Background
The
global prevalence of metabolic diseases such as obesity, non-alcoholic fatty
liver disease (NAFLD), insulin resistance, type 2 diabetes mellitus (T2DM),
atherosclerosis (AS) and polycystic ovary syndrome (PCOS) has increased
dramatically . Over the past few decades, the consumption of high-calorie foods
has increased and physical activity has been replaced by sedentary activities,
ultimately resulting in energy intake exceeding energy expenditure and becoming
a major risk factor for obesity and obesity-related diseases. In this
condition, adipose tissue exceeds the body's ability to store all excess energy
in the form of triglycerides, causing lipids to overflow into the circulation.
This excess recruitment of lipids in non-disaccharide tissues results in
ectopic fat storage, in which the ability of non-adipose tissue to increase fat
oxidation upon increased fatty acid utilization is impaired. Excessive accumulation
of fat in adipocytes can trigger increased production and secretion of
pro-inflammatory adipokine, leading to the occurrence of insulin resistance,
which is related to the occurrence of T2DM and NAFLD. Genetically speaking,
more than 99% of human genes are microorganisms, and there are at least as many
microbial cells as there are human body cells. The gut microbiota refers to the
trillions of microorganisms residing in the gut, including bacteria, viruses,
fungi, archaea, phages, and protozoa, which can interact with the host in a
variety of ways.
Introduction
Professor
Changtao Jiang and his team from Peking University Third Hospital published a
review titled The role of the gut microbiome and its metabolites in metabolic
diseases [1] in the journal Protein Cell (IF: 10.164), focusing on the
intestinal microbiota. and the role of their metabolites in the onset and
progression of many metabolic diseases, as well as the underlying mechanisms
and new technologies for creating a range of various target-specific drugs for
treatment. This review aims to provide guidance for future research in the
emerging field of gut microbiota relevant to the development of metabolic diseases
in humans.
Main results
Correlation
between gut microbiota and metabolic diseases
The
potential role of the gut microbiota in the development of various diseases in
humans has received considerable attention over the past decade. In particular,
the gut microbiota has evolved to become an important factor in the development
of many metabolic diseases, such as obesity, type 2 diabetes, and non-alcoholic
fatty liver disease. We summarize changes in gut microbiota composition in
metabolic diseases. The current global obesity epidemic is associated with
lifestyle changes characterized by excessive energy intake and reduced physical
activity. Western diet-induced obesity leads to changes in the composition of
the gut microbiota, such as a significant increase in Firmicutes. As a
potential mechanistic driver of obesity and its related comorbidities, the
impact of intestinal microbiota has become a focus of attention in recent
years. The gut microbiota is key to energy acquisition as it converts food into
nutrients for the host, and obesity-associated gut microbiota are more capable
of harvesting energy from the diet. Previous studies have shown that intestinal
microbiota has an important impact on the occurrence and development of
non-alcoholic fatty liver disease in humans. The abundance of Bacteroidetes was
increased in patients with non-alcoholic fatty liver disease, while the
abundance of short-chain fatty acid-producing and 7α-dehydroxyfirmicutes was
significantly decreased. A study using a transplanted mouse model demonstrates
the role of the gut microbiota in the development of non-alcoholic fatty liver
disease. Mice fed a high-fat diet developed hepatic macrovesicular steatosis
after colonization with microbiota from hyperglycemic mice, whereas control
mice developed only low-level steatosis after treatment with microbiota from
normoglycemic mice. . Differences in microbiota composition can determine how
mice respond to HFD disease. In summary, the intestinal microbiota has a
significant impact on systemic metabolic homeostasis, and a healthy intestinal
microbiota plays an important role in the overall health of the host.
Major metabolites
produced in the gut microbiota
The
human gut microbiota is driven by macronutrients in the diet and produces bioactive
compounds composed of bile acids, short-chain fatty acids, ammonia, phenols,
endotoxins, and more. These microbiota-derived metabolites act as mediators of
microbe-host communication, which is essential for maintaining host physiology.
Bile acid
Primary
bile acids are converted from cholesterol to taurine and glycine conjugates in
the liver and secreted into the intestine where they are converted to secondary
bile acids in the intestinal microbiota by bile salt hydrolase (BSH). Bile
acids alter metabolism by activating certain
receptors, including farnesoid X receptors (FXR), pregnane X receptors, and G
protein-coupled receptors (GPCRs), such as TGR5. The secondary bile acids
deoxycholic acid (DCA) and lithocholic acid (LCA) are the most abundant
metabolites in the intestinal microbiota, accumulating at a concentration of
approximately 500 μmol/L and regulating the host through the G protein-coupled
receptor TGR5 Energy homeostasis and metabolism. Intestinal FXR activation
induces hepatic fibroblast growth factor 15 (FGF15) expression and inhibits
cholesterol 7α-hydroxylase (CYP7A1) expression. CYP7A1 is the rate-limiting
step in bile acid synthesis and thus can lead to decreased bile acid levels
through the gut-microbiota-liver feedback pathway.
Modulation
of the gut microbiota-bile acid-FXR axis is associated with obesity-induced
insulin resistance and hepatic steatosis in mice. Figure 1 summarizes the
previous related work of our laboratory, revealing that regulating CYP7A1, a
key enzyme in the bile acid synthesis pathway of hamsters, eliminates
intestinal microbiota to reduce HFD-induced glucose intolerance, hepatic
steatosis, and inflammation. Provides potential targets for modulating
diet-induced obesity.
Figure
1. Regulation of the gut microbiota-bile acid-FXR axis
The regulatory
role of bile acids
The
intestinal microbiota is critical for maintaining the host's physiological
state and metabolic homeostasis. The intestinal flora of patients with
metabolic diseases is dysbiosis, and the interaction between the intestinal
flora and the host is disordered. Therefore, modulating the host gut microbiota
may be a promising therapeutic approach to treat metabolic diseases. Gut
microbiota colonization is thought to begin primarily at birth, when the infant
is exposed to maternal microbiota during delivery. Multiple factors early in
life influence the composition of the gut microbiota, including mode of
delivery, host genetics, immune response, antibiotic administration, lifestyle,
circadian rhythms, host disease status, and environment.
Effects of
dietary intervention on gut microbiota and bile acid composition
Throughout
a person's life, diet may have the greatest impact on the relationship between
the gut microbiota and its mammalian host. The consumption of various nutrients
affects the structure of the microbiota and provides substrates for microbial
metabolism. The gut microbiota interacts with nutrients in food to influence
host health. Furthermore, the structure and activity of the gut microbiota are
largely regulated by human dietary intake, and this process is rapid and
reproducible. Therefore, dietary intervention is a powerful tool to alter the
composition of the gut microbiota. There were significant differences in gut
microbiota composition between herbivorous and carnivorous individuals, with a
carnivorous diet increasing the abundance of bile-tolerant microorganisms and
reducing levels of Firmicutes that metabolize dietary plant polysaccharides,
such as Roseberia , rectal eubacteria and Ruminococcus brucei, etc.
Gut-targeted
drugs to treat metabolic diseases
In
addition to dietary intervention, drugs are the main intervention strategy for
metabolic diseases. The gut microbiota is widely recognized as a major
regulator of host health and a driver of changes in microbial composition and
function, with important impacts on host health. The gut microbiota interacts
with several common antidiabetic drugs, including metformin,
thiazolidinediones, miglitol, acarbose, and liraglutide, among others.
Probiotic
administration
Currently,
probiotic treatment is commonly used to prevent metabolic diseases such as
diabetes and non-alcoholic fatty liver disease. In order to study the effects
of probiotics on the host, it is crucial to assess whether probiotics colonize
the intestine. A recent systematic review reported that six out of seven
analyzed studies found no effect of probiotics on fecal microbiota composition.
In contrast, other studies have observed changes in fecal microbiota
composition in probiotic-treated individuals.
Gene editing
technology for gut microbiota
In
addition to the dietary interventions and probiotics mentioned above, there are
other ways to modulate the composition of the gut microbiota. A recent
publication by Stanford University researchers developed a system for
constructing a complete knockout of Clostridium difficile and determined the
function of the microbial product. Clostridium is a commensal bacterium of the
phylum Firmicutes that is commonly found in the gut of mammals. Clostridia
produce a range of metabolites that diffuse into the host circulation and are
genetically difficult to manipulate. To study the role of molecules produced by
the gut microbiota, Guo et al. developed a CRISPR-Cas9-based genetic system to
create deletions in model Clostridium commensalis that stop the production of specific
molecules.
Conclusion and
outlook
Our
guts are home to a vast array of microorganisms, from bacteria, viruses, fungi
and archaea to bacteriophages and protozoa. The intestinal microbiota can
regulate nutrient metabolism during dietary intake and produce many metabolites
that interact with the host in various ways, including regulating glucose and
lipid metabolism pathways, affecting the differentiation and function of immune
cells, affecting insulin sensitivity, etc. Extensive human and animal data
provide strong evidence that the gut microbiota and its metabolites play a
crucial role in the onset and progression of many metabolic diseases. Based on
recent research and experimental results, we have discovered many ways to
improve metabolic diseases by modulating the gut microbiota, including dietary
intervention, probiotic administration, gene editing technology, and drug use.
In addition to the applications mentioned above, we can also predict a person's
susceptibility to disease or response to drugs by detecting characteristics of
a person's microbiome.
According
to many clinical follow-up studies from different countries, the majority of
individuals (perhaps up to 70% with a prediabetic state, including impaired
fasting glucose (IFG) and impaired glucose tolerance (IGT)) may eventually
develop type 2 diabetes. Furthermore, prediabetes is strongly associated with
other manifestations, including obesity, hypertension, nonalcoholic fatty liver
disease, hypertriglyceridemia, and cardiovascular disease. A 2015 cohort study
continuously monitored the blood sugar levels of 800 subjects for a week and
collected data on their microbiome, genetics, eating habits, anthropometry and
physical activity. The researchers demonstrated that people respond differently
to the same meal and designed a machine learning algorithm to use individual
and microbiota characteristics to accurately predict glucose responses.
There
is no doubt that we have made great progress in the composition of the gut
microbiota and the analysis of key metabolites. However, we need to do more
than simple correlation. The complex mechanisms of interactions between the gut
microbiota and the host await further investigation.
Original
link
https://link.springer.com/article/10.1007/s13238-020-00814-7
references
1.Wu
Jiayu,Wang Kai,Wang Xuemei et al. The role of the gut microbiome and its
metabolites in metabolic diseases.[J] .Protein Cell, 2020, undefined:
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