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Life Sciences 273 (2021) 119311
Available online 1 March 2021
0024-3205/© 2021 Elsevier Inc. All rights reserved.
Unravelling the involvement of gut microbiota in type 2 diabetes mellitus 
Arpita Arora a,1, Tapan Behl a,*,1, Aayush Sehgal a, Sukhbir Singh a, Neelam Sharma a, 
Saurabh Bhatia b,c, Eduardo Sobarzo-Sanchez d,e, Simona Bungau f 
a Chitkara College of Pharmacy, Chitkara University, Punjab, India 
b Amity Institute of Pharmacy, Amity University, Haryana, India 
c Natural and Medical Sciences Research Center, University of Nizwa, Nizwa, Oman 
d Instituto de investigacion y Postgrado, Facultad de Ciencias de la Salud, Universidad Central de Chile, Santiago, Chile 
e Department of Organic Chemistry, Faculty of Pharmacy, University of Santiago de Compostela, Santiago de Compostela, Spain 
f Department of Pharmacy, Faculty of Pharmacy, University of Oradea, Romania 
A R T I C L E I N F O 
Keywords: 
Type 2 diabetes mellitus 
Gut microbiome 
Microbiota dysfunction 
Metabolic disorder 
A B S T R A C T 
Type 2 diabetes mellitus is the most prevalent metabolic disorder characterized by hyperglycemia, hyperlipid-
emia as well as insulin resistance and is affecting the lives of a huge population across the globe. Genetic mu-
tations, obesity and lack of physical activity constitute the possible factors that can lead to onset and progression 
of this disorder. However, there is another major factor that can be the root cause of type 2 diabetes mellitus and 
that is an imbalance in the microorganisms that inhabit the gut. The gut microbiome is a vital component that 
needs to be given significant attention because any “dysbiosis” in the colonic microorganisms can transform the 
host from a state of health to a state of disease. This transformation is quite obvious since the gut barrier 
integrity, host metabolism such as sensitivity to insulin and maintaining blood glucose level are carried out by 
the tiny organisms inhabiting our intestine. In fact, the normal functioning of the human body is accredited to the 
microbes, particularly the bacteria, because they generate their metabolites that communicate with host cells and 
maintain normal physiology. Giving importance to gut health is, therefore, necessary to prevent metabolic 
diseases that can be maintained by the intake of prebiotics, probiotics, synbiotics along with healthy diet. The 
tiny microorganisms in the gut that keep our body free of disorders such as type 2 diabetes mellitus need to be in 
a state of ‘eubiosis’, else the consequences of disturbance in gut microbes can progress to serious complications in 
the host. 
1. Introduction 
Defects of metabolism include disorders of the cardiovascular sys-
tem, diabetes mellitus, particularly type 2 diabetes and various other 
lifestyle disorders including obesity, hypertension, increased levels of 
glucose and low-density lipoproteins or decreased levels of high-density 
lipoproteins [1]. Type 2 diabetes mellitus is the most common metabolic 
disorder affecting majority of the population across the globe. The In-
ternational Diabetes Federation states that the number of cases of dia-
betes will increase to 592 million cases and 175 million cases eluding 
diagnosis by 2035 [2,3]. Though genetic factors, obesity, lack of phys-
ical activity, fetal programming are the predisposing factors for diabetes 
mellitus [4], dysbiosis in the gut microbiota is considered to be a novel 
hallmark in the pathogenesis involving diabetes mellitus. The gut 
microorganisms regulate the impact of sedentary lifestyle leading to the 
development of diabetes. The gut houses microorganisms in trillions 
that weigh approximately one and a half kilograms and hence, can be 
labeled as a ‘microbial organ’. Out of the approximately 1000 species of 
bacteria in the gut, about 90% [5] belong to the phyla bacteroidetes 
(that include gram negative bacteria) as well as firmicutes (that include 
gram positive bacteria) [6]. About one hundred and sixty species of 
bacteria are present in a single person and various genes in microor-
ganisms are important for the performance of gut microbiota functions 
[5]. The ecosystem of microorganisms protects the human host from the 
disease causing microorganisms by acting as a competitor for nutrition 
as well as space, ameliorating immune system, maintenance of integrity 
of intestine as well as biotransformation of drugs [7–10]. Not only this, 
the gut microbes maintain good health, helping in the synthesis of 
* Corresponding author. 
E-mail address: tapan.behl@chitkara.edu.in (T. Behl). 
1 Authors with equal contributions. 
Contents lists available at ScienceDirect 
Life Sciences 
journal homepage: www.elsevier.com/locate/lifescie 
https://doi.org/10.1016/j.lfs.2021.119311 
Received 31 January 2021; Received in revised form 23 February 2021; Accepted 25 February 2021 
mailto:tapan.behl@chitkara.edu.in
www.sciencedirect.com/science/journal/00243205
https://www.elsevier.com/locate/lifescie
https://doi.org/10.1016/j.lfs.2021.119311
https://doi.org/10.1016/j.lfs.2021.119311
https://doi.org/10.1016/j.lfs.2021.119311
http://crossmark.crossref.org/dialog/?doi=10.1016/j.lfs.2021.119311&domain=pdf
Life Sciences 273 (2021) 119311
2
hormones and vitamins, absorption of nutrients and neurological char-
acters [11,12]. They also help in the biological synthesis of amino acids, 
isoprenoids, vitamins and glycans [13,14]. Any dysbiosis in the gut 
micro flora can alter the functions of the barrier of intestine as well as 
the metabolism which in one way or the other leads to the advancement 
of insulin resistance in type 2 diabetes mellitus. Various drugs such as 
nonsteroidal anti-inflammatory drugs and antibiotics can alter the 
constitution of gut bacteria progressing to altered physiological func-
tions [15]. Metabolic disorders such as type 2 diabetes mellitus can be 
treated by probiotics, such as Bifidobacterium and Lactobacillus, which 
are the live and good bacteria and keep our gut healthy [16,17]. Also, 
the use of prebiotics is in since they induce the growth of favorable 
microorganisms [18]. No doubt the gut micro flora performs numerous 
important functions but any discrepancy in the microbiota can progress 
to various disorders such as colon-rectal cancer, inflammatory bowel 
disease, Crohn’s disease [19–23]. Alteration in the gut micro flora is also 
related to metabolic disorders such as obesity, diabetes as well as food 
allergy [24–27]. Novel techniques such as 16S rRNA, gradient gel 
electrophoresis based on the denaturing of polymerase chain reaction, 
meta-genomics, meta-transcriptomics, microarrays have helped to 
explore the widespread species of microorganisms inhabiting the gut 
[28,29]. Probiotics, antibiotics, prebiotics, fecal micro-biota trans-
plantation and synbiotics help improve the flora of the gut and this 
perspective for the treatment of type 2 diabetes mellitus is worth to be 
pondered upon [30,31]. 
Here, we review diabetes mellitus, the metabolites connecting gut 
microbiome and diabetes mellitus, therapeutic role of micro flora in 
diabetic patients as well as the future perspectives of gut microbiome 
eubiosis. 
1.1. Type 2 diabetes mellitus: the most common metabolic disorder 
Type 2 diabetes mellitus is the most common metabolic disorder and 
it is not a novel disorder. The first case was reported in Egypt about three 
thousand years back [32] and the epidemiological data (2017) states 
that about 425 million people (age: 20 to 79) have diabetes and this 
number will be elevated to 629 million eventually [33]. Type 2 diabetes 
mellitus is also known as non-insulin-dependent diabetes mellitus and 
the primary symptoms include insulin resistance, hyperglycemia as well 
as deficiency of insulin [34]. People suffering from this disorder are 
prone to various complications that can be fatal from them. This is 
because this is a very common disorder which develops gradually and is 
diagnosed at a later stage particularlyin countries like Africa which are 
not well developed [35]. The disorder mainly arises because of alter-
ations in the gene sequence or an imbalance in the lifestyle [36] such as 
lack of physical exercise, smoking as well as alcohol intake [37]. The 
major contributor is obesity which is responsible for about 55% of the 
diabetic cases [38], especially in teenagers as well as children since 
obesity in the young is rising at an alarming rate [39]. A major factor for 
the development of type 2 diabetes mellitus is the toxins present in the 
environment and this is evident from the fact that the urine of diabetic 
patients contained bis-phenol that is a component of plastic [40]. Type 2 
diabetes mellitus can be inherited particularly if the relatives of first 
degree suffer from the disorder. Inheritance of the disorder in the twins 
originating from a single egg (monozygotic) is 100% as well as 25% of 
those who have the disorder share a family history of the same [41]. The 
genes such as SLC30A8, KCNJ11, IGF2BP2, TCF7L2 among others are 
linked to the onset of type 2 diabetes mellitus [42]. Also, since obesity 
can be transferred from parent to progeny, it forms an important risk 
factor for developing the disorder [43]. Moreover, high blood pressure, 
obesity, increased levels of cholesterol; that can be collectively called as 
metabolic syndrome or Reaven’s syndrome or syndrome X can initiate 
the disorder and even aggravate it [44] and certain other conditions 
such as tumor of adrenal gland, excessive production of thyroid hor-
mones, carcinoma, intake of certain drugs [45], fat rich diet, aging as 
well as sedentary way of life do add to the risk factors in case of type 2 
diabetes [46]. The pathophysiology related to the disorder mainly re-
volves around reduced sensitivity to insulin also termed as ‘insulin 
resistance’ as well as the impairment of beta cells of the pancreas 
[47,48] that leads to the impairment of transport of sugar to the skeletal 
muscle, liver as well as adipose tissue. Thus, blood sugar level elevates 
along with lipolysis. The pathophysiology linked to the disorder is 
indicated in Fig. 1. 
Another recent addition to the pathology of the disorder is the 
impaired functioning of alpha cells of the pancreas [49]. Activity of 
gastric inhibitory polypeptide that stimulates insulin secretion is 
Fig. 1. Pathophysiology of type 2 diabetes mellitus leading to hyperglycemia. 
A. Arora et al. 
Life Sciences 273 (2021) 119311
3
decreased in type 2 diabetes mellitus patients but the insulin like activity 
of glucagon like peptide 1is retained and that makes glucagon like 
peptide 1 a possible therapeutic approach [49]; but this glucagon like 
peptide 1 is inhibited by dipeptidyl peptidase IV. Two types of drugs are 
used for the treatment of diabetes, mainly, analogs of glucagon like 
peptide 1 as well as dipeptidyl peptidase IV inhibitors [49]. Both these 
classes of drugs can optimize glucose levels both before and after meals 
as well as improve the functioning of beta cells [50]. Studies are going 
on to understand the link between dysfunctional mitochondria in insulin 
insensitivity as well as the cause that underlies type 2 diabetes mellitus 
[51] along with a focus on the fat tissue because the ‘endocrine organ 
hypothesis’ involves the release tumor necrosis factor alpha, leptin, 
adiponectin as well as resistin that makes the body insulin insensitive as 
well as hampers the functioning of pancreatic beta cells [50]. The reason 
why fat tissue plays a prominent role in type 2 diabetes mellitus is 
because majority of the diabetic patients have obesity. The hypothesis 
that supports this fact is the “visceral/portal hypothesis” providing a 
major part in increased level of fatty acids that lack ester moiety; apart 
from these 2 novel hypotheses include “ectopic fat storage syndrome” 
that leads to the accumulation of lipids in the liver, cells of the pancreas 
as well as skeletal muscle, thereby linking resistance to insulin with 
pancreatic cellular dysfunction in type 2 diabetes mellitus [50]. The 
diagnostic, as well as screening tests for type 2 diabetes mellitus, are 
identical and a positive test result indicates pre-diabetic or type 2 dia-
betes mellitus [52]. Approximately, 25% of type 2 diabetic patients 
exhibit defects in the microvasculature when diagnosed with the dis-
order and this shows that they had the disorder for greater than five 
years but remained undiagnosed [53]. The guidelines of American 
Diabetic Association (1997) diagnose diabetes mellitus by checking the 
fasting plasma glucose whereas World Health Organization does so by 
focusing on oral glucose tolerance test [52]. Other diagnostic parame-
ters include glycated hemoglobin as well as fructosamine; along with 
this the International Expert Committee has suggested a yet another 
diagnostic parameter, i.e., when the concentration of glycated hemo-
globin is equal to or greater than 6.5%, then the person has type 2 
diabetes mellitus. Also, this committee does not define pre-diabetic 
condition and has specified that if the level of glycated hemoglobin 
exceeds 6.5% or is equal to it, then there is a greater probability of 
developing diabetes mellitus [54]. When it comes to the management of 
the disorder, changes in the diet as well as lifestyle such as consuming 
diet that is rich in fiber and unsaturated fats, resisting smoking and 
intake of alcohol as well as exercising regularly [38,55–58]. The patients 
who suffer from type 2 diabetes mellitus should get clinical advice on 
diet as well as lifestyle according to the need of the patient [59]. Apart 
from managing the lifestyle as well as diet, various hypoglycemic agents 
are being administered for the therapy of type 2 diabetes mellitus, the 
most important drug of which is metformin that comes under the class of 
biguanides and it is helpful in treating the disorder by decreasing the 
formation of glucose from non-carbohydrate precursors in the liver 
(decreasing gluconeogenesis), enhancing responsiveness to insulin, 
reducing absorption of glucose as well as increasing the uptake of 
glucose [60]. Metformin is able to perform these actions since it is an 
activator of adenosine monophosphate activated kinase enzyme that is 
associated with the increase in the gluconeogenic genes in the liver [61]. 
However, it should be kept in mind that metformin is contraindicated in 
geriatric patients who have type 2 diabetes mellitus and have damaged 
kidney function since it can lead to lactacidosis [60]. Another important 
category of hypoglycemic agents is sulfonylureas which enhance the 
secretion of insulin but carry the chance of developing hypoglycemia or 
decrease in blood sugar level [59] and this possibility of hypoglycemia is 
Fig. 2. Gut microbiota produces metabolites that maintain eubiosis resulting in good health while dysbiosis has an opposite effect, promoting metabolic disorders. 
A. Arora et al. 
Life Sciences 273 (2021) 119311
4
much greater (about 36%) in geriatric subjects than in young subjects 
[62]. The examples of sulfonylureas include glipizide, glyburide, out of 
which the latter causes greater decrease in blood sugar level [63]. Pos-
sibility of reduction in blood sugar level is greater when the functioning 
of kidney is impaired, when drugs that enhance the sensitivity to insulin 
are used, patient is of sixty years or more, excessive intake of alcohol, or 
if various other medicines are taken simultaneously [64]. Other 
important drugs that are beingused clinically are repaglinide as well as 
nateglinide which belong to the chemical class of meglitinide analogs 
that show action on the potassium ion channels of the beta cells of the 
pancreas and thus, enhance the secretion of insulin just like sulfonyl-
ureas, however, the site on potassium channels is distinct [65]. These 
drugs act rapidly and the duration for which they act is small and hence, 
decrease in blood sugar level is not found with their use; also, these are 
administered prior to eating so that blood glucose level remains under 
control after eating, so, even if meal is skipped, the possibility of 
decreased blood sugar is significantly less [66]. The liver is the main 
metabolizing organ for meglinitides and modification of the dose is not 
required in those who have impaired kidney functioning but needed in 
those who are at the last stage of chronic kidney disease [65]. Then came 
the thiazolidinedione class that enhances sensitivity to insulin and ac-
tivates peroxisome proliferator activated receptor gamma that causes 
transcription of insulin responsive genes, thus treats insulin resistance 
associated with type 2 diabetes mellitus [67]. Since rosiglitazone has 
cardiac side effects, pioglitazone is the only drug of this class being used 
clinically [57]. Pioglitazone does not lower blood sugar level, can be 
administered to patients with impaired kidney function and is most 
suitable to be used in geriatric patients, but at the same time, some of its 
adverse effects limit its use in geriatrics, i.e., retention of fluids, possi-
bility of fracture in females and is also contraindicated in those who 
suffer from congestive heart failure as well as in class three or four heart 
failure [68]. Other drugs that can be administered to diabetic patients 
include alpha glucosidase inhibitors such as voglibose, acarbose are 
safer drugs but are not in much use as well as have adverse effects 
including bloating and diarrhea [59]. Voglibose belonging to this cate-
gory can increase toleration to glucose [69]. There are various incretin 
associated treatments such as congeners of glucagon like peptide 1 (e.g.: 
exenatide) that cause improved blood glucose levels as well as manages 
body weight; apart from this, improve cardiac as well as liver health and 
improve inflammation [70]. Some drugs inhibit dipeptidyl peptidase IV 
enzyme that inhibits glucagon like peptide 1 as well as gastric inhibitory 
polypeptide, elevates the concentration of these active hormones 
thereby having a positive impact on pancreatic cell functioning along 
with controlling blood sugar levels in those who suffer from type 2 
diabetes mellitus [71]. In some cases insulin can also be administered 
with hypoglycemic agents, especially when “rescue therapy” is required 
due to excessive accumulation of glucose [72]. Sodium-glucose 
cotransporter-2 inhibitors are also a possible option for diabetic melli-
tus patients that inhibit the reabsorption of glucose in the proximal 
convulated tubules and hence, the level of glucose in the circulation 
reduces [73]. Sodium-glucose cotransporter-2 inhibitors have been 
approved by the food and drug administration for the management of 
diabetes. Dapagliflozin, empagliflozin as well as Canagliflozin comprise 
sodium-glucose cotransporters-2 but these drugs also produce side ef-
fects such as urinary tract infection, bone fracture, cancer, diabetic 
ketoacidosis [74]. No doubt insulin and various other oral hypoglycemic 
agents are available that can efficiently manage type 2 diabetes mellitus 
but these work only on the symptoms and not the root cause, thus, 
improving the gut micro flora is important to cure the disorder 
completely. 
1.2. Gut microbiota dysbiosis linked to type 2 diabetes mellitus 
The gut microbiome is involved in the pathology involving type 2 
diabetes mellitus. An imbalance in the dispersal of various species of 
microorganisms as well as their impaired metabolism accounts for 
dysbiosis. The condition of ‘eubiosis’ and ‘dysbiosis’ is clearly indicated 
in Fig. 2 that correlates eubiosis with good health and dysbiosis with 
disease in the body. So, knowledge about gut microbial dysbiosis would 
help to comprehend the pathology associated with metabolic diseases 
including type 2 diabetes mellitus [51]. 
Dysbiosis in case of type 2 diabetes mellitus leads to the beginning 
and continuation of insulin resistance [75]. The majority of bacterial 
phyla present in the gut constitute Bacteroidetes, Firmecutes, Actino-
bacteria, Proteobacteria, Verrucomicrobia, Cyanobacteria as well as 
Fuscobateria. When the ratio of Firmecutes to Proteobacteria and bac-
teroidetes is increased [76] as well as when Akkermansia is decreased 
[77,78], the result is a number of chronic disorders including gastro- 
intestinal diseases [79,80]. Larsen et al. reported considerable distinc-
tion between the gut micro flora in type 2 diabetes mellitus patients as 
well as in healthy subjects [81] wherein the bacteria present in the feces 
of about eighteen males were examined through 16S rRNA sequence. 
According to the reports, type 2 diabetes mellitus patients exhibited a 
decrease in the concentration of Firmecutes along with an elevation in 
Proteobacteria and Bacteroidetes. Moreover, in another study, many 
bacteria producing butyric acid such as Roseburia intestinalis, Clostridium, 
etc. decreased in concentration in diabetic patients [82,83] along with 
an augmentation in the disease causing microorganisms [84]. Also, the 
bacteria causing reduction of sulphate such as Lactobacillus gasseri, 
Lactobacillus plantarum increase in the intestine of diabetes mellitus 
patients [82,83]. An imbalance in the gut microbiota can even progress 
to the build up of toxic metabolites of bacteria. According to phylogeny, 
an imbalance in gut micro flora and higher permeability of the intestine 
leads to obesity before the occurrence of diabetes [83]. There are various 
molecular patterns linked with disease causing microorganisms such as 
flagellin, lipopolysaccharide, peptidoglycan as well as lipoteichoic acid 
that influence the normal functioning and disease occurrence in the host 
body and this is regulated by those receptors which have the ability to 
recognize patterns such as toll like receptors. The responses of these 
receptors are generated in the presence of a pathogen and in response to 
injury to tissues. This results in the generation of cytokines [85]. These 
toll like receptors can identify ligand molecules, for instance, endo-toxin, 
produced by cells of the immune system and can produce inflammation. 
There has been an increase in the concentration and functioning of toll 
like receptors in case of metabolic diseases like diabetes as well as 
obesity [86,87]. Particularly in case of type 2 diabetes mellitus, elevated 
levels of cytokines involved in inflammation such as interleukin-6, 
interleukin-18 and tumor necrosis factor alpha are noted in the serum 
of the patients suffering from the disorder [88,89] along with the 
involvement of lipopolysaccharide layer of gram negative bacteria in the 
pathology of diabetes mellitus [27,90]. There is production of glucagon 
like peptide 1 and 2 when food is ingested. Glucagon like peptide 1 
increases the production of insulin in response to glucose and does not 
allow release of glucagon along with inhibition of feeding and emptying 
of stomach contents. On the other hand, glucagon like peptide 2 mod-
ulates glucose transport, ingestion of food, acid release and emptying of 
stomach contents, thereby enhancing the functioning of barrier of in-
testine [91]. 
1.3. Pathways and metabolites connecting type 2 diabetes mellitus and gut 
microbiome 
The bacteria in the gut produce various metabolites such as amino 
acids, short chain fatty acids, bile acids, indole propionic acids, tri-
methyl amine nitrogen oxide which mediate the host metabolism and 
are essential to keep the intestinal barrier intact. Moreover, these me-tabolites considerably connect gut micro flora as well as normal glucose 
levels in the human body [51]. 
Fermentation of bacteria in the large intestine generates short chain 
fatty acids and can transmit signals between gut micro flora and human 
body [92]. The bacteria mainly involved in the production of short chain 
fatty acids include Eubacterium, Megasphaera, Ruminococcus, Coprococcus 
A. Arora et al. 
Life Sciences 273 (2021) 119311
5
and various others. An imbalance in the concentration of these microbes 
in the gut of the patients suffering from type 2 diabetes mellitus can lead 
to their deficiency and deteriorate health [93]. In diabetes mellitus, the 
bacteria which produce butyric acid diminish in their concentration 
[84,94]. Butyric acid is essential for maintaining a healthy gut since it 
provides energy [95] by utilizing noncarbohydrate precursors to pro-
duce glucose maintaining optimum glucose-energy levels, decreases 
glucose synthesis by the liver along with improving intestinal barrier 
integrity [96]. The polysaccharides obtained from diet generating short 
chain fatty acids are fermented and absorbed by microbes present in the 
gut and they modulate the deposition of fat. So, short chain fatty acids 
can be used in the mitigation and therapy of type 2 diabetes mellitus. 
These fatty acids can even activate the cells of the gut via G-protein 
coupled receptors and regulate the immunity of the intestine [97,98]. 
They also stimulate the release of glucagon like peptide 1 and 2 that 
results in the increase in insulin sensitivity along with an increase in the 
concentration of beta cells of the pancreas. Overall, the short chain fatty 
acids improve metabolism in diabetic patients. 
Tryptophan is utilized in the intestine by microbes in order to syn-
thesize indole propionic acid which on absorption enters the blood [99]. 
Indole propionic acid guards against oxidative stress and inflammation 
along with improvement of metabolism of glucose. The role of indole 
propionic acid with metabolism of bacteria in human host has been 
proved by the fact that indole propionic acid generation occurs in bac-
terial culture and when antibiotics are administered, reduction in the 
level of indole propionic acid occurs [100,101]. Indole propionic acid is 
a probable biomarker in type 2 diabetes mellitus and exerts beneficial 
effect by retaining the functioning of beta cells of the pancreas 
[102,103]. When these indole acids are produced by microbes, glucagon 
like peptide 1 is secreted from endocrine cells of the intestine [104,105] 
and it also hampers the potassium ion channels that changes the char-
acteristics of action potential of L-type calcium ion channels leading to 
increased influx of calcium ions triggering further release of glucagon 
like peptide 1 [106]. Indole blocks the NADH dehydrogenase enzyme 
thereby decreasing generation of ATP that can progress to indefinite 
decrease in the production of glucagon like peptide 1. Thus, indole 
propionic acid obtained from the micro flora in the intestine does play a 
role in the human metabolism [106]. Indole propionic acid can prevent 
the development of type 2 diabetes mellitus that is mediated by the 
consumption of fiber and inflammatory responses or by the action of 
indole propionic acid on the functioning of beta cells of pancreas [107]. 
Another metabolite connecting gut micro flora and glucose levels in 
the host is bile acid that is synthesized in liver where cholesterol acts as 
the precursor for its synthesis and as soon as it is produced it binds to 
glycine or taurine in order to elevate its solubilization [108]. Majority of 
the bile acids (primary) on conjugation re-enter the circulation through 
entero-hepatic route and those which enter the intestine undergo 
transformation to secondary bile acids through Firmicutes. The mi-
crobes in the intestine can convert primary bile acids to secondary bile 
acids. The farnesoid x receptor is stimulated by primary bile acids while 
secondary bile acids stimulate G-protein coupled receptor 19. The G- 
protein coupled receptor 19 releases glucagon like peptide 1 from the 
enteroendocrine cells that saves the host from obesity produced by diet 
intake [109]. Farnesoid X receptor, as well as G-protein coupled receptor 
19, maintains the metabolism of glucose; the former stimulates glucose 
metabolism while the latter hinders it [110,111]. The level of secondary 
bile acids is decreased in obese people as well as those who suffer from 
type 2 diabetes mellitus. Thus, bile acid sequestrants can be adminis-
tered for enhancing the metabolism of glucose in those who suffer from 
type 2 diabetes mellitus [112]. Obesity, as well as type 2 diabetes mel-
litus, can be treated with sleeve gastrectomy as well as Roux-en-Y gastric 
bypass that are the variants of bariatric surgery [113]. The sole purpose 
of bariatric surgery is to reduce obesity as well as improve glucose ho-
meostasis as the level of bile acids increases after undergoing bariatric 
surgery. The sleeve gastrectomy elevates the level of bile acids and this 
includes the total bile acid as well as conjugated/unconjugated bile acid 
concentration in those who suffer from type 2 diabetes mellitus [114]. 
These bile acids promote metabolic activities since they interact with 
farnesoid X receptor. At the same time, when the concentration of far-
nesoid X receptor is decreased then the capacity of vertical sleeve gas-
trectomy to decrease obesity as well as increase sensitivity to insulin is 
reduced to a great extent [115]. So, regulating the concentration of bile 
acids can serve as a therapy for type 2 diabetes mellitus patients. 
A yet another important gut microbiota metabolite, trimethylamine 
N-oxide, produced from phosphatidylcholine, L-carnitine as well as 
choline [116,117], the metabolism of these nutrient precursors such as 
choline generates trimethylamine that is transported to the liver and it is 
biotransformed through the enzyme flavin mono oxygenase 3 in order to 
generate trimethylamine N-oxide [118,119]. There are various species 
of bacteria including Anaerococcushydrogenalis, Escherichia fergusonii, 
Proteobacteria, Providencia rettgeri and many others that have the ca-
pacity to generate trimethylamine N-oxide [120]. There is also a 
connection of development of cardiac diseases with concentration of 
trimethylamine N-oxide [121,122]. Moreover, those suffering from 
disorders of the kidney exhibit a greater concentration of the gut micro 
flora that synthesizes trimethylamine N-oxide, thus indicating a relation 
between biomarkers of inflammation, biomarkers of the metabolite 
trimethylamine N-oxide as well as impaired functioning of the epithe-
lium [123]. Elevation in the level of this particular metabolite enhances 
the possibility of acquiring type 2 diabetes mellitus [124,125] because it 
has been observed during animal studies that trimethylamine N-oxide 
increased insensitivity to glucose thereby leading to increase in the 
blood sugar level. This probably occurs because the metabolite inhibits 
the insulin signaling path in the liver progressing to inflammatory signs 
in the fat tissue [126]. Thus, decreasing the level of trimethylamine N- 
oxide in the plasma could be helpful in lowering the levels of insulin and 
the best way to achieve this is the inhibition of the enzyme that produces 
it, i.e., flavin mono oxygenase 3 [127]. No doubt those type 2 diabetes 
mellitus exhibit greater concentration of the metabolite but at the same 
time those who have elevated levels of the metabolite are also prone to 
the development of the disorder [128]. Thus, trimethylamine N-oxide 
might act as a biomarker and a regulator for metabolic disorders 
[126,129,130]. 
Branchedchain amino acids obtained from proteins play an impor-
tant role in the metabolism of glucose as well as protein [131,132] and 
an increase in their level can indicate the onset of type 2 diabetes mel-
litus [133]. The level of these amino acids can elevate because of the 
breakdown of proteins of fat tissue, liver as well as skeletal muscles 
[134,135]. The micro flora in the gut can alter the breakdown of pro-
teins as well as alter the level of branched chain amino acids in the 
plasma [136]. The bacteria in the gut are important to provide branched 
chain amino acids in humans through the generation of new amino acids 
or altering the absorption of nutritional elements [137]. Any imbalance 
in the gut microbiota facilitates transport of saccharin as well as 
branched chain amino acids leading to responsiveness to accumulation 
of free radicals [138]. The animals who exhibited obesity indicated 
decreased concentration of Bacteroidetes along with increased concen-
tration of Firmecutes in the gut [76]. Among the branched chain amino 
acids, leucine interrupts insulin signals through activation of rapamycin 
as well as S6 kinase along with the attachment of phosphorus to serine 
amino acids of insulin receptor substrate 1 [138]. Also, those who suffer 
from insulin insensitivity, the elevated levels of branched chain amino 
acids could be possibly obtained from gut micro biome [137,139]. Thus, 
if the intake of these branched chain amino acids is decreased then the 
release of insulin after meals is reduced along with increase in the 
biotransformation of white fat tissue as well as composition of intestinal 
microflora [140]. Inadequate levels of certain amino acids, especially 
glycine, that is needed to synthesize glutathione, can alter the func-
tioning in the human body and progress to insulin resistance [141]. In 
such a case if glycine is administered, there is seen an increase in the 
level of glutathione as well as reduce insulin resistance in those who 
suffer from type 2 diabetes mellitus [142]. The summary of microbial 
A. Arora et al. 
Life Sciences 273 (2021) 119311
6
metabolites and their role is illustrated in Fig. 3. 
1.4. Therapies for type2 diabetes mellitus associated with Intestinal Micro 
Flora 
The potential therapeutic approaches linked to gut microbiota for the 
treatment of type 2 diabetes mellitus include probiotics, prebiotics, 
synbiotics and fecal microbiome transplantation that are discussed in 
this section. 
Probiotics were earlier known as the “microbes causing the growth of 
other microbes” but afterward described as “live microbes that have 
beneficial effect at adequate levels on human health” [143]. According 
to the Food and Drug Administration, probiotics cannot be the basic part 
of managing disorders since their efficiency and safety are not well 
known [144]. Advantages of probiotics include healthy gut, relief from 
lactose sensitivity, prevention of proliferation of pathogens, synthesis of 
short chain fatty acids, improving immunity as well as decreasing the 
chance of developing disorders. The intake of probiotics can alter the 
composition of gut micro flora by proliferating healthy microorganisms 
and prevent the development of type 2 diabetes mellitus [145]; since in 
type 2 diabetes mellitus, inflammatory changes, insulin release as well 
as free radical accumulation are benefitted by probiotics intake 
[146,147]. Many species of bacteria such as Streptococcus, Lactobacillus, 
Lactococcus, Bifidobacterium are used commercially in the form of sa-
chets, gums as well as capsules [148,149]. When these species of bac-
teria are given in the form of probiotics will improve gut health and 
tolerance to glucose. Also, probiotics decrease the concentration of 
glycated hemoglobin, homeostatic model assessment as well as stan-
dardized mean difference, thereby improving metabolism in diabetes 
mellitus patients [146]. Thus, probiotics are essential to improve insulin 
resistance linked to type 2 diabetes mellitus and a mild effect was 
observed in diabetic subjects [31]. The probiotics that are in current use 
are indicated in Table 1. 
Prebiotics are the polysaccharides or the oligosaccharides which 
provide benefit by promoting the growth of useful bacteria in the gut. 
Prebiotics are only those substances that are unaffected by gastric acid as 
well as biocatalysts in the host, can be fermented by microbes in the 
colon, have the capacity to increase longevity of essential bacteria 
[157,158]. Alteration of the intestinal micro flora, decrease in mild in-
flammatory changes in the gut, increasing the intestinal integrity (as a 
result bringing down the lipids as well as glucose concentration), 
decreasing weight as well as elevating sensitivity to insulin [159]. Pre-
biotics can prevent increase in weight, diabetes mellitus, oxidative 
Fig. 3. Metabolites from diet as well as from microbes and their resulting effects. 
Table 1 
Frequently used probiotic microorganisms. 
Microorganism Health benefits References 
Lactobacillus 
rhamnosus 
Prevents against diabetes (evident from fecal 
samples of newborn) [150], help to decrease 
weight in females who suffer from obesity 
[151], prevents damage to colon from 
lipopolysaccharides [152] 
[150–152] 
Lactobacillus 
reuteri 
Lowers the level of low density lipoproteins [153] 
Enterococcus 
durans 
Anti-oxidant activity [154] 
Lactobacillus 
fermentum 
Decreases resistance to insulin along with 
decrease in cholesterol level 
[155] 
Bacillus coagulans Support immunity [156] 
A. Arora et al. 
Life Sciences 273 (2021) 119311
7
stress, inflammation, microbiota dysbiosis and when fiber intake is 
accompanied with prebiotics intake, it can decrease fasting glucose level 
as well as glycated hemoglobin level in those who suffer from type 2 
diabetes mellitus [160]. Few examples of prebiotics include fructooli-
gosaccharides, galactooligosaccharidesand inulin; inulin as well as 
fructans which resemble inulin comprises water soluble roughage while 
galactooligosaccharides (made up of galactose monomers) are obtained 
from lactose, are not digested and occur in milk of mammals [115]. The 
fructans that resemble inulin produce active congeners of glucagon like 
peptide 1 contributing to balanced level of glucose in the blood [161]. 
Moreover, to determine the effectiveness of inulin type fructans, thirteen 
trials were conducted in which barely four patients exhibited reduction 
in glucose concentration [162]. There was one more trial conducted to 
test the effect of inulin type fructans on serum lipid level, fasting blood 
glucose, level of insulin as well as those who had type 2 diabetes mellitus 
and it came out that fructans suppressed glucose concentration in dia-
betic subjects [163]. Elevation in the concentration of F. prausnitziias 
well as A. muciniphila improves metabolism and decreases risk of weight 
gain [164] as well as diabetes mellitus (type 2) [165]. Inulin type 
fructans caused F. prausnitzii to proliferate in abundance in females with 
obesity while the placebo, i.e., maltodextrin led to its proliferation to a 
lesser extent [166] and, the concentration of this bacterial species (about 
34%) also elevated when food rich in energy was given to those who 
suffer from type 2 diabetes mellitus [167]. F. prausnitzii are not only 
prebiotics but also probiotics and these are present in large amount in 
chickpea/food rich in raffinose (oligosaccharide), thus indicating that 
these bacteria also serve as probiotics [168]. Fiberrich diet also helps to 
improve metabolism; one such important fiber component is arabinox-
ylan that is commonly found in cereals and it has hemi cellulose con-
taining xylose as well as arabinose [169]. It has been seen in type 2 
diabetes mellitus mice that arabinoxylans are beneficial in lipid, amino 
acid as well as carbohydrate biotransformation indicating different 
pathways involved in diabetes mellitus [170] and also that intake of 
approximately fifteen grams of arabinoxylan per day might control 
glucose level [171]. Not only fibers, but polyphenols are also beneficial 
for gut micro biota balance that do not show sufficient absorption in the 
initial part of intestine and undergo fermentation by microbes in the gut 
[172]. Resveratrol which is a natural phenolic compound majorly pre-
sent in peanuts, grapes is proven for mitigation of a number of disorders 
[173] and also treats unresponsiveness to insulin as seen in animal 
studies [174,175]. Therapy with resveratrol has positive impact on 
microbiome in the gut, reduces inflammation in rats [176], increases 
tolerance to glucose, elevates glucagon like peptide 1(active) and insulin 
[177]. 
A combination of pre and pro biotic exhibits synergism along with 
increased efficiency and is termed as ‘synbiotic’ [143] and these syn-
biotics affect glucose as well as insulin levels [178]. The bacteria 
Lactobacillus acidophilus produced much greater amount of butyric acid 
with pectin/inulin as compared to glucose [179]. Beneficial effect on the 
biotransformation of lipids as well as glucose is observed with syn-
biotics/prebiotics in those who have type 2 diabetes mellitus [180]. 
The current, as well as future benefits of the use of prebiotics, pro-
biotics and synbiotics, are shown in Fig. 4. 
A novel approach is ‘fecal micro flora transplantation’ that can be 
used clinically since it was used in the therapy of disease caused by 
Clostridium difficile [181,182] and it is also a verified therapy [181]. 
Based on the reports of 2013, this technique has achieved upto 90% 
efficacy for the therapy of repeated disease caused by Clostridium difficile 
[183], thus signaling the importance of fecal micro flora transplantation 
for the therapy of metabolic disorders. According to another report, 
when fecal micro flora transplantation was transferred from thin sub-
jects to those with Reaven’s syndrome, a positive impact was seen on 
sensitivity to insulin as well as an elevation in the microbes synthesizing 
butyric acid in the receiver’s fecal micro flora [184]. In this case, when 
the sensitivity to insulin as well as the concentration of microbes 
releasing butyric acid was observed in the receivers after six weeks, the 
Fig. 4. Current and future potential of prebiotics, probiotics and symbiotic. 
A. Arora et al. 
Life Sciences 273 (2021) 119311
8
result was improvement in insulin resistance as well as increase in the 
beneficial bacteria [185]. Similarly, the intestinal microbes were 
transferred to mice suffering from diabetes mellitus and positive results 
were seen and along with that when fecal microbes were given to mice, 
then there was an elevation in Clostridiaceae as well as Lachnospir-
aceaeplus a downfall in Lactobacillaceae [186]. No doubt ‘fecal micro 
flora transplantation’ is an excellent approach for promoting healthy 
microorganisms in the gut but more clinical evidence is required for the 
same. Table 2 indicates the diseases in which fecal micro flora trans-
plantation has the potential to be utilized. 
2. Future perspectives and conclusion 
Micro flora in the gut is linked to a number of lifestyle disorders such 
as obesity, atherosclerosis, type 2 diabetes mellitus, cancer of the colon, 
i.e., there is a great expectation associated with maintaining gut eubiosis 
for the diagnosis, prognosis as well as therapy of these metabolic dis-
eases but without enough clinical evidence, it is not correct to be carried 
away by this fact. Preclinical studies are quite different from clinical 
ones and hence, more research is needed to establish that homeostasis in 
the gut microbiome can prevent or reduce the progression of metabolic 
disorders. Targeting eubiosis condition in the gut is essential by 
consuming healthy diet, rich in protein, probiotics, prebiotics, syn-
biotics, maintaining a non-sedentary lifestyle, otherwise problems such 
as obesity as well as hyperglycemia come up. Targeting the gut microbes 
takes longer time for recovery of these disorders but still it has a great 
future potential in the field of education, therapy of metabolic syn-
dromes, tracking gut microbes in real time, modifying intestinal mi-
crobes as well as regulating gut health. 
Declaration of competing interest 
The authors declare that there are no conflicts of interest. 
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Table 2 
Diseases in which fecal micro flora transplantation holds future therapy poten-
tial [187]. 
• Obesity 
• Parkinson’s Disease 
• Metabolic syndrome 
• Type 2 diabetes mellitus 
• Autism 
• Autoimmune diseases 
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