Obesity has reached epidemic levels, leading to a global crisis characterized by myriad health issues, premature mortality, and significant economic burdens. The historical approach to weight loss has been fraught with challenges. While lifestyle changes, drugs, and surgery are options that can be effective in the short term, many people fail to keep the weight off due to sabotage by environmental, biological, and behavioral factors. Clearly, different strategies are needed to address this complex issue.
In recent years, increasing evidence has linked obesity to the gut microbiota. This blog explores the evidence linking the gut microbiome with obesity as well as the therapeutics targeting the gut microbiome that may potentially provide novel treatments.
Obesity, in brief
Obesity (BMI higher than 30 kg/m2), has nearly tripled since 1975. Today more than 1 billion people worldwide are obese – 650 million adults, 340 million adolescents, and 39 million children. Impacting multiple body systems, obesity can lead to heart, liver, kidney, joint, and reproductive issues. It is linked to Type 2 diabetes, cardiovascular disease, hypertension, stroke, various cancers, mental health problems, and an increase in hospitalization risk for some viral infections.
Obesity primarily results from an imbalance between calories consumed and calories expended, but in some cases, genetics, hypothyroidism, Cushing’s disease, depression, and certain medications can contribute to fat accrual.
Proper diet, exercise, and behavioral therapies are the conservative treatment of choice for obesity management though maintenance can be difficult. This struggle arises because body weight, controlled by intricate hormonal, neural, and metabolic processes, is influenced by numerous external factors and internal responses.
Drug therapy appeared in the 1930s with amphetamines, followed by numerous compounds (many since withdrawn because of harmful side effects and even fatal consequences.) Popular now are gut peptide analogs such as semaglutide and tirzepatide, which help control blood sugar and slow gastric emptying to dramatically decrease appetite and incur weight loss.
Bariatric surgery was introduced in the 1950s and has evolved to include surgical procedures including Roux en-Y bypass, sleeve gastrectomy, and biliopancreatic diversion with duodenal switch. Though quite effective in reducing weight and reducing mortality, such surgeries also carry considerable risks.
While these therapies may help shed pounds, maintaining the weight loss over the long term is hard to achieve. In search of the holy grail (and sizeable profit), the multibillion-dollar weight loss industry has offered a gamut of therapies including herbs, supplements, hypnosis, enemas, wired jaws, tongue patches, and considerably more.
However, an optimum solution for treating obesity is elusive; global numbers continue to escalate despite numerous types of available weight management therapies. New evidence suggests that by exploiting the complex interface between the gut microbiota and obesity, novel alternatives may be developed.
Obesity and the gut microbiota
The gut microbiota plays a crucial role in digestion, vitamin synthesis, and metabolism, potentially influencing energy production, inflammation, and fatty acid composition. It has been proposed that disruptions in the gut microbiome could contribute to obesity alongside other factors like nutrition, genetics, and lifestyle.
First of all, the microbiome residing in the human gut can differ between obese and normal-weight individuals. While research in this field is ongoing, several key observations have emerged:
Diversity: Studies have shown that obese individuals tend to have a less diverse gut microbiome (more diversity is considered healthier) compared to those with a normal weight. In addition, microbial diversity has been shown to have a preventive effect on long-term weight gain in healthy individuals.
Composition: Obese individuals may have a higher abundance of certain bacteria, such as Firmicutes, and a lower abundance of others, such as Bacteroidetes. However, these findings can vary between studies and individuals suggesting that the impact of the gut microbiome on obesity goes beyond a simple disruption in the abundance of these bacterial phyla.
Functionality: The metabolic functions of the microbiome can also differ. In a seminal 2006 study, researchers found the gut microbiome in obese mice had an enhanced ability to extract energy from dietary sources. When germ-free mice were colonized with microbiota from obese donors as opposed to lean counterparts, there was a greater increase in total body fat. However, recent research reported that housing conditions of germ-free mice can lead to contradictory results.
Inflammation: The microbiome can influence inflammation in the gut and distant sites. Some research suggests that obese individuals may have a microbiome profile associated with low-grade chronic inflammation, which can be a factor in obesity-related health issues.
Metabolism: Alterations in the microbiome composition can affect how the body processes nutrients, potentially influencing weight gain or loss.
Hormone Regulation: The gut microbiome can influence hormones related to appetite and satiety, such as ghrelin and leptin. Dysregulation of these hormones can contribute to overeating and weight gain.
Influence of Diet: Diet is a significant factor in shaping the microbiome. A diet high in fiber, fruits, and vegetables tends to promote a more diverse and potentially healthier microbiome. Conversely, a diet high in sugar and fats can lead to an imbalance in the microbiome.
Antibiotics Impact: Research indicates that the use of antibiotics during crucial stages of early microbiota development could potentially impact weight gain and the onset of obesity later in life, with studies in both humans and rodents highlighting the significant involvement of the gut microbiota in this phenomenon.
In addition to differences in the gut microbiome, distinct microbial profiles have recently been reported in the liver, adipose tissue, and plasma of individuals with morbid obesity and diabetes.
While links between the microbiome and obesity exist, causality isn’t yet proven. Obesity is a multifaceted condition shaped by genetics, lifestyle, and environmental factors, with the microbiome being just one factor. Individual variation in microbiome composition and its impact on weight can also be substantial.
As our understanding of the gut microbiome’s role in obesity has deepened, harnessing it to control weight has been studied.
In obese mice fed a high-fat diet, gut microbiota showed reduced diversity while a high-sucrose diet altered structure. Introducing probiotics led to a slowdown in weight gain in both groups.
In other research, supplementing obese mice with specific strains of bacterial species including Lactiplantibacillus plantarum and Latilactobacillus sakei reduced adipose deposition and enhanced lipid oxidative gene expression.
More recently, supplementation with a probiotic in obese rats significantly reduced weight gain and improved metabolic parameters compared to the control group.
However, these studies differ in bacterial strains used, animal obesity models, and treatment period, making it difficult to report the most effective probiotic on weight reduction and how it translates to humans.
In clinical studies, probiotic supplementation has demonstrated several positive effects on weight management and metabolic health.
In individuals consuming a high-fat diet in one early study, a multistrain probiotic reduced weight gain compared to a placebo.
A 2018 meta-analysis reported that probiotics led to significant reductions in BMI, body weight, and fat mass when compared to placebo. A subgroup analysis revealed that lactobacillishowed reductions in BMI and the greatest reductions in body weight and fat mass.
A later meta-analysis also revealed that probiotics led to reductions in obesity and associated metabolic parameters. Greater fat mass reduction was observed with higher probiotic doses and single-strain probiotics.
Moreover, probiotics may enhance weight loss when delivered as an adjunct to diet and exercise interventions. A meta-analysis of eleven trials found that intervention plus probiotics resulted in increased reductions in weight, fat mass, and waist circumference when compared with dietary and exercise interventions alone.
Studies conducted on probiotics and their effects on obesity-causing factors are briefly summarized here.
Prebiotics, such as fructo-oligosaccharides (FOS), galacto-oligosaccharides (GOS), and inulin influence the gut microbiota, with potential benefits for weight management and health.
Many prebiotics increase the number of Bifidobacterium species and other butyrate producers, leading to improvements in metabolic outcomes and the gut barrier against pathogens.
FOS, in particular, has demonstrated bifidogenic properties, but more research is needed for conclusive evidence on weight reduction. In studies, an increase in Bifidobacterium is accompanied by a rise in Lactobacillus species following the addition of FOS, resulting in a decline in ghrelin levels, PYY, and food intake.
Supplementation with GOS in healthy individuals has been shown to raise the number of Bifidobacterium spp. and decrease the number of Bacteroides.
In mice, the fermentable carbohydrate inulin is able to increase the density of cells that produce the appetite-suppressing hormone PYY by 87%, thus suggesting a role in reducing food intake and enhancing obesity treatment.
These results indicate that prebiotic consumption may reinforce microbial diversity and have beneficial effects on the health of the host.
Additional gut microbiota influencers
Different diets can significantly affect the composition and diversity of the intestinal microbiota. For example, a review of both animal and human studies found that the “Western diet” is linked to an obesogenic microbial profile (decreased diversity, increased Firmicutes, and decreased Bacteroidetes) whereas a high-fiber diet is associated with increased diversity and an increased Firmicutes/Bacteroidetes ratio. A full list of diet effects on gut microbiota includes that of the Mediterranean diet, vegetarian, high-fat, and high-protein diets.
In addition to dietary patterns, various therapeutic interventions including medications, fecal microbiota transplantation, and bariatric surgery have been studied to ascertain how they may modulate the gut microbiome and influence obesity, with some interventions leading to alterations in bacterial diversity and composition and potential improvements in metabolism, inflammation, and weight management.
Considering the complex nature of obesity and the interplay of physiological mechanisms governing weight and appetite, a multi-faceted approach might offer greater efficacy than a singular strategy.
Potential mechanisms of action
Microbiota-targeted interventions may benefit host metabolism by several mechanisms, including increasing short-chain fatty acid (SCFA) and other beneficial metabolite-producing bacteria, decreasing lipopolysaccharide tissue damage and inflammation, and limiting opportunistic pathogens and their metabolites. For example, the SCFAs butyrate and propionate stimulate the secretion of gut peptides which can modulate appetite and food intake, enhance glucose metabolism, and mitigate inflammation.
Obesity is a global health crisis with traditional weight loss methods often falling short. Emerging research highlights the gut microbiome’s role in obesity, offering new avenues for treatment.
As insights into the role of the intestinal microbiome in obesity grow, the possibility of managing weight through modulation of the gut microbiome becomes an increasingly appealing strategy. Probiotics and prebiotics show promise in altering the gut microbiome to improve metabolism and weight management.
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