The Role of Gut Microbiota in Insulin Resistance

Abstract

The gut microbiota has a significant impact on the host health. Several studies have proven it has a significant role in digestion, immune function, nutrient metabolism and other biological functions. This review aims to synthesize the current body of evidence on the relationship between gut microbiota composition and insulin resistance, highlighting key findings, therapeutic strategies, and future research directions.

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Introduction

The increase of incidence of obesity is a worldwide concern today. In 2022, the number of obese individuals is estimated to be 890 million globally[10]. The widespread availability of fast food, high-fat diet and sedentary lifestyle have contributed significantly in this trend. Obesity is associated with many adverse health outcomes, including cardiovascular disease (CVD) which remains the predominant cause of global mortality, accounting for 33% of all deaths worldwide[9].

Insulin resistance is a precursor to many metabolic disorders, including type 2 diabetes, and is influenced by many factors such as diet, genetics, and lifestyle. Among these, the gut microbiota has emerged as a critical determinant of metabolic health.

Gut microbiota modulation offers a promising therapeutic solution to address insulin resistance. Studies have proven the effect of gut microbiota profile on the host glycemic control. This body of evidence has inspired a lot of researchers to investigate possible treatment options centred on modulation of the microbial profile of patients with type 2 diabetes, obesity and related metabolic disorders.

In this review, we will examine the current literature on the role of gut microbiota in insulin resistance, discuss the mechanisms by which it influences metabolic processes, and explore potential therapeutic interventions.

Background

Insulin resistance

Insulin resistance refers to systemic decreased sensitivity to insulin in cells of insulin-sensitive tissues. This leads to impaired glucose transport from blood into cells, causing hyperglycemia and compensatory hyperinsulinemia. Insulin resistance is caused mainly by obesity, but can also be caused by infections and sepsis-induced inflammation that affects insulin-sensitive tissues, such as liver, muscle, adipose tissue and hypothalamus[1].

Chronic inflammation

Chronic systemic inflammation is a key characteristic in obesity. Chronic systemic inflammation is caused by abnormal cytokine release, mainly TNF-alpha. TNF-alpha is a proinflammatory cytokine that activate various pathways that are critical insulin action inhibitors. TNF-alpha is overexpressed in the adipose and muscular tissues of obese humans, playing a key role in development of insulin resistance in this population[2].

The adipose tissue contributes to the immune system by secreting a large number of peptide hormones and cytokines (known as adipokines)[3]. High amount of cytokines induce insulin resistance in multiple ways; TNF-alpha inhibits the action of insulin in insulin-sensitive tisuses[2]. TNF-alpha also enhances lipolysis and downregulates triglyceride synthesis and storage in adipocytes, increasing levels or circulating free fatty acids, and including triglyceride deposition in muscular tissue[3].

Microbiota

The gut microbiota refers to the complex community of microorganisms that reside in the intestinal tract in symbiosis with the host. These microorganisms are predominantly bacteria, with viruses and fungi also contributing to this intricate ecosystem. This diverse community plays a crucial role in various physiological processes, including digestion, immune function, and hemeostasis[4].

The link between gut microbiota composition and glucose metabolism

The composition of gut microbiota seems to have a significant impact on glucose metabolism. Several studies suggest that low Bacteriodetes (Gram-negative bacteria) to Firmicutes (Gram-positive bacteria) ratio is associated with high BMI[1]. Multiple mechanisms appear to act synergistically. Some of the proposed mechanisms are:

• Short-Chain Fatty Acids (SCFAs): Some organisms in gut microbiota affects glucose absorption via production of short-chain fatty acids. Gut microbiota degrades polysaccharides (not digestible by mammalian intestine) into short-chain fatty acids that can be absorbed through passive diffusion[1]. SCFAs (like acetate, propionate and butyrate) induce the secretion of incretin, leading to lower blood glucose level[5]. SCFAs also induce fatty acid oxidation and energy expenditure[1]. SCFA can also modulate satiety, since acetate infusion induces an increase in the circulating levels of GLP-1 and PYY, decreasing the appetite of the host[6].
• Lipopolysaccharides (LPS): Gram-negative bacteria contain LPS. Elevated levels of LPS have been shown in obese humans. This may seem like a paradox, because obesity is associated with an increase in the percentage of Firmicutes, which are Gram-positive, in the microbiota, however, this increase in LPS is directly related to increased intestinal permeability, which is caused by reduction of expression of proteins that compose the gut epithelial barrier[6]. SCFA also have a protective effect on intestinal barrier[6]. High blood levels of LPS can lead to endotoxemia, systemic inflammation and insulin resistance[1].
• Branched-Chain Amino Acids: The gut microbiota is an important producer or Branched-Chain Amino Acids (BCAA) in mammalian hosts. These BCAA, like leucine, isoleucine, and valine, are associated with increased risk of developing Type II Diabetes Mellitus. The mechanism by which BCAA contribute to insulin resistance is still unclear[6].

Therapeutic strategies

The significant effect of gut microbiota on glucose metabolism has inspired a lot of researchers to attempt to modulate the gut microbiota in order to promote health, prevent insulin resistance and treat obesity. Modulation of intestinal microbiota for therapeutic goals can be achieved via dietary changes, intake of probiotics, prebiotics, synbiotics, postbiotics and antibiotics.

Diet and bariatric surgery

Diet-induced weight loss has a substantial role in modulating gut microbiota and improving overall health. Healthy, energy restricted diet is associated with increase in Bacteroides group in gut microbiota and decreased Firmicutes[4].

Bariatric surgery also modulates the composition of gut microbiota. Some studies found that Roux-en-Y gastric by-pass promotes evident changes in the intestinal microbiota, contributing to the weight loss[4]. Firmicutes, which seem to contribute to the increased energy extraction from fermentation of polysaccharides in obese subjects, are strongly decreased after RYGB[4].

Probiotics

Probiotics are living microorganisms taken orally, offering health benefits on the host. The most common species used as probiotics are Lactobacillus and Bifidobacterium[7].

Several studies have shown an improvement in metabolic diseases treated with probiotics. Many trials showed that patients with type II diabetes mellitus treated with probiotic yogurt showed decreased fasting glucose and glycated Hb (HbA1c), but one study of overweight adults showed a conflicting result, reporting that intake of probiotic yogurt increased HOMO-IR, and probiotic capsules increased fasting glucose levels[7].

A more-recent review investigating the effect of probiotics on insulin resistance has showed that supplementation of helps decrease the expression of inflammatory cytokines, improve insulin sensitivity and normalize insulin levels[8].

Prebiotics

Prebiotics are consumable substances selectively utilized by microorganisms in the host and confer a benefit to the host microbiota composition. The most studied prebiotics are the inulin.

Prebiotics contribute to modify gut microbial composition, enhancing the growth of beneficial bacteria like Bacteroides, and promoting the relative decrease of Firmicutes. Moreover, they contribute to reduce body weight by regulating food intake and appetite, by promoting the production of GLP-1, peptide YY and the decrease of ghrelin[4].

Synbiotics

Synbiotics are combination of probiotics and prebiotics administered together. Combining probiotics and prebiotics can have a synergistic effect that is better that one of them alone. Current synbiotics include the most well-studied probiotics, including Bifidobacterium and Lactobacillus, combined with indigestible sugars, such as fructo-oligosaccharides. Synbiotics are thought to aid the organisms of the probiotic for further fermentation and processing of food[8].

Postbiotics

Postbiotics are dead or inactivated microorganisms with or without their components and metabolites that confer a health benefit to the host. The mechanism of this benefit seems to be a due to both inactivated organism components and its metabolites like SCFAs[8]. Postbiotics have the advantage of safety, since microorganisms that could not be administered live due to safety concerns can be adminstered after inactivation[8].

Antibiotics

Broad-spectrum antibiotics can greatly modify and gut microbiota composition[1]. The main mechanism accepted is that antibiotics intake leads to decreased circulating LPS levels, which suppresses inflammation and improves the insulin resistance[1]. Translating this strategy to humans have a big challenge, since chronic administration of antibiotics can lead to antibiotic resistance.

Fecal Microbiota Transplantation (FMT)

Fecal Microbiota Transplantation is a medical procedure that involves transferring fecal microbiota from a healthy donor to the gastrointestinal tract of the patient. A recent study operated on mice has shown that FMT from aerobic-exercise group to high-fat diet group significantly improved blood lipids and inflammation markers in the second group through gut microbiota remodelling and replication of the aerobic exercise phenotype[9]. Further research is needed to investigate this effect on humans.

Analysis and conclusion

The gut microbiota has a significant role in individual health. Its impact has inspired many researchers to try to employ the microbiota composition to cure or improve various diseases. Human gut microbiota supplementation offers a promising therapeutic target for insulin resistance, T2DM and obesity. Current research is directed towards investigating the effects of gut microbiota supplementation on glucose metabolism. Further research is needed to discover novel mechanisms of host-microbiota interactions, and find their associations with T2DM and cardiovascular disease.

Refrences

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