The document summarizes the complex relationship between the gut microbiome and type 2 diabetes. It discusses how the gut microbiota is composed of various microbes that impact human health throughout life. Early life events like cesarean delivery and antibiotic use can negatively impact the microbiota. Studies show the gut microbiome affects overall health by impacting organ systems. Certain microbes are negatively associated with type 2 diabetes while others are positively associated. The gut microbiota interacts with food components and affects permeability, insulin sensitivity, and metabolism. Imbalances in the gut microbiota can contribute to type 2 diabetes by impacting the immune system and levels of various cells and cytokines.

1. The microbiota comprises various microbes in the body, including bacteria, viruses, fungi,
and parasites. The majority of the microbiota are found in the colon, but they also play critical
roles in our body's defense mechanisms in the skin, mouth cavity, small intestine, and vagina.
Bacteroidetes and Firmicutes, including the genera Lactobacillus, Clostridium, Bacillus,
Ruminococcus (of the first phylum), Enterococcus, Prevotella (of the second phylum), and
Bacteroides, are the major phyla in the intestine (representing over 90% of the population).1
Microorganisms begin to colonize the body at birth and alter over the first year of life,
impacting human health for the duration of life. Early life occurrences like cesarean delivery,
medication exposure, and artificial milk feeding can deleteriously impact microbiota. The
maternal and neonatal gut microbiota appears to be influenced by cesarean delivery and
antibiotic medication provided to a mother. Additionally, if a mother received antibiotic
treatment during pregnancy or breastfeeding, the amount of Bifidobacterium and Lactobacillus in
breast milk declines. The gut microbiota can be changed by various events, not just in newborns
but also in young children. Adults may also experience changes in the makeup and functionality
of their microbiota due to environmental influences, medical situations, or lifestyle choices.2,3
Studies show that the gut microbiome affects overall health and can impact organ function,
including the cardiovascular9
, neurological, hepatic, and renal systems. Larsent et al. conducted a
study and found that there is a correlation between the ratio of Bacteroidetes to Firmicutes and
the Bacteroides-Prevotella group to Clostridium coccoides-Eubacterium rectale group with
serum glucose levels. They also discovered that diabetic individuals have a decrease in butyrate-
producing bacteria such as Eubacterium rectale, Faecalibacterium prausnitzi, Roseburia
intestinalis, and Clostridiales spp, and an increase in Lactobacillus species. This increase in
Lactobacillus species can have a pro-inflammatory effect on diabetic individuals due to
numerous pathobionts within proteobacteria. In addition, the V4V5 region of 16S rRNA genes
revealed a significant decrease in butyrate-producing bacteria such as Akkermansia and
Bifidobacterium and an abundance of Dorea spp. Researchers also found that Anaerostipes,
Acidaminococcus Aggregatibacter, Dorea, Faecalibacterium, Desulfovibrio, and Blautia gut
concentrations are related to diabetes. Bacteroides, Bifidobacterium, Faecalibacterium,
Roseburia, and Akkermansia were negatively associated with Type 2 diabetes mellitus (T2DM),
while Ruminococcus, Blautia, and Fusobacterium were positively associated with diabetes.
Fusobacterium is a phylum that contributes to the adhesion and inflammation of host epithelial

2. cells. Research suggests that a decrease in Akkermansia muciniphila can be used as an early
biomarker for diabetes detection. Patients with T2DM have lower levels of Bifidobacterium spp.
compared to control patients, high Actinobacteria and Firmicutes levels are positively correlated
with fasting glucose levels. On the other hand, Proteobacteria and Bacteroidetes have a negative
relationship. Bacteroides and other commensal bacteria can change intestinal mucus and
glycocalyx, which affects intestinal permeability. Bifidobacterium spp. has anti-inflammatory
properties and safeguards the epithelial barrier’s tight junctions.3,4,5
Based on a cross-sectional study, individuals with a healthier diet who are at risk for
developing diabetes have lower levels of Prevotella and higher levels of Faecalibacterium
prausnitzii. The study also found an increase in the number of lactic acid bacteria. These findings
indicate that if patients with healthy diets can promote the growth of beneficial bacteria, it may
help protect an obese population with advanced age and prediabetes from developing type 2
diabetes. Functional correlation analysis revealed a significant correlation between altered
Bacteroidaceae and Verrucomicrobiaceae gut levels and alterations in fecal metabolites, and
obese T2DM patients lack the Verrucomicrobia phylum. This microorganism helps improve
insulin sensitivity and has anti-inflammatory effects on the gut. T2DM Japanese subjects had
decreased propionate and fecal butyrate levels, increased faecal Bifidobacterium spp. and
Lactobacillales populations, and decreased faecal Bacteroides spp. populations. Additionally, the
level of Lactobacillales species was negatively correlated with protein intake, whereas the level
of Bifidobacterium spp. was negatively correlated with carbohydrate intake. Others discovered
that T2DM-obese subjects have lower amounts of L. acidophilus, L. reuteri, and L. plantarum
than controls.6
The microbiota in the gut has an impact on inflammation, interacts with food components,
and affects the permeability of the gut, as well as insulin sensitivity, glucose and lipid
metabolism, and overall energy balance in the mammalian host. There are several metabolites
produced by the gut microbiota, including short-chain fatty acids (SCFAs), amino acids,
trimethylamine N-oxide (TMAO), bile acids, and indole propionic acids, that are involved in
regulating the metabolism and gut health of the host. These metabolites are linked to diseases
such as diabetes, and the gut microbiota plays a significant role in moderating and affecting their
effects.3,6

3. The imbalance of the immune system is a factor that contributes to the dysbiosis of gut
microbiota and the onset of type 2 diabetes. The gut microbiota and its byproducts play a crucial
role in maintaining the balance and functioning of the T helper 17/regulatory T cells (Th17/Treg)
and the gut-associated lymphoid tissues (GALT). The gut microbiota is crucial in distinguishing
between self and non-self organisms and promoting the production of innate hematolymphoid
cells (ILC1, -2, and -3), natural killer (NK) cells, cytotoxic and noncytotoxic cells, as well as
helper lymphoid cells. By stimulating the immune system to produce IL-17, IL-12, and
immunoglobulin A (IgA), metabolites such as tryptophan and galactosylceramide prevent
specific microorganisms from entering the bloodstream. The ILCs are essential components of
the natural immune system that produce regulatory and pro-inflammatory cytokines for tissue
repair, immunity, and inflammation. ILC2s may help regulate glucose levels and prevent insulin
resistance, whereas high levels of ILC1s are associated with an increased risk of developing
diabetes. Research shows that individuals with type 2 diabetes have elevated levels of ILCs1 in
their bloodstream and adipose tissue.6,7
The intestinal Th17 cells play a crucial role in controlling glucose homeostasis and
adipogenesis, regulating immune tolerance, and developing insulin resistance by reducing
intestinal ROR γ+ and IL-17-producing CD4+ T cells. Studies have shown that the gut
microbiota and its products can regulate the balance of Th1/Th2 cell functions in the intestine.
The production of a CBir1 antigen by a commensal A4 Lachnospiraceae bacteria, induced by
dendritic cell TGF production, inhibits intestinal Th2-cell responses. Bacteroides fragilis, on the
other hand, produce polysaccharide A, which stimulates the production of proinflammatory
cytokines like p40 and IL-12, promoting Th1 activation. IL-12 is a crucial immunoregulatory
factor in T2DM and its complications, as it attaches to its pancreatic-cell receptors through the
STAT4 signaling pathway, triggering proinflammatory cytokines and inducing cell apoptosis.
Obese rodents with type 2 diabetes experience increased angiogenesis when IL-12 is disrupted.
This occurs through a mechanism involving endothelial nitric oxide synthase, Akt, vascular
endothelial growth factor receptor 2, oxidative stress, and inflammation.6,7,8

4. Figure 1. The complex relationship between gut dysbiosis and type 2 diabetes.3
Certain microbes and microbial products, particularly lipopolysaccharides (LPS), induce
low-grade inflammation and metabolic endotoxemia, while others stimulate anti-inflammatory
chemokines and cytokines. IL-10 induction by Bacteroides fragilis, Lactobacillus casei,
Lactobacillus plantarum, Akkermansia muciniphila, and Roseburia intestinalis may contribute to
the improvement of glucose metabolism because overexpression of this cytokine in muscle
protects against age-associated insulin resistance. Moreover, R. intestinalis can increase the
production of IL-22, an anti-inflammatory cytokine that restores insulin sensitivity and alleviates
diabetes. Additionally, it can stimulate the differentiation of T regulatory cells, induce TGF-b,
and suppress intestinal inflammation. Similarly, Bacteroides the-taiotaomicron stimulates the
expression of genes in T regulatory cells.1-4,6
To prevent inflammation, beneficial microorganisms inhibit pro-inflammatory cytokines
and chemokines. Diverse Lactobacillus species (L. paracasei, L. plantarum, L. casei) can inhibit
the production of IL-1ẞ, IL-8, MCP-1, ICAM-1, and CRP, CD36, B. fragilis, and L. paracasei
both inhibit the expression of IL-6. Lactobacillus, Bacteroides, and Akkermansia inhibit TNF-a.
L. paracasei and anti-inflammatory molecules from F. prausnitzii inhibit NF-kB activity.
Faecalibacterium and Roseburia both produce butyrate, and it is known to inhibit NF-kB activity.
Roseburia intestinalis and Lactobacillus casei inhibit IFN-γ production, whereas Roseburia

5. intestinalis inhibits the production of IL-17. Bacteroides thetaiotaomicron inhibits mice's Th1,
Th2, and Th17 cytokine production. Pathobionts such as Ruminococcus gnavus and
Fusobacterium nucleatum can increase the number of inflammatory cytokines in other
inflammatory disorders.7
Figure 2. Influence of microbiota on glucose homeostasis.7
One of the defining characteristics of T2DM in humans is increased intestinal permeability.
This leads to the movement of microbial products from the intestines into the bloodstream,
causing metabolic endotoxemia. However, studies have shown that two specific types of
bacteria, Bacteroides vulgatus and B. dorei, may benefit individuals with T2DM. These bacteria
can upregulate the expression of tight junction genes in the colon, resulting in a decrease in gut
permeability, a reduction in LPS production, and an improvement in endotoxemia in a mouse
model. Another bacterium, Akkermansia muciniphila, can improve intestinal tight junctions by
activating AMPK in the epithelium through its extracellular vesicles. Its outer membrane protein,
Amuc 1100, can increase the expression of occludin and tight junction protein-1 (Tjp-1), thereby
improving the integrity of the gastrointestinal tract. Additionally, Amuc 1100 inhibits
cannabinoid receptor type 1 (CB1) in the gut, thus reducing gut permeability and systemic LPS
concentrations. While the specific bacterial component of Faecalibacte-rum prausnitzii has not
been identified, studies have shown that the supernatant of the cultured bacterium can improve
the expression of tight junction proteins, improving intestinal barrier functions in a model of

6. colitis. Finally, Faecalibacterium and Roseburia produced butyrate can potentially decrease gut
permeability through PPAR-g pathways and serotonin transporters.8
In addition to impacting glucose homeostasis and insulin resistance in major metabolic
organs such as the muscle, liver, and fat, gut microbiota may influence T2DM by regulating the
digestion of sugars and synthesizing gut hormones that regulate this process. Bifidobacterium
lactis can stimulate glycogen production and inhibit gene expression in hepatic gluconeogenesis.
According to the same study, B. lactis improved the translocation of glucose transporter-4
(GLUT4) and insulin-stimulated glucose uptake. Additionally, Lactobacillus gasseri BNR17
raises GLUT-4 expression in muscle, indicating a possible anti-diabetes action. Akkermansia
muciniphila and Lactobacillus plantarum inhibit the production of hepatic flavin monooxygenase
3 (Fmo3), a critical enzyme of xenobiotic metabolism whose knockdown prevents
hyperglycemia and hyperlipidemia in rats with insulin resistance. Lactobacillus casei can reduce
insulin resistance by elevating the mRNA levels of insulin receptor substrate 2 (IRS2), Akt2,
phosphatidylinositol-3-kinase (PI3K), AMPK, and glycogen production in the liver. The action
of this specific bacterium extends beyond the liver. Additionally, L. casei decreases
hyperglycemia by a bile acid-chloride exchange process involving the overexpression of
numerous genes, including ClC1-7, GlyRa1, SLC26A3, SLC26A6, GABAAa1, Bestrophin-3,
and CFTR. In addition, it decreases insulin-degrading enzyme (IDE) in caco-2 cells and insulin-
like growth factor binding proteins-3 (IGFBP-3) in white adipose tissue. Another lactobacillus
species, L. rhamnosus, raises adiponectin levels in epididymal fat, increasing insulin sensitivity.9
Increasing fatty acid oxidation and energy expenditure while decreasing fatty acid
synthesis alleviates obesity and type 2 diabetes. It has been reported that Bacteroides acidifies,
Akkermansia muciniphila, Lactobacillus gasseri, and SCFAs promote adipose tissue fatty acid
oxidation. In addition, Through the TGR5-PPAR-a pathway, Bacteroides acidifaciens increases
the oxidation of fatty acids in adipose tissue. Similarly, by blocking the muscle's histone
deacetylation mechanism, butyrate can boost fatty acid oxidation and thermogenesis, partially
increasing energy expenditure by increasing mitochondrial power functions. Butyrate and two
other SCFAs, propionate and acetate, decrease the expression of PPAR-g in the liver and adipose
tissue, thereby increasing fatty acid oxidation. It has been demonstrated that Lactobacillus
gasseri reduces obesity by enhancing heavy acid oxidation genes and decreasing fatty acid
synthesis genes. Malondialdehyde, a marker of oxidative damage to lipids, is decreased in

7. diabetic rodents by Lactobacillus casei and Akkermansia muciniphila. Thus, microbiota members
with beneficial effects on T2DM modulate the host's fatty acid metabolism and associated energy
expenditure, alleviating obesity and T2DM.7,10
SCFAs are absorbed in the intestine, providing energy (particularly butyrate) to colonic
epithelial cells while the remainder enters the portal venous system; butyrate also significantly
reduces intestinal permeability. The bacteria in our colon transform complex carbohydrates into
simpler forms, which are then broken down further into SCFAs and gases through fermentation.
SCFAs have a variety of benefits, including the stimulation of protective peptides, phagocytes
cytokines, and chemokines. They also regulate sugar and fat metabolism by activating receptors
in various types of cells, including those in the pancreas and brain. SCFAs are the main source of
energy for cells in the colon and intestine, and they can also help reduce inflammation and
oxidative stress in the gut. Certain peptides, proteins, and fibers that are not digested in the upper
digestive tract are metabolized by bacteria in the colon, producing butyric, propionic, and acetic
acid as intermediate products. SCFAs are then used by colon cells or released into the
bloodstream, affecting the host's health. The activation of certain receptors by SCFAs leads to the
secretion of hormones that promote insulin sensitivity and pancreatic cell proliferation, as well as
increased satiety and glucose homeostasis. The gut microbiota mediates this process.11
Bile acids (BAs) are typically synthesized from cholesterol in the hepatic parenchyma as
chenodeoxycholic acid (CDCA) and cholic acid via a classical pathway. In contrast, the
alternative route generates CDCA primarily. Under the influence of Firmicutes, the intestinal
microbiota converts primary BAs into secondary BAs by dihydroxylation, deconjugation,
dehydrogenation, and epimerization. Nuclear farnesoid X receptors (FXR) are stimulated by
primary BAs, altering the metabolism of glucose. Secondary bile acids can attach to a receptor
called GPBAR 1/TGR5, which helps regulate glucose levels and maintain glucose balance.
Uncontrolled T2DM individuals exhibit elevated BAs in addition to elevated deoxycholic acid
(DCA) and decreased CDCA. Via binding and activating nuclear transcription factors such as
FXR in the gut and liver, their ability to mediate energy metabolism is enhanced, and
manipulating BAs via modification of the gut microbiota could improve glucose management
and prevention of metabolic memory in early-onset T2DM patients.10,11,12,13
Amines and polyamines are fermented products of diverse intestinal bacteria.
Trimethylamine oxide is produced when trimethylamine is oxidized by flavin monooxygenase 3

8. (FMO3) in the liver (TMAO). TMAO has atherogenic properties. Choline, phosphatidylcholine,
carnitine, c-butyrobetaine, betaine, crotonobetaine, and glycerophosphocholine are the original
compounds that, with the assistance of gut bacteria, are converted into TMA via hepatic FMO.
Choline is a crucial nutrient that plays a vital role in lipid metabolism and the production of very
low-density lipoproteins (VLDL) in the liver. TMAO plays a critical role in the development and
continuation of T2DM and increases the risk of other metabolic syndromes significantly..12,13
Gut microbiota degrades approximately 10 g of proteins daily into some examples of
metabolites, including amines, phenols, thiols, ammonium, and indoles. Intestinal microbiota
produced Indole-3-propionic acid or 3-Indolepropionic acid (IPA) endogenously from
tryptophan, taken up by the gut lining and then transported into the bloodstream. In addition to
indoxyl sulfate and indoleacetic acid, the degradation of tryptophan produces indoleacetic acid
and indoxyl sulfate. Plasma IPA may be a potential biomarker for diabetes due to its association
with the development of T2DM and its protective effects on ẞ-cell function.6,7,11
BCAAs are essential components of the glucose and protein metabolic pathways.
Dysbiosis affects the breakdown of BCAA, oxidative stress response promotion, and enhanced
membrane cell transport of sugars and BCAA. BCAAs are primarily produced by Bacteroides
spp—vulgatus and Prevotellacopri. According to data, A short-term reduction of BCAAs in one's
diet can improve the metabolism of white adipose tissue and the composition of intestinal
microbiota while also decreasing postprandial insulin secretion..3
The composition of the gut facilitates the production of hydrogen sulfide (H2S) from
fermented proteins. Recent research has highlighted the effects of H2S and dysbiosis on the
signaling and function of organisms. Adipose tissue lipolysis, insulin sensitivity, inflammation,
and the production of adipokines are mediated by H2S. Additionally, it can stimulate
gluconeogenesis and glycogenolysis in the liver and inhibit glucose use and storage. High-fat
diets and insulin resistance influence the H2S configuration in adipose and hepatic tissue, which
is highly diet-dependent. Additionally, pancreatic cells express these enzymes that secrete
insulin, and by activating ATP-sensitive K+ channels, it is possible for them to inhibit insulin
secretion, thereby exerting pro-apoptotic or anti-apoptotic effects on cells. Excessive pancreatic
H2S could promote the development of T2DM.3
It is common knowledge that antibiotics, non-antibiotic medicines, and anti-diabetic
medications can modify microbiota and ameliorate diabetes. The baseline microbiota can affect

9. the pharmacokinetics and pharmacodynamics of numerous drugs and chemicals positively and
negatively. However, more studies have yet to investigate how modifying gut microbiota
(through prebiotics and/or probiotics) affects anti-diabetic drugs efficacy. A recent study
investigated the impact of Bifidobacterium animalis ssp: lactis 420, polydextrose, and their
combination with sitagliptin on diabetic rats. Several T2DM parameters were effectively reduced
by the combination of pre- and probiotics and sitagliptin. Combining prebiotic polysaccharides
with the anti-diabetic medicines metformin and sitagliptin lowered hyperglycemia and obesity in
Zucker diabetic rats compared to using the treatments alone. In a separate investigation, diabetic
mice caused by streptozocin were given prebiotics plus metformin. Compared to metformin or
MOS alone, the combination therapy enhanced glucose tolerance, glucose at fasting, and insulin
resistance.7

10. Daftar Pustaka
1. Jayaswal RP, Vijayasimha M, Prabhakar PK. Gut microbiota and diabetes mellitus—
An interlinkage. Asian J. Pharm. Clin. Res. 2018;11:13-6.
2. Craciun CI, Neag MA, Catinean A, Mitre AO, Rusu A, Bala C, Roman G, Buzoianu
AD, Muntean DM, Craciun AE. The relationships between gut microbiota and
diabetes mellitus, and treatments for diabetes mellitus. Biomedicines. 2022 Jan
28;10(2):308.
3. Tanase DM, Gosav EM, Neculae E, Costea CF, Ciocoiu M, Hurjui LL, Tarniceriu
CC, Maranduca MA, Lacatusu CM, Floria M, Serban IL. Role of gut microbiota on
onset and progression of microvascular complications of type 2 diabetes (T2DM).
Nutrients. 2020 Dec 2;12(12):3719.
4. Munoz-Garach A, Diaz-Perdigones C, Tinahones FJ. Gut microbiota and type 2
diabetes mellitus. Endocrinología y Nutrición (English Edition). 2016 Dec
1;63(10):560-8.
5. Lau WL, Tran T, Rhee CM, Kalantar-Zadeh K, Vaziri ND. Diabetes and the gut
microbiome. InSeminars in nephrology 2021 Mar 1 (Vol. 41, No. 2, pp. 104-113).
WB Saunders.
6. Gurung M, Li Z, You H, Rodrigues R, Jump DB, Morgun A, Shulzhenko N. Role of
gut microbiota in type 2 diabetes pathophysiology. EBioMedicine. 2020 Jan 1;51.
7. Cunningham AL, Stephens JW, Harris DA. Gut microbiota influence in type 2
diabetes mellitus (T2DM). Gut Pathogens. 2021 Dec;13(1):1-3.
8. Zhang L, Chu J, Hao W, Zhang J, Li H, Yang C, Yang J, Chen X, Wang H. Gut
microbiota and type 2 diabetes mellitus: Association, mechanism, and translational
applications. Mediators of Inflammation. 2021 Aug 17;2021.
9. Snelson M, de Pasquale C, Ekinci EI, Coughlan MT. Gut microbiome, prebiotics,
intestinal permeability, and diabetes complications. Best Practice & Research Clinical
Endocrinology & Metabolism. 2021 May 1;35(3):101507.
10. Yang G, Wei J, Liu P, Zhang Q, Tian Y, Hou G, Meng L, Xin Y, Jiang X. Role of the
gut microbiota in type 2 diabetes and related diseases. Metabolism. 2021 Apr
1;117:154712.
11. Chen Z, Radjabzadeh D, Chen L, Kurilshikov A, Kavousi M, Ahmadizar F, Ikram
MA, Uitterlinden AG, Zhernakova A, Fu J, Kraaij R. Association of insulin resistance
and type 2 diabetes with gut microbial diversity: a microbiome-wide analysis from
population studies. JAMA Network Open. 2021 Jul 1;4(7):e2118811-.
12. Bajinka O, Tan Y, Darboe A, Ighaede-Edwards IG, Abdelhalim KA. The gut
microbiota pathway mechanisms of diabetes. AMB Express. 2023 Dec;13(1):1-0.
13. Chen T, Zhang Y, Zhang Y, Shan C, Zhang Y, Fang K, Xia Y, Shi Z. Relationships
between gut microbiota, plasma glucose, and gestational diabetes mellitus. Journal of
diabetes investigation. 2021 Apr;12(4):641-50.