
individual was paired with a control for comparisons. Furthermore, this study was attempted in
Finland, yet, a large proportion of the T1DM children older than 2.9 years did not come from
Finland, which may have obscured the correlation between Bacteroides and T1DM in this age
group. Despite the weaknesses of the de Goffau et al6 study, its results were supported in other
research.
Giongo et al,7 measured bacterial composition from fecal samples through DNA
extraction with two groups: 4 individuals with T1DM autoimmunity that were matched by age
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and genotype to 4 without autoimmunity. In support of the findings of the de Goffau et al6 and
Soyucen et al4 studies, this study found that bacterial diversity diminishes over time in
autoimmune individuals. Results showed a decrease of Fermicutes and Clostridium in the study
group, and the opposite in the control. Similar to the results of Murri et al,3 Eubacterium Rectale
was lower in individuals with T1DM. Also consistent with Murri et al3 and de Goffau et al,6
Bacteroidetes increased over time in T1DM, while it decreased over time in control groups.
Results further showed that Firmicutes and Clostridium to have an opposite effect to
Bacteroidetes, as they decreased over time in T1DM. This study showed that, while both groups
exhibited a high amount of Bacteroides, T1DM individuals had an overall higher amount of
Bacteroides.7
de Goffau et al5 also measured bacterial composition from fecal samples through DNA
extraction, comparing 18 individuals with at least two diabetes-associated autoantibodies and
HLA conferred susceptibility to T1DM, and displayed signs of Beta-cell autoimmunity, with 18
controls who were autoantibody negative. This study also found that a low abundance of lactateproducing and butyrate-producing species were associated with Beta-cell autoimmunity.5 As
previously stated, butyrate-producing bacteria are essential for gut health. A bacterial imbalance
involving bacteria that are so essential for gut health could lead to the development of a
permeable gut, wherein potentially harmful bacteria that is found in the T1DM microbiome
could translocate, leading to autoimmunity and T1DM.14 Similar to Soyucen et al4 and Murri et
al,3 this study found a lack of the two most dominant Bifidobacterium species. de Goffau et al5
also found an increase in Clostridium, though this opposes the findings of de Goffau et al6 and
Giongo et al.7 Similar to some of the other studies, de Goffau et al5 found higher levels of
Bacteroides and Bacteroidetes in T1DM individuals, but lower levels of microbial diversity.
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Hansen et al8 investigated the effect of vancomycin, a broad-spectrum antibiotic, on gut

microbiota and T1DM incidence using 15-21 non-obese diabetic (NOD) mice in each of three
groups. One group received vancomycin from birth until weaning (28 days), another received
vancomycin from 8 weeks old until T1DM onset, and the third was a control that did not receive
vancomycin. The study found that the neonatally treated mice had a dominant bacterial species
in their gut microbiome, Akkermansia muciniphila, and that these mice had a lower incidence of
T1DM compared with the control group. This suggests that timing is important when attempting
to prevent T1DM, and that A. muciniphila may play a protective role in the development of the
disease. This study was the only found that used antibiotics, and also the only that found A.
muciniphila had any significance in relation to T1DM.
In contrast to Hansen et al,8 Lee et al9 infected NOD mice with a pathogenic bacteria,
Citrobacter rodentium. C. rodentium is an enteric pathogen capable of causing intestinal
epithelial barrier disruption. This study used 30 uninfected controls, 25 infected with wild-type
(WT) C. rodentium that was capable of causing barrier disruption and 24 infected with C.
rodentium that was incapable of causing barrier disruption. Lee et al9 found that prediabetic
NOD WT mice had accelerated insulitis development when compared to prediabetic NOD nonWT mice. The WT group also had increased activation of diabetogenic cytotoxic T cells. These
results suggest that damage to the intestinal epithelial barrier by bacterial pathogens may
increase risk for T1DM by activating these T cells and increasing insulitis, supporting the theory
that there may be a pathogenic bacterial trigger for the onset of T1DM. This correlates with the
knowledge that T1DM onset often occurs immediately after an illness, and supports the theory
that T1DM is correlated with gut dysbiosis.

Valladares et al10 also infected mice with a strain of bacteria, though instead of a known
pathogen, used Lactobacillus johnsonii, a bacterium known to inhabit the healthy human
intestine. To examine the effect on the onset of T1D, Valladares et al10 injected Lactobacillus
johnsonii strain N6.2 (L. johnsonii N6.2) to controlled BioBreeding Diabetes Prone (BBDP) rats,
which was taken from BioBreeding Diabetes Resistant (BBDR) rats. In BBDP rats, they were
able to resist the onset of T1DM after being fed L. johnsonii N6.2 compared to the control or
BBDP rats fed a second strain of Lactobacillus, Lactobacillus reuteri strain TD1 (LrTD1).
Compared to the control, L. johnsonii N6.2-fed groups showed larger number of goblet cells,
which sustain mucus production as well as prevent damage from enteric pathogens. In addition,
administration of L. johnsonii N6.2 changes the intestinal microbiota through adjusting the
expression of tight junction proteins, which helps to prevent the onset of T1D. From the
Valladares et al10 study, the group of L. johnsonii N6.2 fed animals increased the expression
claudin-1 and decreased the expression of occludin. In other words, the feeding of L. johnsonii
N6.2 decrease triggers in intestinal environment and lower the T1D development. Although
Valladares et al10 used a smaller sample size, 10 rats per group, they clearly show that L.
johnsonii N6.2 inhibits the progression of T1D when administered post-weaning.
Lactobacillus was also examined in some of the human studies. The findings of
Valladares et al10 were similar to those of Murri et al,3 who found low numbers of Lactobacillus
in children with T1DM, and also de Goffau et al6, who showed large numbers of Lactobacilli in
intestinal microbiota of non-diabetic children. In other words, children who do not have diabetes
have a higher prevalence of Lactobacillus in their microbiota.
For all three of the animal studies, the major weakness is the fact that they were animal
studies, and therefore cannot be directly applied to human experience. They do, however, have
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broader implications that can be applied to theories regarding the potential protective effect of
certain bacteria, like Akkermansia muciniphila or Lactobacillus johnsonii, or the diseaseinducing trigger effect of enteric pathogenic bacteria. More generally speaking, the results of
these animal studies support the potential for microbiome manipulation via antibiotic treatment
or simple oral transfer.
Conclusion
The results of the human studies reviewed revealed, first and foremost, that there was a
significant difference between the microbiomes of healthy individuals and individuals with type
1 diabetes mellitus or beta cell autoimmunity. The strongest evidence (supported by the most
studies) was a positive correlation between levels of gastrointestinal Bacteroidetes and risk for
T1DM, while risk for T1DM was negatively correlated with levels of Bifidobacterium and
overall bacterial diversity.3-7 This evidence supports the theory that T1DM may be partially
caused by gut dysbiosis. Additional results were less conclusive. The inconsistencies,
particularly with Clostridium and Lactobacillus, may warrant further investigation, as certain
species within these genuses may be helpful or harmful regarding T1DM pathogenesis. It would
also be valuable to differentiate the genuses and species of Bacteroidetes, as inconsistencies were
found in levels of Bacteroides when comparing healthy individuals to those with T1DM.
The animal studies reviewed support the theory that T1DM is correlated to gut dysbiosis,
showing that certain bacterial species may have a protective effect against T1DM and that
infection by pathogenic bacteria that create gut disturbances can induce the disease.8-10
Identifying the connection between particular bacterial species and/or the ratio of certain
types of gut bacteria and the onset of type 1 diabetes mellitus would help to further our
understanding of the pathophysiology of the disease. This has implications for potential T1DM
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prevention via microbiome manipulation. This connection may also help drive further study in
gut microbiota and general disease prevention.
It would be beneficial to do more NOD mice studies to test the results of administration
of various bacteria, as well as human birth cohort studies to evaluate the microbiome of children
prior to and after the development of beta cell autoimmunity.
Because complete prevention of exposure to potentially harmful bacteria is impractical,
medical intervention may be the best way to prevent the disease. From infancy, children could be
tested for genetic predisposition to T1DM, and if found to be genetically predisposed, periodic
testing throughout life could be a means to identify any change in gut microbiota that is
associated with T1DM onset. Patients could then receive treatment to correct their dysbiosis.
Further study would also be needed to determine what type of treatment would be beneficial, and
research should be done on prebiotics (particularly with regard to butyrate-producing bacteria),
probiotics, antibiotic therapy and fecal transplantation.

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