The gut microbiome as a modulator of longevity, health, and disease

The gut microbiome is a complex ecosystem predominantly found in the gastrointestinal (GI) tract. Compositional or functional changes within the gut microbiota have been shown to contribute to health and disease, including immune, metabolic and neuro-behavioral attributes. Gut microbiota composition can be highly variable and diverse between individuals, though some key bacterial species are typically present in most.

The human GI tract contains up to 10¹³-10¹⁴ bacterial cells, consisting of up to 1000 different species. This is ten times more than cells in the human body. It is estimated that over 70% of all microbes in the human body are contained in the gut (small and large intestines).

Gut microbiota seems to exert a great range of functional properties impacting human physiology and pathology; modulation of energy absorption and harvest through the production of vitamins and fermentation of non-digestible food constituents, the influence of intestinal homeostasis, the development, function, and maturation of the immune system, and drug metabolism.

 

Non-dietary factors that affect the gut microbiota

The gut microbiota is shaped by a combination of extrinsic (e.g., lifestyle and drug use) and intrinsic (e.g., genetics) factors. However, genetics are responsible for a mere average level of 8,8% for the gut microbiota composition. The latter is rather highly individualized to the host and shaped across a lifespan, with a unique makeup of bacteria commencing at birth.

Since the early stages of life, several ‘’non-dietary’’ factors seem to influence gut microbial composition. Key influences on the neonatal microbiota are delivery mode, infant feeding, antibiotic use, gestational age, and infant hospitalization. Term birth, vaginal delivery, short hospitalization, less antibiotic exposure, and breastfeeding are associated with a more ‘’beneficial’’ gut microbiota. Therefore, the gut microbiota undergoes dramatic changes soon after birth with lactation, followed by a secondary shift on the introduction of solid foods, and stabilizes at around three years of age. By three years, a more stable and adult-like microbial environment has been established with greater resistance to perturbations. After that time, environmental factors such as diet and medication, but also the disruption of the immune system, can still influence the gut microbiome composition. It is actually suspected that the gut microbiota continues developing past early childhood.

 

The effect of diet on gut microbiota

Despite a tendency for microbial stability in adulthood, nutrient quality and quantity may still impact the gut microbiota. Specifically, diet is thought to explain over 20% of the microbial structural variations in humans, signaling the potential for dietary strategies in disease management through gut microbiota modulation.  A diverse diet, and in particular, the number of different types of plant foods consumed, has been associated with greater microbial diversity. Diet alterations may induce new species and proliferate others, increasing the diversity and richness of beneficial bacteria. However, the duration of any dietary intervention required to elicit a permanent change to the core microbial profile is still unknown. In humans, there are rapid but transient changes in the gut microbiota in response to dietary interventions. For example, changes in fiber intake are positively correlated with a change in abundance of 15% of the microbial community the following day. Fiber content, amount, and type appear to be critical determinants of microbiota, especially fruit and grain fiber. Nevertheless, without continued consumption, the microbial changes are lost within twenty-eight days without continued consumption. 

Similarly, exclusively plant-based or exclusively animal-based diets shifted gut microbiota composition, with the animal-based diet displaying significantly decreased levels of good bacteria within 24 hours. However, the microbiota of the subjects returned to baseline within three days after the intervention.

Furthermore, diet-induced weight loss is associated with specific changes in gut microbial composition in terms of increased beneficial anti-inflammatory bacteria and reduced pathogens.

All in all, while diet has been shown to facilitate shifts in microbial composition in as little as three days, long-term diet and sustainable changes to the habitual diet are the primary drivers for maintaining the dietary effects on gut microbiota. 

Dietary fiber is the most commonly accepted nutrient to exert a beneficial impact on microbiota composition. Other food components, such as polyphenols, a group of antioxidants, are also considered beneficial. On the other end of the spectrum, a Western dietary pattern, with increased consumption of refined carbohydrates, high-fat animal products, and highly-processed foods, is linked to unfavorable changes in gut microbial composition. 

However, current knowledge of how specific dietary habits impact the gut microbiota long term is limited; hence robust conclusions cannot be made.

 

Gut microbiota and metabolic health

Recent evidence suggests the gut microbiota’s potential role as a pathogenic factor affecting host metabolic balance and disorders, such as metabolic syndrome. The metabolic syndrome is defined by interconnected physiological, biochemical, clinical, and metabolic factors linked to an increased risk of cardiovascular disease and type II diabetes mellitus. More specifically, the main features of metabolic syndrome are raised blood pressure, dyslipidemia, raised fasting glucose, and central obesity. 

The mechanism through which gut bacteria lead to obesity passes through complex metabolic functions, including host appetite, energy absorption, and energy harvest. More specifically, gut microbes hydrolyze and ferment dietary polysaccharides that are not digested and absorbed by the small intestine and produce short-chain fatty acids (SCFAs). In turn, SCFAs, like propionate, butyrate, and acetate, are absorbed in the colon and used as a source of energy by the host, increasing the daily caloric intake. 

Eventually, the interaction between the microbial products, such as SCFAs, and the host’s immune system lead to metabolic endotoxemia, which is then responsible for the development of obesity and insulin resistance, hence the metabolic syndrome. The progressive development of glucose intolerance and diabetes proceeds with a corresponding decrease in anti-inflammatory bacteria and an increase in pathogens.

Overweight and obesity, on the other hand, cause functional changes in the gut microbiota themselves, leading to even more increased production of SCFAs, with a consequently raised capacity of energy harvest, hence more detrimental effects on weight and metabolic health. 

However, it is not clear how and why, in obese subjects, gut microbiota seems to extract more energy from ingested food.

Nevertheless, it is recognized that low genetic richness in gut microbiota, reflecting a reduced microbial diversity, is correlated with overall adiposity, insulin resistance, increased numbers of inflammatory gut microbes, and decreased numbers of beneficial gut microbes compared to high bacterial gene richness individuals. 

Furthermore, a subgroup of subjects with low microbial gene richness has shown less responsiveness to therapeutic strategies against metabolic syndrome, such as diet and exercise. 

 

Probiotics and prebiotics

Probiotics are live microorganisms that, when administered in adequate amounts, can colonize and proliferate in the gut, thereby influencing the gut microbiota and possibly conferring a beneficial health effect on the host. Several studies have demonstrated that probiotic strains, particularly those of Lactobacillus and Bifidobacterium species, exert multiple beneficial effects, including the treatment of infections and antibiotic-associated diarrhea, improved glucose tolerance and insulin resistance in type II diabetes as well as the remission and maintenance of inflammatory bowel disease (IBD), among others, and reduce metabolic endotoxemia. However, the available evidence suggesting the use of probiotics for managing these diseases is still weak.

On the other hand, prebiotics are defined as non-digestible polysaccharides that promote the selective stimulation of the growth of a limited number of gut microbiota species that confer health benefits to the host. The most studied prebiotics are inulin and various types of fructooligosaccharides, namely plant sugars, naturally occurring in fruits and vegetables. A recent clinical trial exploring the beneficial effects of prebiotics on subjects with metabolic syndrome reported a statistically significant reduction of post-prandial glucose and insulin levels. However, data regarding their impact on body weight, fat loss, and satiety are still controversial.

As a result, although several studies have reported encouraging results for their administration, solid clinical evidence recommending their therapeutic use for metabolic diseases has not yet emerged, and knowledge about their long-term efficacy and clinical impact on gut microbiota composition is still lacking.