Gut Microbiota and Incretin

Review Article

Gut Microbiota and Incretin

Corresponding author: YueZe Liu, Professor and PhD, Second hospital Shanxi Medical University, Taiyuan, Shanxi, PR China. Email: yuezeliu@163.com

Abstract

Not only does the gut microbiota perform a number of essential protective, structural, and metabolic functions for host health, but it also is involved in endocrine function. Incretin hormone produced by intestinal endocrine cells regulates glucose homeostasis by stimulating the secretion of insulin from pancreatic -cells. Secretion of incretin is also regulated by gut microbiota. This action of gastrointestinal tract is termed as the ‘incretin effect’. Not only gut microbiota influence incretin secretion, but also incretin in turn plays an important role in microbiota regulation. This bidirectional interaction is important for our health.

Key words: Microbiota; Incretin; Gut-Brain Axis; Insulin; Gastrointestinal tract

Background

Microbiome science has risen in recent years, and the exciting discoveries emerging one after another have forced us to reevaluate microorganisms which reside in the human gastrointestinal tract in particular [1]. The human intestinal tract is inhabited by over 100 trillion microorganisms; including over 1000 species of known bacteria [2]. Gut microorganisms encode >150 times more genes than the human genome and are highly involved in numerous metabolic reactions which influence normal host physiology and metabolism [3]. Not only does the gut microbiota perform a number of essential protective, structural, and metabolic functions for host health, but it also is involved in endocrine function. Considering the ability to influence the function of distal organs and systems, in many respects, the gut microbiota resembles an endocrine organ [4]. Incretin hormone produced by intestinal endocrine cells regulates glucose homeostasis by stimulating the secretion of insulin from pancreatic -cells. Secretion of incretin is also regulated by gut microbiota.  For example, indole, a metabolite produced from the dissimilation of tryptophan, is able to modulate the secretion of glucagon-like peptide-1 (GLP-1) from immortalized and primary mouse colonic L cells. [5].  Vice versa, incretin impact on microbiota by regulating metabolism as well as gastrointestinal motility. The absorption of digested food is largely affected by the state of gastrointestinal motility. Incretin may be an important gut hormone for mediating the effect of the gut microbiota on not only metabolism but also gastrointestinal motility [6].

Gut Microbiota and Microbial Endocrinology

Gut microbiota is an integral component of the host and plays important roles in host health. The gut microbiota was enriched with functional potentials that were related to transporters, DNA repair and recombination proteins, two component system, secretion system, bacterial motility proteins, purine metabolism and ribosome [7]. Gut microbiota consists of about 1000 bacterial species which belonging to the Bacteroidetes phyla and firmicutes. Microbial genes are a key for essential metabolic processes, e.g. the biosynthesis of short-chain fatty acids; amino acids; bile acids and/or vitamins. Gut microbiota is also involved in aged-related disease including metabolic syndrome, T2DM, inflammatory, bowel diseases and neurodegenerative diseases. Considering the microbiota responding to homeostatic and physiological changes, it should be seen as an endocrine organ [8]. Increasing researches have being focused on the cell biotherapies for those aged-diseases utilizing gut microbiota. By three pathways gut microbiota is connect with the whole body: direct neuronal communication, endocrine signaling mediators and the immune system [9]. Irritable bowel syndrome (IBS) is classic case. As evidenced by patients who develop IBS, infective gastroenteritis could cause systemic inflammation and altered microbiome diversity, which in turn perpetuates a cycle of chronic, low-grade, subclinical inflammation. Apart from mucosal inflammation, neuroinflammation is probably involved in the pathophysiology of IBS via the “gut-brain” axis, resulting in altered neuroendocrine pathways and glucocorticoid receptor genes. This gives rise to an overall proinflammatory phenotype and dysregulated hypothalamic-pituitary-adrenal axis and serotonergic (5-HT) functioning, which could, at least in part, account for the symptoms of IBS [11]. Hormones derived from gut play a key role in control of energy intake and homeostasis. They are released in response to nutrients and provide the opportunity for rapid metabolic feedback loops. Microbiobial products and metabolites also modify their release.

Enteroendocrine in Gut and Brain

The interaction between the brain and the gut has been known for many centuries. This bidirectional interaction occurs via neural, immunological and hormonal routes. The interaction may play role in shaping higher cognitive function such as feelings and subconscious decision-making [11]. Accumulating evidences have been shown that the bidirectional interactions between the central nervous system and the gut demonstrated a key role for the gut microbiota in these gut-brain interactions. The gut microbiota influences the development of emotional behavior, stress and pain-modulation systems, and brain neurotransmitter systems. Some preclinical and clinical studies have demonstrated the positive impact of probiotic supplementation on depressive symptoms. A recent meta-analysis showed that probiotic supplementation may alleviate depressive symptoms [12]. The gut flora of depressed patients also appears to comprise a higher proportion of pathogenic Gram-negative microbes. Patients with depression had significantly increased levels of Enterobacteriaceae and Alistipes but lowered levels of Faecalibacterium [13]. In adult mice, microbial metabolites influence the basic physiology of the blood–brain barrier. Gut microbes break down complex carbohydrates into short-chain fatty acids with an array of effects: the fatty acid butyrate, for example, fortifies the blood–brain barrier by tightening connections between cells. Recent studies also demonstrate that gut microbes directly alter neurotransmitter levels, which may enable them to communicate with neurons. A seminal study also showed how certain metabolites from gut microbes could promote serotonin production in the cells lining the colon [14]. Multiple mechanisms, including endocrine and neurocrine pathways, may be involved in gut microbiota–to–brain signaling and the brain can in turn alter the microbial composition and behavior via the autonomic nervous system [15]. Germ-free (GF) animals which were born in aseptic conditions were often used in the studies of gut microbiota. There is a wide range of differences in brain biochemistry [16]; hypothalamic/pituitary/ adrenal (HPA) axis responses [17]; and affective [18], social [19], metabolic function, and ingestive behaviors [20] between GF animals and control animals. Multiple factors affecting the maternal gut microbiota can also influence the brain development in utero via microbial metabolites, drug derived chemical metabolites, and inflammatory changes [20].

The signals originated from brain reaching to the gut, through neural, hormonal and immunological routes. These include the sympatho-adrenal axis and hypothalamic-pituitary-adrenal (HPA) axis, the two branches of the autonomic nervous system, and the monoaminergic pathways, which modify the dorsal horn excitability and spinal reflexes. The hypothalamus and amygdala are two main subcortical structures contributing to these routes. Clarke et al. [22] showed that male GF animals had a significant elevation in the hippocampal concentration of 5-hydroxytryptamine and 5-hydroxyindoleacetic acid compared with the control animals. Concentrations of tryptophan, the precursor of serotonin, are increased in the plasma of male GF animals, suggesting a humoral route through which the microbiota can influence CNS serotonergic neurotransmission. Restoration of the gut microbiota can also attenuate anxiety in GF animals. These results demonstrate that the absence of a normal gut microbiota can profoundly disturb CNS neurotransmission. Bravo et al. [23] showed that orally treatment with L. rhamnosus induced region-dependent alterations in GABA (B1b) mRNA in the brain with increases in cortical regions (cingulate and prelimbic) and concomitant reductions in expression in the hippocampus, amygdala, and locus coeruleus, in comparison with control-fed mice. L. rhamnosus reduced GABA(Aα2) mRNA expression in the prefrontal cortex and amygdala, but increased GABA(Aα2) in the hippocampus. Importantly, L. rhamnosus reduced stress-induced corticosterone and anxiety- and depression-related behavior. Enteroendocrine cells may be involved in detection of the bacterial content of the lumen. Bacterial products can also regulate other GIT function such as gastric emptying and food intake, glucose homeostasis. It suggests the possible existence of a “bug-gut-brain axis” [24]. Melles et al. [25] explored the protective effect of liraglutide against American lifestyle-induced obesity syndrome (ALIOS) in mouse model that mimicked the western diet-induced pathophysiology. Results showed that Liraglutide could reduce visceral adiposity and liver weight, improve glucose and insulin tolerance, reduce improved hypertension, and reduce cardiac hypertrophy. Surprisingly, liver from the mice treated by liraglutide had significantly higher levels of fatty acid binding protein, acyl-CoA oxidase II, very long-chain acyl-CoA dehydrogenase, and microsomal triglyceride transfer protein. They concluded that liraglutide reduced the harmful effects of an ALIOS diet by improving insulin sensitivity and by reducing lipid accumulation in liver through multiple mechanisms including, transport, and increase β-oxidation.

Gut -Brain Axis

Considering huge intestinal surface area that is 100 times larger than the human surface area of skin it is easy to understand that the enteric nervous system(ENS)has more than 200 million neurons and over twenty different kinds of enteroendocrine cells in despite of gut endocrine cells representing a very small proportion of the total epithelial cell population in the GIT. Hence, ENS is also regarded as the “second brain” [26]. The ENS governs the function of the GIT system. Therefore, although being in direct contact with the CNS through innervation by the autonomic nervous system (i.e., sympathetic and parasympathetic), the GIT tract has its own independent reflex activity. The interaction between the ENS and CNS often described as the gut–brain axis [27]. Increasing evidence suggests that incretin has a very important role in the regulation of blood glucose [28]. A number of peptides and regulatory molecules in the intestinal lumen including incretin hormones containing glucose-dependent insulinotropic peptide (GIP), glucagon-like peptides, GLP-1 [29] and 5-hydroxytrypatmine [28] were released from insulin stimulation.

Microbial Endocrinology and Incretin

The most important endocrine function of the GIT is what relates to intestinal-derived peptides, which are fundamentally involved in postprandial insulin release. This action is termed as the ‘incretin effect’. Changes in the gut microbiota have been proven to be an important mediator of the development of obesity and related metabolic diseases as well as the secretion of incretin hormone. The microbiome in obese population is associated with an increased capacity to harvest energy from the diet, and this capacity can be transmitted by colonizing germ-free mice with the microbiota from obese individuals. Germ-free mice transplanted with an endotoxin-producing strain isolated from the gut in an obese human developed obesity and insulin was resistance on a high-fat diet. Specific metabolites of gut microbiota may trigger the secretion of GLP-1 via the activation of G-protein-coupled receptors [30].

Incretin and Liver

Incretin derived from gut play a key role in control of energy intake and homeostasis. Nutrients, microbial products and metabolites also modify incretin release. Incretins augment glucose-mediated insulin secretion, inhibit glucagon release, slow food absorption by reducing gastric emptying and inhibit appetite. Hence incretins may be an attractive therapeutic target for non-alcoholic-fatty-liver-disease and non-alcoholic-steatohepatitis (NAFLD/NASH) [31].

Incretin and Microbiota

Not only gut microbiota influence incretin secretion, but also incretin in turn plays an important role in microbiota regulation [32]. Gut microbiota fermentation products influence incretin. For example, acetate and propionate are able to stimulate incretin secretion via the G-protein-coupled free fatty acid receptor 2 and 3 [33]. Vice versa, incretin influence also gut microbiota fermentation products. Wang et al. [34] explored the effects of liraglutide and sitagliptin on the composition of the gut microbiota in mice. They showed that liraglutide changed the overall structure of the gut microbiota as well as the relative abundance of weight-relevant phylotypes. Mechanically they postulated that GLP-1 can modify the gut lumen internal environment (local pH value and nutrient composition) and thus affect microbiota composition by influencing the gut transit time and gastric emptying rate. Liraglutide reduces microbial diversity in mice fed a high fat diet (HFD). While only the Firmicutes are enriched, the Bacteroidetes, proteobacteria and actinobacteria phyla are depleted. Wang et al. [34] showed that liraglutide induced the enrichment in 13 phylotypes in genera allobaculum, turicibacter, anaerostipes, blautia, lactobacillus, butyricimonas, desulfovibrio, whereas it decreased 20 phylotypes in the orders clostridiales and bacteroidalesin HFD-fed or diabetes-induced mice. Further, they showed that among the seven genera and three families associated with weight decrease, liraglutide promoted only Lactobacillus, Turicibacter, Blautia and Coprococcus, while it reduced all obesity-related phylotypes (erysipelotrichaceaeincertaesedis, marvinbryantia, roseburia, candidatusarthromitus and parabacteroides). Saxagliptin was able to decrease the relative abundance of only one phylotype associated with weight gain, the genus Candidatus Arthromitus. Yan et al. [35] explored effects of sitagliptin on gut microbiota associated with obesity and T2DM in high fat/high carbohydrate fed rats treated by streptozotocin STZ. They showed that sitagliptin restored the gut microbiota structure at the phylum level in diabetic-induced rats. Sitagliptin induced an increase in the relative abundance of Bacteroidetes and Proteobacteria and a decrease in Firmicutes. At the genus level, sitagliptin influenced the short-chain fatty acids-producing bacteria. They also showed that probiotics such as Lactobacillus and Bifidobacterium were depleted in feces from diabetic rats. However, sitagliptin was able to prevent only the Bifido bacterium reduction and seemed to exacerbate Lactobacillus decrease.

Conclusions

Growing evidence indicates that the gut microbiota may represent a novel site of intervention for the prevention and/or treatment of aged-related diseases [36]. The intestinal microbiome plays an important role in modulating risk of several chronic diseases, including inflammatory bowel disease, obesity, type 2 diabetes, cardiovascular disease, and cancer. At the same time, it is now understood that diet plays a significant role in shaping the microbiome, with experiments showing that dietary alterations can induce large, temporary microbial shifts within 24 h. Given this association, there may be significant therapeutic utility in altering microbial composition through diet. This review systematically evaluates current data regarding the effects of several common dietary components on intestinal microbiota. [37, 38]. The gut microbiota is also key components of the gut-brain axis, the bidirectional communication pathway between the gut and the central nervous system (CNS). In addition, the CNS is closely interconnected with the endocrine system to regulate many physiological processes. As the peptides secreted from intestine incretin perform extensive protective effects by balancing energy, reducing blood glucose, and inhibiting neurodeneration. There has been interest in the interaction between microbiota and incretin. Gut microbiota fermentation products influence incretin. Vice versa,incretin influence also gut microbiota fermentation products. Further knowledge on the relationship between gut microbiota and incretin can provide a strategy for treatment of aged-related diseases. The human gut-brain axis is far from being fully understood. It remains unclear whether these altered serotonin levels in the gut trigger a cascade of molecular events, which in turn affect brain activity — and whether similar events take place in humans, as most studies have been conducted in animal models. There are also still existing gaps in knowledge regarding the interaction between the microbiome and the host in vivo, and the pathway of its metabolites, and how their metabolites influence the microenvironment. Metabolomic profiling might help answer these important questions. 

Compliance with Ethical Standards

Funding: This work was funded by Shanxi Scholarship Council of China (2017- important 4), the Scientific and Technological Innovation Projects in Shanxi Universities 201802062 and PhD Early Development Program of Shanxi Medical University BS201727.

Conflict of Interest: Professor Yueze Liu has no conflicts of interest to report, financial or otherwise                         

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