Review Article |
Corresponding author: Venelin Dimitrov Denchev ( v.denchev@medfac.mu-sofia.bg ) Academic editor: Magdalena Kondeva-Burdina
© 2023 Venelin Dimitrov Denchev, Teodora Svetoslavova Handjieva-Darlenska.
This is an open access article distributed under the terms of the Creative Commons Attribution License (CC BY 4.0), which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited.
Citation:
Denchev VD, Handjieva-Darlenska TS (2023) Pharmacological methods for weight reduction and their connection with the human gut microbiota. Pharmacia 70(4): 1471-1477. https://doi.org/10.3897/pharmacia.70.e114567
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In the beginning of the twenty-first century, obesity has become a concerning world-wide issue due to its high prevalence in modern society. It is a metabolic disorder, caused by excessive accumulation of adipose tissue in the human organism – the main reason for which is increased caloric intake and decreased caloric expenditure in combination with dysregulation of hunger. It is a chronic systematic disease that leads to the development of a large number of health complications, the most common of which are: diabetes mellitus type 2, arterial hypertension, atherosclerosis, sleep apnea, different types of cancer and more.
During the last decade, significant advancements have been made in regard to treatment of many endocrine and metabolic conditions, using pharmacological means, and some of these novel medications have proven to be an effective therapy for obesity. There is emerging evidence that such drugs can exhibit an effect over the human gut microbiota – the complex system of commensal bacteria located in the gastrointestinal tract, which could affect appetite, mucosal integrity, nutrient absorption, and that interaction can be the key to understanding the pathogenesis of obesity and its treatment.
antiobesity drugs, GI tract microorganisms, obesity, weight reduction
Obesity and its closely related condition metabolic syndrome are becoming more and more relevant problems for our modern society with every passing year – they represent a serious threat to the health of people, especially in developed and developing countries, and there is a clear tendency for progressively increasing numbers of affected patients – both in the adult population and also in children (
Obesity can lead to significant long-term damage to several organs and increase the risk for developing of: cardiovascular system conditions (endothelial dysfunction, atherosclerosis, myocardial infarction, brain stroke), chronic kidney disease (glomerular damage), liver steatosis (non-alcoholic fatty liver disease – NAFLD), malignant tumors (including hepatocellular and pancreatic cancer), metabolic and endocrine system conditions (diabetes mellitus type 2) (
Due to the significant impact that obesity has on society, it is important to take into consideration different strategies and approaches for prevention of weight gain and treatment of obese patients. The successful management of obesity should start with a plan that identifies the patient’s individual profile and needs – the potential contributory factors to weight gain, dietary habits, physical activity, genetic predisposition and family history of obesity, previous attempts at weight loss and other medical underlying conditions or medications that may lead to increase in body weight – such information can provide useful insight about the origins of obesity in the specific patient’s case (
Lifestyle interventions form the basis for initial therapy for obesity and include diet modification, increased physical activity and cognitive behavioral therapy (
Normal weight BMI = 20–24.9 | Overweight BMI = 25–29.9 | Class I Obesity BMI = 30–34.9 | Class II Obesity BMI = 35–39.9 | Class III Obesity BMI > 40 | |
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Balanced diet Physical activity | + | + | + | + | + |
Cognitive Behavioral Therapy | + | + | + | + | |
Pharmacological Therapy | * In the presence of obesity-related complications; comorbidities | + | + | + | |
Surgical therapy | * If pharmacological and cognitive behavioral therapy proves ineffective; comorbidities | * In the presence of obesity-related complications; comorbidities | + |
If this first line of multidisciplinary treatment does not prove effective, the patient may require additional pharmacological therapy in order to meet the required weight loss goals and health goals (usually such approach is reserved for cases of persistent obesity, not influenced by the use of previously mentioned methods, and showing signs of early development of obesity-related health complications).
Recent research has shown that improper interaction between hormones and the central nervous system (CNS) satiety centers is responsible for excessive food consumption – specifically, a dysregulation of the orexigenic hormones (increased levels of ghrelin) and anorexigenic hormones (decreased levels of leptin, cholecystokinin, peptide YY /PYY/, glucagon-like peptide-1 /GLP-1/) – the impaired interaction between these regulatory molecules and the hypothalamic satiety centers is a significant component of the pathophysiology of obesity (
In recent years the incretin system has been identified as a promising therapeutic target – incretins are small peptide molecules (secreted from the enteroendocrine L-type cells of the small intestines in the presence of glucose), that include the glucagon-like peptide-1 /GLP-1/ and glucose-dependent insulinotropic polypeptide /GIP/ (
It has been established that the naturally occurring incretin GLP-1 has a severely limited use as a medication because of its extremely short half-life (~2 min) due to being susceptible to quick degradation from the plasma enzyme DiPeptidylPeptidase-4 (DPP-4) (
GLP-1 Receptor Agonist Generic name | GLP-1 Receptor Agonist Trademark name (Authorized for use in the EU) | Method of administration | Pharmacological effects (identical for all medications in the group) | Side effects (identical for all medications in the group) |
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Exenatide | Byetta ® | subcutaneous | ↑ insulin | GI disturbance |
Bydureon ® | subcutaneous | secretion | - nausea | |
Liraglutide | Victoza ® | subcutaneous | ↓ glucagon | - vomiting |
Saxenda ® | subcutaneous | secretion | - diarrhea | |
Semaglutide | Ozempic ® | subcutaneous | ↓ blood glucose | Hypoglycemia |
Wegovy ® | subcutaneous | levels | /rare/ | |
Rybelsus ® | oral tablets | ↓ weight | (?) ↑ risk of | |
Dulaglutide | Trulicity ® | subcutaneous | ↓ hunger | pancreatitis |
Lixisenatide | Lyxumia ® | subcutaneous | ↓ appetite | pancreatic |
↓ food intake | cancer |
GLP-1 receptor agonists appear to be generally safe and very well tolerated. The side effects include: gastrointestinal tract disturbances – commonly nausea, vomiting, diarrhea (in severe cases that could be a reason for discontinuation of therapy), very rare instances of hypoglycemia (usually in higher doses when combined with other antidiabetic drugs from the sulfonylurea class; extremely uncommon when used independently) and local inflammatory skin reaction near the site of injection (for the ones applied subcutaneously) (
In addition to all previously mentioned therapeutic effects there is also emerging evidence that these medications may also interact with and influence the complex system of bacterial microorganisms in the gastrointestinal tract, known as the human gut microbiota, which by itself is proving to be a fundamental target for treatment of endocrine and metabolic disorders like obesity and diabetes mellitus type 2.
The gut microbiota is a complex system formed by all commensal bacteria that inhabit the human gastrointestinal system, mainly – the intestines (and the colon in particular). Due to extensive research in this area in the last couple of decades, we have gained valuable information about the physiological function and composition of the gut microbiota, but also about its relation to the pathogenesis of different health conditions (
These bacteria play an important role in the regulation of processes both locally in the GI tract but also systematically in the entire human organism – research shows that some of their physiological effects include: inhibition of growth of pathogenic intestinal bacteria, promoting normal barrier function of the epithelial layer of intestinal mucosa, contribution to normal digestion, fermentation of food products in the colon, regulating energy balance through modifying nutrient absorption, supporting human macroorganism homeostasis by affecting endocrine and metabolic functions (
For example, in normal weight patients, the gut microbiota consists mainly of the two large phyla Firmicutes and Bacteroidetes, which together compose up to 90% of all GI tract bacteria (
There has been an increasing scientific interest during the last decade in regard to the interaction between commensal bacterial cells and human host cells from the intestinal epithelium, especially the regulatory enteroendocrine cells, due to their innate ability to interact with chemical compounds inside of the lumen and correspond by secreting peptide molecules that regulate homeostasis in the organism (
The GLP-1 receptor agonists have proven themselves as highly effective drugs for therapy of both diabetes mellitus type 2 and obesity in the past decade (
All of the above-mentioned variations as well as the individual peculiarities, dietary habits, age, comorbidities, ethnicity, genetic predisposition exhibit an influence on gut dysbiosis associated with obesity and related diseases and it is interesting to look into how these novel medications could lead to reduction of weight through modifications of gut microbiota composition (
In conclusion, emerging data from recent studies supports a growing body of evidence showing that novel anti-diabetic drugs – GLP-1 receptor agonists like liraglutide – have the capability to modulate the gut microbiome and that topic is a promising direction for researching the pathogenesis of obesity. The changes in the GI tract bacterial composition include: improving the diversity and richness of the intestinal bacterial community, increasing the relative abundance of lean-related microbial phenotypes and decreasing obesity-related microbial phenotypes, normalizing the Firmicutes/Bacteroidetes ratio – and all of these effects were observed in both subjects with obesity and/or diabetes mellitus type 2. However, at the current moment the evidence about this fine interplay between the antiobesity drugs and microorganisms is still severely limited, it comes mainly from animal experimental models and further and much more in-depth clinical studies in patients are required to explore the specific mechanism by which liraglutide affects intestinal microbiota and to what extent the weight-controlling effects of liraglutide are dependent on that modulation.