Maintaining a Healthy Microbiome
The Human Microbiome Project (HMP) was launched in 2008 by the National Institutes of Health (NIH) as an extension of the Human Genome Project (Turnbaugh 2007; Huse 2012; Peterson 2009). It is an ongoing worldwide undertaking that seeks to understand microbial communities and their variations in and on healthy humans (Turnbaugh 2007), beginning with five major body regions: the gastrointestinal tract, skin, vagina, respiratory tract, and oral cavity (Gevers 2012). A major goal of the HMP is to create a resource for determining how altered microbial patterns may contribute to disease and how to restore healthy microbial balance (Ursell 2012; Gevers 2012; Foxman 2010). Thanks to advances in gene sequencing technologies, knowledge about the microbiome is expanding rapidly (Knight 2017).
The human microbiome is extremely diverse and surprisingly variable: while only approximately 0.5% of the human genome is variable between individuals, the microbiome can vary dramatically between individuals (Ursell 2012; Mayor 2007). Much of this variability is due to differences in diet, environment, genetics, antibiotic use, and microbial exposure early in life (Human Microbiome Project Consortium 2012; Lloyd-Price 2016; Wischmeyer 2016). The diversity and variability of the human microbiome makes its characterization extremely challenging (Ursell 2012; Lloyd-Price 2016; Johnson 2016; Lozupone 2012).
The largest and most heavily studied component of the human microbiome resides in the gut. Microbiome researchers have estimated that each person is host to about 160 distinct intestinal bacterial species (Lloyd-Price 2016). Lactobacillus and Bifidobacterium species, encountered during birth and present in breastmilk, are among the earliest colonizers of the infant gut, and they shape subsequent colonization with other species (Koboziev 2014). While Lactobacillus and Bifidobacterium species become less abundant in the intestinal microbiome of adults as compared with infants (Arboleya 2016; Sghir 2000), they have been the focus of much attention due to their beneficial health effects, modulation by diet and environment, and possible therapeutic effects when used as probiotic supplements (Evivie 2017; O'Callaghan 2016; Derrien 2015; Rodriguez 2015).
Functions of a Healthy Microbiome
Microbes in the intestines produce enzymes that can break down certain food components that human digestive mechanisms alone cannot (Thursby 2017; Kau 2011). A healthy microbiome therefore allows us to tolerate otherwise indigestible plant foods and extract otherwise inaccessible nutrients from them (Turnbaugh 2007; Krajmalnik-Brown 2012).
Microbial enzymes are especially important for breaking down indigestible and partially digestible carbohydrates, including certain starches and fibers. This enhances the body’s ability to extract and absorb monosaccharides (single-unit sugars) that can be turned into energy (Flint 2012; Krajmalnik-Brown 2012). Gut bacteria metabolize and activate many plant polyphenols and other phytochemicals, which may have important implications for health (Ozdal 2016; Tomas-Barberan 2016; Theilmann 2017; Swanson 2015). For example, certain intestinal bacteria transform lignans and isoflavones into active compounds linked to improved female hormone signaling (Gaya 2016).
The gut microbiome is also equipped with enzymes to digest dietary proteins. Some microbes are more efficient protein-digesters than others. Some of the byproducts of microbial protein digestion can have toxic effects that may contribute to negative health outcomes. A Western-style diet, which is high in animal protein and low in indigestible fibers, has a considerable detrimental impact on gut microbiome composition by supporting species that can best adapt to a high-protein environment (Montemurno 2014; Graf 2015; David 2014).
A major metabolic pathway used by intestinal microbes to produce energy is fermentation, which is a metabolic process that does not require oxygen (Thursby 2017; Monda 2017). The main byproducts of microbial fermentation, primarily of dietary fibers, are short-chain fatty acids, including butyrate, acetate, and propionate. Short-chain fatty acids are not only a major energy source for cells lining the large intestine, but also regulate immune activity, prevent infections, reduce inflammation, enhance the absorption of minerals such as calcium, have anti-cancer properties, and can influence cholesterol levels, appetite, and weight gain (Sharon 2014; Flint 2012; Krajmalnik-Brown 2012; Whisner 2017).
Byproducts of protein fermentation are somewhat different than those of carbohydrate fermentation and include a number of compounds that are potentially toxic. Some of these toxic byproducts are believed to contribute to health problems associated with diets high in animal protein, such as colon cancer and some chronic diseases (Montemurno 2014).
Bile acids are the main components of bile, which is secreted from the gallbladder into the small intestine during digestion (Taoka 2016). Microbial enzymes transform bile acids into a wide array of byproducts, some of which are reabsorbed (Ryan 2017). In addition to assisting in the digestion and assimilation of fats and fatty compounds, reabsorbed bile acids and their byproducts help regulate lipid and glucose metabolism and energy production (Taoka 2016; Ryan 2017). How bile acids modulate cardio-metabolic conditions such as obesity, diabetes, fatty liver, and heart disease is still being explored (Ryan 2017; Chiang 2017).
Interestingly, bile acids also contribute to shaping the gut microbiome via antimicrobial effects and interactions with the immune system (Ramirez-Perez 2017; Chiang 2017; Ridlon 2014; Nie 2015). Bile acids may be one of the ways to connect diet, which influences the types of bile acids produced, to the composition of the gut microbial populations, which may be supported or suppressed by the presence of certain bile acids (Ridlon 2014; Islam 2011; Wahlstrom 2016).
Other byproducts of microbial activity that benefit human hosts include B vitamins, vitamin K, and amino acids such as tryptophan (Jandhyala 2015; Etienne-Mesmin 2017; Conly 1992; Morowitz 2011; Paiva 1998). Several tryptophan-derived compounds have important impacts on the functions of the immune and nervous systems (Cervenka 2017; Jenkins 2016). For example, approximately 90% of the body’s serotonin is made in the gastrointestinal tract from tryptophan (Sharon 2014; Kato 2013; Mawe 2013). Bacteria that colonize the intestines may also produce other neurotransmitters, such as acetylcholine, norepinephrine, dopamine, and gamma-aminobutyric acid (GABA) (Clark 2016; Galland 2014). These neurotransmitters exert a host of peripheral effects, such as modulation of the stress response, which ultimately influences brain function and mood (Galland 2014; Jenkins 2016; Robson 2017).
Gut microbes play an important role in metabolizing some medications, in some cases activating them prior to absorption (Noh 2017). Some of these medications, such as the anti-diabetes drug metformin, appear to rely at least in part on altering the gut microbiome to achieve their therapeutic effect (Wu 2017; Rena 2017). In one case report, targeting the growth of beneficial microbes with a food-based supplement improved both metformin’s tolerability and efficacy (Greenway 2014). Based on this intriguing case report, researchers carried out a small clinical study on 10 diabetic individuals. They found supplementation with the microbiome-targeted nutrients agave inulin, oat beta-glucan, and blueberry polyphenols improved metformin’s tolerability and efficacy (Burton 2015). Gut microbes also help process and detoxify harmful environmental compounds such as carcinogens (Turnbaugh 2007; Moon 2016).
A critical function of the microbiome is preventing the overgrowth of harmful microbes. Some mechanisms by which it achieves this are: maintaining an acidic pH; secreting antimicrobial substances; inhibiting microbial toxicity; competing for nutrients and resources; preventing harmful organisms from adhering to superficial cells; and activating local immune cells (Tosh 2012; Surendran Nair 2017; Knaus 2017).
The microbiome plays an integral role in immune regulation (Gulden 2017). Almost all tissues and organs, whether in direct contact with or further away from the microbiota, are influenced by the microbiota. Microbes and their products communicate with the immune system, promote its development and maturation, and guide immune responsiveness (Brown 2017; Shi 2017; Correa-Oliveira 2016; Shibata 2017; Belkaid 2014).
The immune regulatory role of the microbiome also helps prevent the dysfunctional immune activity that can lead to allergies, autoimmune diseases, and chronic inflammatory conditions (Brown 2017; Fujimura 2015). Microbiome disturbances have been linked to chronic inflammatory conditions such as periodontal disease, bacterial vaginosis, atopic dermatitis, inflammatory bowel disease, rheumatoid arthritis, and obesity (Correa-Oliveira 2016; Yamazaki 2017). Furthermore, interactions between the gut microbiome and immune system are important for stimulating the renewal and repair of cells lining the gut epithelium where the gut microbiome resides (Turnbaugh 2007).
The microbiome, particularly in the gut, appears to play a substantial role in regulating metabolism. From the very beginning of life, factors that shape the microbiome have been shown to be indicators of the risk of obesity or metabolic diseases. For example, Cesarean section (C-section) birth, a formula-based diet, illness, and antibiotic use early in life have all been correlated with higher rates of childhood overweight and obesity (Rosenbaum 2015; Mueller 2015; Korpela 2016; Li 2017). Maternal antibiotic use during pregnancy or breastfeeding has also been shown to impact the infant microbiome and has been correlated with childhood obesity risk (Cassidy-Bushrow 2017; Lemas 2016; Mor 2015).
Patterns of gut microbial imbalance have been seen in adults with metabolic diseases such as obesity, non-alcoholic fatty liver disease, and type 2 diabetes (Sedighi 2017; He 2017; Lippert 2017; Ma 2017). Certain dietary changes, such as consuming more fiber or capsaicin from chili peppers, calorie restriction, and weight loss, have been associated with beneficial changes in the gut microbiome, which may contribute to improvements in metabolic disturbances. Diets high in fat, protein, and sugar, on the other hand, can disrupt microbiome health (Vinke 2017; Rosenbaum 2015; Yang 2017; Ley 2006; Kang, Wang 2017; Singh 2017; Kang 2016; Turnbaugh 2009).
The intestinal microbiome undergoes daily shifts in composition that are driven in part by dietary patterns. In an animal model, interruptions in circadian rhythms intended to mimic jet lag or night-shift work altered the normal cycling of the microbiome, leading to metabolic disturbances (Thaiss 2014; Zarrinpar 2016). Emerging evidence further indicates that the relationship between circadian rhythms and the microbiome may be bidirectional, so that imbalances in the microbiome can disrupt circadian signaling, resulting in a cycle of disordered daily biological rhythms and metabolic perturbations (Thaiss 2014; Leone 2015; Wang, Kuang 2017).