Journal of the Endocrine Society, 2023, 7, 1–12

https://doi.org/10.1210/jendso/bvac184
Advance access publication 30 November 2022
Mini-Review

Type 2 Diabetes and the Microbiome

Gillian M. Barlow1 and Ruchi Mathur1,2
1
Medically Associated Science and Technology (MAST) Program, Cedars-Sinai, Los Angeles, CA, USA
2
Division of Endocrinology, Diabetes, and Metabolism, Department of Medicine, Cedars-Sinai, Los Angeles, CA, USA
Correspondence: Ruchi Mathur, MD, FRCPC, Director, Clinical Diabetes, Cedars-Sinai, 700 N San Vicente, Ste G271, West Hollywood, CA 90069, USA.
Email: ruchi.mathur@cshs.org.

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Abstract
Diabetes represents one of the most significant, and rapidly escalating, global healthcare crises we face today. Diabetes already affects one-tenth
of the world’s adults—more than 537 million people, numbers that have tripled since 2000 and are estimated to reach 643 million by 2030. Type 2
diabetes (T2D), the most prevalent form, is a complex disease with numerous contributing factors, including genetics, epigenetics, diet, lifestyle,
medication use, and socioeconomic factors. In addition, the gut microbiome has emerged as a significant potential contributing factor in T2D
development and progression. Gut microbes and their metabolites strongly influence host metabolism and immune function, and are now
known to contribute to vitamin biosynthesis, gut hormone production, satiety, maintenance of gut barrier integrity, and protection against
pathogens, as well as digestion and nutrient absorption. In turn, gut microbes are influenced by diet and lifestyle factors such as alcohol and
medication use, including antibiotic use and the consumption of probiotics and prebiotics. Here we review current evidence regarding
changes in microbial populations in T2D and the mechanisms by which gut microbes influence glucose metabolism and insulin resistance,
including inflammation, gut permeability, and bile acid production. We also explore the interrelationships between gut microbes and different
T2D medications and other interventions, including prebiotics, probiotics, and bariatric surgery. Lastly, we explore the particular role of the
small bowel in digestion and metabolism and the importance of studying small bowel microbes directly in our search to find metabolically
relevant biomarkers and therapeutic targets for T2D.
Key Words: type 2 diabetes, insulin resistance, gut microbiome, small intestine, inflammation, gut permeability

Diabetes—Prevalence and Significance may lead to metabolic imbalances and ultimately to the devel­
opment of T2D [3, 6]. For example, impairments in any of the
The global prevalence of diabetes has reached crisis levels, af­
pathways involved in insulin binding can lead to reduced glu­
fecting more than half a billion adults worldwide (537 mil­
cose uptake, resulting in higher circulating glucose levels
lion), or 1 in 10 of the adult population, in 2021 [1] (Fig. 1).
(hyperglycemia) and placing increasing demands on insulin-
These numbers have more than tripled since 2000 and, unless
producing pancreatic beta cells [3, 7] and, as noted above, im­
checked, are projected to rise to 643 million by 2030 and 783
paired insulin detection and/or uptake by target tissues such as
million by 2045 [1]. Significantly, it is also estimated that al­
skeletal muscle, adipose tissue, and the liver can result in insu­
most 1 in 2 adults with diabetes (240 million) are undiagnosed
lin resistance [3, 7]. Of note, this also leads to inflammation in
and hence unaware of their condition and strategies for its
the target tissues, with increases in circulating levels of proin­
management, and that a further 541 million adults have im­
flammatory cytokines [3, 7].
paired glucose tolerance and thus have an increased risk for
developing diabetes, specifically type 2 diabetes (T2D) [1].
In the United States, 37.3 million people are estimated to
have diabetes (11.3% of the population), of whom 8.5 million
Risk Factors for T2D
are undiagnosed [2]. While T2D is inextricably linked to obesity [which constitutes
another escalating global crisis (8)], multiple other factors are
also involved, including smoking, sleep quality, family his­
Pathophysiology of T2D tory, hypertension, dyslipidema, and others [recently re­
T2D accounts for approximately 90% of diabetes cases glo­ viewed by Ismail et al (9)]. Tellingly, in the 2022 National
bally [1]. It can be precipitated by deficiencies in the produc­ Diabetes Statistics Report [2], the Centers for Disease
tion and release of insulin by pancreatic beta cells and in the Control and Prevention reports that the prevalence of diag­
response of muscle, adipose tissue, and/or liver cells to insulin nosed diabetes in US adults is highest in families with incomes
[3–5]. A full analysis of T2D pathophysiology is beyond the below the federal poverty level (14.1%) and is also higher in
scope of this review, but, as discussed in a recent review by American Indian and Alaska Native (14.5%), non-Hispanic
Galicia-Garcia et al [6], the mechanisms underlying insulin Black (12.1%), Hispanic (11.8%), and Asian (9.5%) people
production and release, and its detection and uptake by target when compared to non-Hispanic White people (7.4%) [2].
tissues, are all tightly regulated, and defects in any of these Rates are also higher in individuals with lower education

Received: 3 August 2022. Editorial Decision: 23 November 2022. Corrected and Typeset: 22 December 2022
© The Author(s) 2022. Published by Oxford University Press on behalf of the Endocrine Society.
This is an Open Access article distributed under the terms of the Creative Commons Attribution-NonCommercial-NoDerivs licence (https://creativecommons.
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2 Journal of the Endocrine Society, 2023, Vol. 7, No. 2

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Figure 1. Estimated age-adjusted prevalence of diabetes in adults aged 20 to 79 years in 2021. Reproduced with permission from: IDF Diabetes Atlas,
10th ed. Brussels, Belgium: International Diabetes Federation, 2021. http://www.diabetesatlas.org.

levels, at 13.4% for those with less than a high school level vs numerous essential functions in maintaining host health.
9.2% for high school and 7.1% for more than high school lev­ The gut microbiome plays roles in vitamin and amino acid
el educations [2]. In addition to these important societal and biosynthesis [13, 14], bile acid deconjugation and other trans­
other (often interrelated) contributing factors such as diet, formations [15], immune responses and protection against
lifestyle, and medication use, data now indicate that changes pathogens [16], and many others [17]. This is made possible
in gut microbial populations may also contribute the develop­ by the collective genomes of the bacteria, Eukarya [18],
ment of T2D. Archaea (primarily methanogens) [19], and viruses [20] that
inhabit the gut, which together harbor over 150 times more
genes than the human genome [21]. Although bacteria pre­
Alterations in the Salivary Microbiome in T2D dominate, contributing an estimated 99.1% of genes in the
Most studies of the influences of the gut microbiome on T2D gut, Archaea contribute around 0.8%, and the remaining
discussed in this review were performed using stool samples, 0.1% are contributed by Eukaryotes and viruses [22].
as are the majority of gut microbiome studies. More recently, Gut microbes strongly influence host metabolism [23],
the salivary microbiome has also been shown to altered in breaking down otherwise indigestible complex carbohydrates
T2D, including decreased abundances of Bifidobacterium via glycoside hydrolases and polysaccharide lyases that are
and increased Streptococcus and Lactobacillus [10], de­ not encoded in the human genome [24, 25], and regulating lip­
creased abundance of the genera Actinomyces and id accumulation, lipopolysaccharide content, and the produc­
Atopobium (both phylum Actinobacteria [11]), and increased tion of short chain fatty acids (SCFAs), which influence many
abundance of Blautia wexlerae, Lactobacillus fermentum, aspects of metabolism [26] including insulin signaling [27].
Nocardia coeliaca, and Selenomonas artemidis in An early study of the gut microbiome in subjects with T2D
treatment-naïve T2D subjects [12]. These findings indicate found significant reductions in phylum Firmicutes, and specif­
that T2D has effects on the whole host, including the entire ali­ ically class Clostridia, when compared to controls, as well as
mentary tract, and that tracking changes in the salivary micro­ increases in class Betaproteobacteria and genus
biome may provide another useful means to monitor the Lactobacillus that correlated with increased plasma glucose
development and progression of T2D. levels [28]. A subsequent study by Karlsson et al found in­
creased relative abundances of Lactobacillus gasseri and
Streptococcus mutans, and decreased Roseburia intestinalis
Alterations in the Gut Microbiome
and Faecalibacterium prausnitzii in T2D subjects, as well as
in T2D—Findings From Stool Studies increased expression of microbial oxidative stress genes
The human host relies on the approximately 3.8 × 1013 micro­ [29], which has been linked to insulin resistance, β-cell dys­
organisms that colonize various body sites and perform function, impaired glucose tolerance, and T2D [27, 30].
Journal of the Endocrine Society, 2023, Vol. 7, No. 2 3

Moreover, there were similarities between these studies, per­ activated B cells (NF-κB) [42]. Alterations in gut microbial
formed using adult Danish males [28] and elderly Swedish fe­ populations, often referred to as dysbiosis, lead to increasing
males, [29] respectively, and a metagenome-wide association bacterial encroachment on the gut epithelium, triggering an
study of Chinese subjects, including increases in inflammatory response [43]. Bacterial components lipopoly­
Lactobacillus species and increased microbial oxidative stress saccharide (LPS) and flagellin are recognized by and bind
functions [31]. Since then, numerous studies have examined to the toll-like receptors TLR4 and TLR5, respectively
gut microbiota in human subjects with T2D. In a systematic [44]. TLR4/5 binding results in expression of TNF-α, which
review of the associated data, Gurung et al found that in add­ has been linked to impaired insulin receptor signaling and in­
ition to Roseburia and Faecalibacterium, the genera sulin resistance [45]. Of note, the effects of TLR4 may be
Bifidobacterium, Bacteroides, and Akkermansia were consist­ cell-type specific, as both TLR4 and its coreceptor CD14
ently found to be decreased in the gut microbiome in T2D sub­ are required to induce adipose tissue insulin resistance in
jects, whereas the genera Ruminococcus, Fusobacterium, and mice [46–48], but knocking out TLR4 in intestinal epithelial
Blautia were consistently increased [32]. In addition, positive cells impairs glucose metabolism and leads to the develop­
associations have been found between the genera Clostridium ment of metabolic syndrome [49]. TNF-α in turn leads to

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and Phascolarctobacterium and insulin sensitivity, and nega­ NF-κB activation [50] [via c-Jun N-terminal kinases and
tive associations with genus Dialister [33], whereas fasting in­ IκB kinase (42)] and translocation to the nucleus, which
sulin correlated negatively with Phascolarctobacterium and propagates further inflammatory responses. IL-1 inhibits
positively with Dialister [33]. Taken together, these clinical β-cell function, and IL-6 translocation to the liver results in
data suggest that gut bacteria may have direct effects on the the production of the inflammatory biomarker C-reactive
mechanisms underlying the development of T2D. protein, which is strongly associated with T2D and cardio­
metabolic health [51]. Of note, increases in LPS have been
Role of Microbial Metabolites in T2D— linked to decreases in Bifidobacterium spp, among others
[52], whereas supplementing diets with specific probiotics
Importance of Short Chain Fatty Acids including Lactobacillus, Bifidobacterium, Clostridium, and
As noted earlier, a common alteration of the gut microbiome Akkermansia have been shown to reduce inflammatory re­
in T2D found in many studies is decreased abundance of R. in­ sponses and increase insulin sensitivity [53, 54], reinforcing
testinalis, F. prausnitzii, and other species that produce the the central role, and potential therapeutic implications, of
SCFA butyrate [29, 31]. Butyrate and the other principal gut microbes in T2D.
SCFAs acetate and propionate are important microbial me­
tabolites produced via fermentation of dietary fibers, and to­
gether they have numerous effects on the host [34]. Acetate Increased Gut Permeability
and propionate are substrates for lipogenesis and gluconeo­ An important factor contributing to the inflammation de­
genesis in the liver and peripheral tissues, whereas butyrate scribed here is increased gut permeability, which has been
is an important energy substrate for the colonic epithelium linked to consumption of a high-fat diet (HFD) [55]. The mu­
[34] and has been shown in mouse studies to activate gluco­ cus lining the gut epithelium is essential for the barrier func­
neogenesis in the small bowel and colon [35]. Studies in mouse tion of the gut (ie, preventing bacterial pathogens, viruses,
models have also revealed that SCFAs can modulate the secre­ and toxins crossing from the lumen in to the epithelium and
tion of key peptide hormones including glucagon-like potentially entering the circulatory or lymphatic systems)
peptide-1 (GLP-1), gastric inhibitory peptide (GIP), GLP-2, [56]. When this barrier fails, detection of LPS or flagellin on
and peptide YY (PYY) in the gut, which can increase insulin encroaching bacteria triggers these inflammatory responses.
sensitivity, decrease inflammation, and increase satiety [36– Mucin produced by goblet cells [57], antimicrobial peptides
38]. Decreased abundance of butyrate producers has been such as defensins and regenerating islet-derived 3-gamma pro­
linked to increased metabolic risks, whereas increased inges­ duced by Paneth cells [58], GLP-2 produced by L-cells, as well
tion of dietary fibers has been specifically linked to enrichment as tight junctions between epithelial cells (composed of the
of butyrate-producing bacteria in human T2D subjects [39] proteins zonula occludens 1, occludin, and claudin) [59] are
and has also been shown to improve glycemic control, de­ all important components of this defense system. Bacterial
crease hyperinsulinemia, and lower plasma lipid concentra­ LPS directly increases tight junction permeability, in a
tions [40]. Taken together, these data illustrate the TLR-dependent manner [59], whereas microbial SCFAs
importance of SCFAs, particularly butyrate, in the develop­ strengthen the intestinal epithelial barrier [26, 60]. Butyrate
ment of T2D. in particular has been shown to upregulate the expression of
claudin-1 [61] and to alter the distribution of occludin and
Mechanisms by Which Gut Microbes Influence zonula occludens 1 [62, 63] in cell studies. SCFAs also increase
mucin production by goblet cells [64], which is important as
Glucose Metabolism and Insulin Resistance
mucin turnover is critical for intestinal barrier integrity, and
Inflammation loss of the mucin-degrading bacteria Akkermansia muciniphi­
Inflammation has emerged as a significant microbial mechan­ la is consistently noted in T2D subjects. Conversely, restoring
ism underlying insulin resistance and the development of A. muciniphila levels normalized insulin resistance in obese
obesity and T2D [reviewed in (41, 42)]. The chronic low- mice [65]. Lastly, both the consumption of specific probiotic
grade inflammation associated with both obesity and T2D is strains [66] and treatment with the prebiotic oligofructose
driven by increased production of inflammatory cytokines in­ (OFS) [67] appear to reduce gut permeability, underscoring
cluding tumor necrosis factor (TNF)-α, the interleukins IL-1 that this is an important mechanism whereby gut microbiota
and IL-6, and nuclear factor kappa-light-chain-enhancer of and their metabolites influence T2D.
4 Journal of the Endocrine Society, 2023, Vol. 7, No. 2

Bile Acids homeostasis described earlier. Metformin also increases the

Bile acids play key roles in regulating glucose homeostasis, abundance of Bifidobacterium bifidum [87] and genus
and gut microbes are involved in modifying primary bile acids Lactobacillus [89] in human subjects, and it has been sug­
synthesized in the liver (cholic acid and chenodeoxycholic gested that the increased abundance of Lactobacillus species
acid) into secondary bile acids (deoxycholate and lithocho­ previously identified in many studies of T2D subjects may in
late) [68]. Specifically, conjugated bile acids (bile salts) can fact be due to confounding effects of metformin [90]. A variety
be deconjugated by ileal microbes, particularly the genera of Bifidobacterium and Lactobacillus species are found in pro­
Lactobacillus, Bifidobacterium, Enterobacter, Bacteroides, biotic supplements [including yogurts (91)] with demon­
and Clostridium, which allows them to avoid being recycled strated antidiabetic effects [92, 93], and increases in these
back to the liver and secreted into the biliary system (entero­ species may contribute to the improvements in glycemic pro­
hepatic circulation) and instead be further metabolized by co­ files seen following metformin treatment [93–95]. Lastly, fecal
lonic microbes into secondary bile acids [34]. Bile acids transfers from metformin-treated human subjects to germ-free
strongly influence glucose homeostasis—for example, cholic mice resulted in improved glucose tolerance [86]. These find­
acid decreases triglyceride levels by reducing expression of ings underscore both that gut microbiota play a key role in me­

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the transcription factor sterol response element binding pro­ diating metformin effects, and that this needs to be taken into
tein 1c, which is an important regulator of lipogenic gene ex­ consideration when assessing the effects of other potential
pression [69], and feeding mice a HFD augmented with cholic therapeutics in T2D subjects taking metformin.
acid increased energy expenditure and prevented insulin
resistance [70]. The effects of primary bile acids are mediated
through farnesoid X receptor, whereas the effects on GLP-1 Receptor Agonists
secondary bile acids are mediated through Takeda While metformin is the preferred front-line therapy of the
G-protein-coupled receptor [34, 71, 72]. Knocking out the American Diabetes Association for treating T2D [96],
farnesoid X receptor gene in mice with genetic and GLP-1 receptor agonists (RAs), such as liraglutide, semaglu­
diet-induced obesity decreased hyperglycemia and hyperinsu­ tide, and dulaglutide, have been used for some time in the
linemia and improved glucose tolerance [73], whereas Takeda treatment of individuals with T2D [97], and more recently
G-protein-coupled receptor promotes GLP-1 secretion and in particular in those with cardiovascular disease or risk fac­
thus glycemic regulation [74]. Interestingly, bile acid seques­ tors [96]. GLP-1 RAs have also been used in the treatment
trants have been tested as potential therapeutics and showed of obesity (liraglutide, semaglutide) [98] and short bowel syn­
benefits in human trials [75–78]. For example, colesevelam drome (exenatide) [99]. In addition to promoting insulin se­
improved glycemic control and reduced low-density lipopro­ cretion, GLP-1 RAs inhibit pancreatic glucagon release,
tein (LDL) cholesterol in adult patients with poorly controlled suppress appetite, and delay gastric emptying and also
T2D on sulfonylurea monotherapy or sulfonylurea in combin­ significantly affect gut microbial composition in both rodent
ation with additional oral antidiabetic agents [77], likely by [100–102] and human [103] studies. For example, liraglutide
increasing GLP-1 secretion [79], and colestimide treatment re­ treatment significantly increased SCFA-producing taxa in a
sulted in significantly decreased LDL cholesterol and in­ diabetic rat model [102], and enriched for genera including
creased A1C levels in Japanese subjects with T2D [75], Allobaculum, Blautia, Desulfovibrio and Lactobacillus while
again likely due to effects on GLP-1 [80]. Lasty, the beneficial reducing the abundance of orders Clostridiales (phylum
effects of Roux-en-Y gastric bypass surgery have been Firmicutes) and Bacteroidales (phylum Bacteroidetes) in
suggested to be mediated via post-surgical increases in mice with induced hyperglycaemia [100]. Increased
A. muciniphila and its effects on bile acids [81], and the Akkermansia abundance has been demonstrated in human
negative effects of the persistent organic pollutants such as T2D subjects treated with liraglutide [103]. In an interesting
2,3,7,8-tetrachlorodibenzofuran on hepatic lipogenesis, study, Tsai et al [104] recently identified gut microbiome sig­
gluconeogenesis, and glycogenolysis are also associated with natures that distinguished responders and nonresponders to
altered microbial bile acid metabolism [82]. GLP-1 RA treatment in T2D subjects. Specifically, responders
had higher abundances of Bacteroides dorei and
Lachnoclostridium species that correlated with glycemic re­
duction, whereas nonresponders had higher abundances of
T2D Medications and the Gut Microbiome
Prevotella copri (which can induce insulin resistance) and
Biguanides Mitsuokella multacida that negatively correlated with glycem­
An important factor to consider in discussing the roles of the ic reduction [104].
gut microbiome in T2D is the potential confounding effects of Similar to GLP-1 RAs, GLP-2 RAs (eg, teduglutide) also re­
diabetes medications. The biguanide metformin suppresses duce insulin sensitivity in HFD-fed mice [105] but are not typ­
hepatic gluconeogenesis via activation of adenosine ically used to treat human subjects with T2D. Interestingly,
monophosphate-activated protein kinase [83] and also enhan­ GLP-1/GLP-2 coagonists have been shown to have greater
ces GLP-1 secretion [84]. It is the most commonly prescribed glycemic effects in a diabetic mouse model when compared
oral medication for T2D [85], and several human [86, 87] and to either liraglutide or teduglutide alone [106], and treatment
mouse [65, 88] studies have shown that the beneficial effects with one of these, the longer-acting GUB09-145, has also been
of metformin are due, at least in part, to effects on gut mi­ shown to affect the gut microbiome, with Lachnospiraceae
crobes. Specifically, metformin increases the abundance of and Clostridiales species specifically correlating with improve­
mucin-degrading A. muciniphila and SCFA-producing genera ments in total cholesterol and glucose tolerance [107].
such as Megasphaera and Blautia [86, 87], resulting in in­ GLP-1R/GIPR dual agonists (“twincretins”) showed bene­
creases in the beneficial effects of mucin and SCFAs on intes­ fits over individual GLP-1 and GIP analogs in rodent models,
tinal barrier integrity, bile acid metabolism, and glucose nonhuman primates, and human subjects [108], and
Journal of the Endocrine Society, 2023, Vol. 7, No. 2 5

following several successful phase 3 clinical trials [reviewed in subjects for subjects with T2D, including improved glucose
(109)], tirzepatide was approved by the Food and Drug metabolism [120, 121]. It has been suggested that these im­
Administration for the treatment of adults with T2D in May provements are, in part, linked to post-surgical changes in
2022 [110]. However, the effects of tirzepatide on the gut mi­ the gut microbiome [122] and resulting changes in SCFA lev­
crobiome remain to be determined. els [119, 123]. Different studies have shown varying results re­
garding which microbial taxa are altered, which may be due to
Sodium-Glucose Cotransporter-2 (SGLT2) Inhibitors differences in the type of surgery performed (eg, Roux-en-Y
gastric bypass vs sleeve gastrectomy) [124] and/or resulting
SGLT2 inhibitors (eg, canagliflozin, dapagliflozin, and empa­
changes in stomach pH [125]. However, consistent findings
gliflozin) have also been approved by the Food and Drug
include increases in the abundance of Sutterella, which has
Administration for the treatment of adults with T2D. These
been linked to glycemic control [120, 121], and of mucin-
drugs block SGLT2 cotransporters in the renal tubes of the
degrading A. muciniphila [81, 120, 121, 126]. As noted earl­
kidneys, thus inhibiting glucose reabsorption and reducing
ier, the beneficial effects of A. muciniphila are thought to re­
glycemia [111]. Few studies have been performed exploring
sult from its effects on bile acids [127, 128]. Consistent with

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the relationship between SGLT2 inhibitors and the micro­
this, a recent study showed that A. muciniphila abundance
biome. A study in diabetic mice showed that dapagliflozin
is decreased in T2D, including lean subjects with newly
treatment improved vascular function and reduced hypergly­
diagnosed T2D, and that its abundance was positively
cemia, with some subtle concomitant changes in the gut mi­
correlated with insulin secretion and levels of fibroblast
crobiome including a reduced Firmicutes:Bacteroidetes ratio
growth factor 15/19 but inversely correlated with serum
and a trend toward increased A. muciniphila, although the au­
3β-chenodeoxycholic acid levels [129]. Further, mice supple­
thors acknowledged that these changes were not definitively
mented with A. muciniphila were protected against
associated with the improved vascular function [112]. A hu­
sucrose-induced impairment of glucose tolerance, and this
man study in which subjects with T2D were treated with da­
protection was linked to increased insulin secretion, increased
pagliflozin or gliclazide for 12 weeks also found no
fibroblast growth factor 15/19 levels, and decreased
significant effects of treatment on the gut microbiome [113].
3β-chenodeoxycholic acid levels [129]. These findings under­
In contrast, a study of diabetic rats treated with dapagliflozin
score the extent of the influences of gut microbes on host me­
found higher abundance of class Deltaproteobacteria and of
tabolism and physiology, as well as the importance of
family Desulfovibrionaceae, as well as a negative association
understanding these influences when studying T2D.
between Desulfovibrionaceae and blood glucose levels
[114]. Taken together, these data suggest that while SGLT2
inhibitors may have some effects on the gut microbiome, Microbiome-Based Interventions and T2D
this may not be a significant mechanism of action for this class Prebiotics
of medications.
In addition to the medications described previously, a variety
of prebiotic and probiotic supplements have been used to treat
Other T2D Medications T2D. Prebiotics promote the growth or action of beneficial
Other oral antidiabetic medications include sulfonylureas and microbes [130] and include fructooligosaccharides or galac­
meglitinides, both of which stimulate the release of insulin tooligosaccharides, lactulose, and nondigestible carbohy­
from pancreatic beta cells, and α-glucosidase inhibitors. No drates (eg, inulin, cellulose, and pectin) [131]. Both inulin
studies exploring the effects of meglitinides on the gut micro­ and the inulin-like fructan OFS have shown promise for ameli­
biome were found. The sulfonylureas Glipizide and orating T2D phenotypes. Dietary supplementation with OFS
Glebclamide appear to have minimal effects on the gut micro­ promotes satiety [132] and has been associated with weight
biome in T2D subjects [115] and a streptozotocin-induced loss and improved glucose regulation in obese and overweight
diabetic rat model [116], respectively, but conclusive state­ subjects [133], and also prevents weight gain and fat
ments cannot be made without larger studies. α-glucosidase mass accumulation in HFD-fed animals [134]. These effects
inhibitors, which include acarbose, voglibose, and miglitol, in­ appear to be mediated by decreases in ghrelin levels and
hibit upper gastrointestinal enzymes, slowing the absorption increases in PYY [133] and GLP-1 [134] and have also
of dietary carbohydrate and reducing post-prandial blood glu­ been linked to reductions in gut permeability [67],
cose concentrations [117]. α-glucosidase inhibitors also have decreases in proinflammatory cytokines, and increases in
anti-arthritic effects, and studies in a mouse model of Bifidobacterium [52]. Similarly, inulin supplementation pro­
collagen-induced arthritis found that both acarose and migli­ tects against HFD-induced obesity, with decreases in food in­
tol treatments affected the gut microbiome, lessening the re­ take, adiposity, liver triglycerides, and leptin levels and also
duction of Firmicutes that occurred after onset of arthritis, improves glucose tolerance [135], effects that were associated
reducing the abundances of genera Lactobacillus, with increased L-cell density and PYY levels [135]. Inulin sup­
Anaeroplasma, Adlercreutzia, and RF39 and improving over­ plementation can also reduce insulin resistance in diabetic
all bacterial diversity and richness [118]. mice, as can dietary supplementation with SCFAs [136]
Lastly, HFDs are associated with increased microbial en­
croachment on the gut epithelium, due to loss of enterocyte
Bariatric Surgery proliferation. Inulin supplementation prevents microbial en­
Bariatric surgeries were originally intended to induce weight croachment and restores epithelial health [137], due to in­
loss by limiting the amount of food the stomach can hold, creased production of IL-22, which pays a key role in
thus reducing calorie intake [119] via restriction and malab­ promoting enterocyte proliferation. It is important to note
sorption. Bariatric surgeries, particularly Roux-en-Y gastric that inulin may have significant gastrointestinal side effects
bypass and sleeve gastrectomy, have also shown benefits for that may mitigate use in some patients.
6 Journal of the Endocrine Society, 2023, Vol. 7, No. 2

Probiotics area of around 30 m2 [146], the small intestine is divided

Probiotics are live microorganisms, predominantly commens­ into the duodenum, jejunum, and ileum [147]. The duode­
al gut bacteria such as Lactobacillus and Bifidobacterium, num, which is the meeting point for chyme from the stomach,
which maintain gut homeostasis and regulate the metabolic enzymes from the pancreas, and bile from the liver, is where
activities of other gut microbes [138]. Numerous studies most digestion occurs and absorption begins [147], after
have now evaluated the efficacy of a variety of probiotic which most absorption occurs in the jejunum, and residual nu­
strains or strain combinations in lowering glucose in T2D, trients, vitamin B12, and bile acids are absorbed in the ileum
many of which were compared in a recent systematic review [147]. The surface area available for absorption is increased
and meta-analysis by Rittiphairoj et al [139]. This meta- by the presence of numerous villi that project into the gut lu­
analysis included 26 trials across the globe that investigated men, with invaginated crypts at the base of the villi [148–150]
different combinations of Lactobacillus species and strains, (see Fig. 2). Although comprised of a single layer of intestinal
Bifidobacterium species and strains, and Streptococcus ther­ epithelial cells, differentiated cell types within villi and crypts
mophilus, delivered in a wide range of formats including yog­ perform specialized functions [148–150]. Columnar entero­
urt, kimchi, fermented milk, bread, honey, powders, capsules, cytes (which cover the villus tips) absorb nutrients and secrete

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and tablets, at doses ranging from 106 to 1019 CFU daily. immunoglobulins, goblet cells secrete the mucus which lines
Despite this variability, the authors found that, overall, probi­ and protects the gut epithelium [57], tuft cells are thought to
otics successfully reduced fasting blood glucose and serum sense luminal contents [148], and Paneth cells (located pri­
cholesterol in T2D subjects and, where reported, also ap­ marily at crypt bases) secrete antimicrobial peptides such as
peared to reduce HbA1c [139]. These effects were most pro­ defensins [58] (see Fig. 2). In addition, a variety of different en­
nounced in subjects who were not already on insulin teroendocrine cells secrete hormones and peptides [57], in­
therapy [139], findings that echo those of previous reviews cluding K cells that secrete the incretin GIP and L cells that
[140, 141]. In a study performed in diabetic db/db mice, ad­ secrete the incretin GLP-1 [151]; the peptide hormone
ministration of a probiotic containing 10 different GLP-2, which induces gut epithelial cell growth and prolifer­
Lactobacillus strains and 4 yeast strains derived from camel’s ation and maintains mucosal integrity and gut barrier func­
milk resulted in decreased fasting blood glucose, glucose area tion [152, 153]; and PYY, which regulates satiety [57],
under the curve and HbA1c, decreased total cholesterol, tri­ among many others (see Fig. 2). Incretins stimulate insulin re­
glycerides and LDL concentrations, and increased secretion lease, and GLP-1 receptor agonists are widely used in T2D
of GLP-1 and insulin, due to upregulation of G protein- treatment [151, 154]. Of note, SCFAs (produced by gut mi­
coupled receptor 43/41 [142], again suggesting that probiotics crobes) modulate the secretion of GLP-1, GLP-2, and PYY
can yield significant benefits in improving T2D phenotypes. by L-cells, as well as the secretion of GIP by K-cells [36, 37,
Mechanistically, the consumption of specific probiotic strains 155]. Taken together, these findings underscore the central
has been shown to help regulate gut membrane integrity and importance of the small intestine in metabolism and the
permeability, and thus prevent endotoxemia and the associ­ need to study its microbial populations directly in developing
ated inflammation [66] and has independently been shown novel, targeted therapies and interventions for T2D (discussed
to decrease levels of pro-inflammatory cytokines while in­ further next).
creasing anti-inflammatory cytokines [143]. Consistent with
this, mucin production and intestinal barrier function were The Importance of Studying the Small Bowel
also improved in the previously described study of db/db Microbiome
mice administered the camel’s milk probiotic, which the au­
thors attributed to increases in the levels of the SCFAs propi­ Despite the importance of the small intestine in metabolism
onate and butyrate, which in turn were likely due to increased and the likely relevance of its microbial populations to meta­
abundances of the SCFA-producing genera Lactobacillus and bolic conditions, including T2D, the majority of gut micro­
Bifidobacterium, as well as C. leptum and Roseburia [142]. biome studies are still performed using stool samples. As
Lastly, Levels of claudin-1 and mucin-2 were also upregulated recently noted in a review by Kastl et al, few studies have an­
in these mice, and circulating levels of bacterial LPS were de­ alyzed the small intestinal microbiome, which is less accessible
creased, further supporting a role for these probiotics in pro­ and requires more invasive sampling procedures [156].
moting gut membrane integrity and preventing bacterial Studies that have been performed in human subjects have uti­
encroachment on the gut epithelium [142]. Of note, while lized techniques such as esophagoduodenogastroscopy and
these findings may be promising, the authors caution against nasoduodenal catheters or have obtained ileal samples during
the use of probiotics as a surrogate for standard care and procedures such as colonoscopy, intestinal resection, or small
note that the desiccation and shelf-handling of many brands bowel transplantation or from ileostomy effluents [156–161].
may diminish their usefulness. While these have provided tremendously valuable insights, as
Kastl et al correctly noted [156], EGD and nasoduodenal sam­
pling are prone to sample contamination with microbes from
Relevance of the Small Bowel in T2D the upper gastrointestinal tract, and colonoscopy and ileos­
While studies of both the stool and salivary microbiomes have tomy samples are prone to contamination with microbes
yielded significant insights and are important particularly in from the lower gastrointestinal tract and skin, respectively.
the identification of potential microbial markers of disease de­ Moreover, while these approaches have been used to study
velopment and progression, the small bowel is central to di­ small intestinal microbes in subjects with inflammatory bowel
gestion, nutrient absorption, and endocrine regulation disease [162, 163], small intestinal bacterial overgrowth,
[144], and our group has shown that its microbial populations short bowel syndrome [164], and irritable bowel syndrome,
differ significantly from those in stool [145]. Typically 3 to 5 and to characterize small intestinal microbial populations
meters in length in an adult and with an absorptive surface and their metabolites [165, 166], to date, small bowel
Journal of the Endocrine Society, 2023, Vol. 7, No. 2 7

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Figure 2. Schematic showing specialized cell types and their products in the small bowel epithelium.

microbial populations have not been studied in subjects with obesity and T2D has little relevance for the small bowel, il­
metabolic conditions such as T2D. lustrating the importance of studying the small bowel direct­
To explore and characterize the microbial populations of ly to find metabolically relevant biomarkers and therapeutic
the human small bowel and their roles in health and disease, targets.
we created the REIMAGINE (Revealing the Entire Intestinal Since these first studies, we have utilized these validated
Microbiota and its Associations with the Genetic, techniques to explore the roles and contributions of changes
Immunologic, and Neuroendocrine Ecosystem) study [167]. in small bowel microbial populations in a variety of condi­
We developed a new catheter design to overcome cross- tions, including small intestinal bacterial overgrowth [170],
contamination with microbes from the mouth and use of proton pump inhibitors [171], age and the ageing pro­
stomach, which plagued traditional open aspiration catheters cess [172], menopause and the use of hormone therapy [173],
[168, 169], and as small intestinal samples have high viscosity, and smoking [174]. These studies have consistently demon­
low microbial biomass, and small sample volumes, we also strated that overabundance of Proteobacterial taxa, particu­
developed improved techniques for sample processing, DNA larly family Enterobacteriaceae and the disruptor genera
recovery and library preparation prior to sequencing, using [175] Escherichia-Shigella and Klebsiella, are associated
duodenal samples [167]. The results indicated that the num­ with loss of microbial diversity and negative effects on the
ber of microbes in the small bowel was significantly higher duodenal microbiome, as are overgrowth of family
than previously thought and also revealed expanded Lactobacillaceae and the genus Lactobacillus, which is an­
microbiome-related pathways [167], suggesting a greater other disruptor in the small bowel [175]. In contrast, families
range of microbial functions than previously thought. Prevotellaceae, Neisseriaceae, and Porphyromonadaceae
Using these validated techniques, we then explored the micro­ are consistently associated with increased duodenal micro­
bial populations of the small bowel (duodenum) and compared bial diversity [173, 174], suggesting that they have positive
them to stool. We found significant differences between their effects in the small bowel. Our next steps will include apply­
respective microbiomes, even at the phylum level. The stool mi­ ing these novel techniques to explore the roles of small bow­
crobiome is characterized by high relative abundance of el microbes and their metabolites in metabolic conditions
Bacteroidetes and Firmicutes, but in the small bowel Firmicutes such as obesity and T2D, which will hopefully allow us to
and Proteobacteria are the most abundant, and Bacteroidetes is identify novel, and successful, microbiome-based therapeut­
far less abundant [145]. Moreover, in the duodenum, phylum ic targets.
Firmicutes was primarily comprised of lactic acid bacteria,
particularly families Streptococcaceae, Lactobacillaceae and
Carnobacteriaceae, and family Veillonellaceae, whereas in stool, Clinical Perspectives and Future Directions
Firmicutes was dominated by families Ruminococcaceae, The impact of the gut microbiome on human disease is un­
Lachnospiraceae, and Christensenellaceae (which is completely deniable. Current research is exploring the specific mecha­
absent from the duodenum) [145] (see Fig. 3). There were also nisms this microcosm has on the human host in a variety of
differences in Proteobacteria composition, with families conditions. Diabetes is a complex and multifactorial disease.
Neisseriaceae, Pasteurellaceae, and Enterobacteriaceae predom­ The role of the microbiome is likely variable depending on
inating in the duodenum and class Deltaproteobacteria predom­ other host conditions and genetics. Having stated this, there
inating in stool [145] (see Fig. 3). Clearly, the Firmicutes: is most probably a subgroup of patients with diabetes (and
Bacteroidetes ratio that is much quoted as being relevant to prediabetes) who have a more defined relationship with
8 Journal of the Endocrine Society, 2023, Vol. 7, No. 2

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Figure 3. Relative abundance of the major families in the duodenum, jejunum, furthest distance reached using endoscopy (FD), and stool, in the same
subjects.

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