Introduction
The intricate relationship between the gut microbiome and host physiology has garnered significant attention in recent years. Microbial communities residing in the colon exert a profound influence on various aspects of host health, including immune function, inter-organ communication, and metabolism. Studies have consistently correlated the gut microbiota's composition, gene expression, and metabolic activity with critical health outcomes such as body weight, glycemic control, and inflammatory bowel diseases. While observational studies and preclinical models have provided valuable insights, the question of whether the gut microbiome is a causal driver or merely a reflection of host physiology remains a key area of investigation.
The impact of the gut microbiome on weight regulation has emerged as a topic of considerable interest, particularly in the context of the global obesity epidemic. Obesity, a major public health concern, stands at the intersection of metabolic diseases such as cardiovascular disease, non-alcoholic fatty liver disease, and type 2 diabetes. The gut microbiome has been identified as a central player in host energy balance, influencing energy harvest from food, gut hormone regulation, and signaling through metabolites like short-chain fatty acids (SCFAs).
The Gut Microbiome and Energy Balance
The gut microbiome's role in energy balance is multifaceted. It affects the amount of energy extracted from food, influences gut hormones that regulate appetite and satiety, and produces metabolites like SCFAs that impact host metabolism. The gut microbiota is an indispensable source of essential vitamins B and K. The alteration of gut microbiota is closely linked to tissue inflammation and to a broad range of metabolic abnormalities, including obesity and insulin resistance.
Current estimations indicate that the human intestine is colonized by a large population of above 100 trillion microbial cells organized in several taxa and constituting the gut microbiota. The total biomass of the gut microbiota exceeds 1kg and is mainly concentrated in the large intestine, where about 1012 bacteria per gram of colonic tissue are found.
Controlled Feeding Studies: A Deep Dive into the Gut
To address critical knowledge gaps in understanding the interplay between host diet and the gut microbiome in human energy balance, researchers have conducted controlled feeding studies in metabolic wards. These studies employ a deep-phenotyping paradigm of quantitative bioenergetics to meticulously assess the impact of dietary interventions on various metabolic parameters.
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One such study involved a highly digestible control Western Diet (WD) and a Microbiome Enhancer Diet (MBD). The MBD was designed to maximize the availability of dietary substrates to the gut microbiome, incorporating four key dietary drivers: dietary fiber, resistant starch, large food particle size, and limited processed foods. The diets were carefully formulated to provide equivalent dietary metabolizable energy (kcal) and total macronutrients (fat, protein, carbohydrates) based on established principles of food digestibility.
Key Findings: The Microbiome Enhancer Diet (MBD)
The study revealed that delivering more dietary substrates to the gut microbiome, as achieved with the MBD, leads to a net negative energy balance. This was accompanied by a robust remodeling of gut microbiota composition, diversity, and function, as well as changes in host enteroendocrine hormones.
Increased Fecal Energy Loss: The MBD significantly increased mean daily fecal energy losses compared to the WD. This indicates that a greater proportion of energy from the MBD was not absorbed by the host and was instead excreted in the feces.
Reduced Host Metabolizable Energy: Consequently, host metabolizable energy, the amount of energy available to the host after accounting for fecal losses, was lower with the MBD. This suggests that the MBD effectively reduced the energy available to the body.
Modulation of the Gut Microbiome: The MBD led to significant changes in the gut microbiome. Fecal bacterial 16S rRNA gene copy number (a surrogate of biomass) was higher on the MBD. Beta-diversity analysis revealed a distinct separation in microbial community structure between the two diets.
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Changes in Microbial Composition: At the species level, the MBD promoted the growth of dietary fiber degraders such as Prevotella copri and Lachnospira pectinoschiza, as well as butyrate producers like Eubacterium eligans. In contrast, the WD favored species that utilize host-derived glycans and simple sugars.
Increased Fermentation: The diet-induced changes in microbial composition were accompanied by increased fermentation, as evidenced by higher levels of SCFAs in both feces and serum.
The Role of Specific Microbial Species
Several microbial species have been identified as key players in the relationship between the gut microbiome and weight management.
Akkermansia muciniphila: This bacterium feeds on mucin, a protective layer lining the gut. It produces toxic molecules like lipopolysaccharide (LPS). A. muciniphila is considered a beneficial probiotic.
Bifidobacterium longum APC1472: This probiotic has been shown to lower fat and weight in mice and improve blood sugar levels in humans.
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Schizosaccharomyces pombe: This potential probiotic is less abundant in overweight humans.
The Importance of Microbial Diversity
Higher microbial diversity in the gut is generally considered beneficial. It may reduce the permeability of the gut, preventing harmful substances from entering the bloodstream.
Dietary Strategies to Modulate the Gut Microbiome
Specific dietary strategies can be employed to modulate the gut microbiome and promote weight loss.
- Prebiotics: These are nutrients that selectively stimulate the growth of beneficial microbes.
- Probiotics: These are live microorganisms that, when administered in adequate amounts, confer a health benefit on the host.
- Synbiotics: These are combinations of probiotics and prebiotics.
The Gut-Brain Axis
The microbiome-gut-brain axis plays a crucial role in regulating appetite and food preferences. Bacteria can influence the release of hormones from gut cells and modulate appetite and reward centers in the brain.
Fungal and Viral Communities in the Gut
Fungi and viruses also play a significant role in the gut microbiome. The fungal signatures of lean and obese individuals are distinct. Viruses, particularly phages, can be recruited to fight harmful bacteria.
Metabolically Healthy Obesity (MHO)
A unique subtype of obese individuals has been identified as metabolically healthy obese (MHO). Despite excessive body fat, MHO patients exhibit higher insulin sensitivity, normal lipid profiles, and lower levels of liver fat and inflammation compared to metabolically unhealthy obese (MUHO) individuals. The gut microbiota is considered a key determinant in the host metabolic profile and may contribute to the MHO phenotype.
Medium Chain Triglycerides (MCTs)
Dietary medium-chain triglycerides (MCTs) have been found to promote lipid catabolism, energy expenditure, and weight loss. They can also improve intestinal ecosystem and permeability, potentially ameliorating metabolic health.
The Role of Gut Permeability
A dysbiosis induced by obesogenic factors adversely enhances intestinal permeability by modulating the expression of epithelial junction genes zo-1 and occludin. An optimal gut microbiota helps maintain intestinal barrier impermeability via the production of SCFA, which serve as metabolic precursors for colonocytes in normal physiologic hypoxia conditions.
Pharmaceutical Interventions
Pharmaceutical interventions that disrupt nutrient digestion, such as orlistat, have been used to treat obesity. Orlistat inhibits lipase, an enzyme responsible for breaking down fats in the intestine. This reduces the amount of fat absorbed by the body, leading to weight loss.
Herbal and Bacterial Products
Numerous plant-derived phytochemicals and bacterial products have been screened for potential lipase inhibition activity. These compounds may offer a natural approach to reducing fat absorption and promoting weight loss.