The Human Gut Microbiome and Its Role in Processing Food
The gut microbiome, also termed gut microbiota or commensal, refers to the entire microbial community that populates the mammalian gastrointestinal (GI) tract, with the majority residing in the colon. The human gut microbiome reaches 3.8 × 1013 microbes in a standard adult male, which outnumbers the human host cells (3.0 × 1013). Each individual hosts at least 160 species out of the total 1150 species that colonize the human GI tract.
There are five major phyla for the human gut microbiota, namely Firmicutes, Bacteroidetes, Actinobacteria, Proteobacteria, and Verrucomicrobe, with the two dominating phyla, Firmicutes and Bacteroidetes, representing 90% of the gut microbiota. Some bacteria termed "pathobionts" can become pathogenic under specific conditions. For example, members of the phylum Proteobacteria belong to "pathobionts", and a bloom of them is seen in inflammatory bowel disease (IBD).
Accumulating evidence has shown that a diversified and well-structured gut microbiota is critical in maintaining health. Dysbiosis, defined as reduced diversity and alterations of the composition of the gut microbiota, is associated with obesity, diabetes, and gastrointestinal diseases such as IBD. Diet is a driving factor in shaping human gut microbiota composition and function.
The human GI tract functions to digest foods and uptake nutrients. It also protects from pathogen infection as well as maintains immune tolerance. Undigested foods reach the colon and serve as substrates for bacterial metabolism. Carbohydrates, proteins, and fats are the three major macronutrients that serve as an energy source in human nutrition; they differ greatly in digestibility and, therefore, provide quite different microbiota-accessible nutrients. The amount and types of macronutrients select the growth of different bacteria and generate different metabolites, which have positive or negative effects on the gut epithelium and mucosal immune system.
Compared with human metabolism, bacterial metabolism is much more powerful considering the fact that the gut microbial genes (3.3 × 106) far outnumber human protein-coded genes by 150-fold. What is more, bacterial metabolism can switch from one substrate to another substrate much faster, depending on substrate availability. Through generating a diverse array of metabolites, the gut microbiome interacts with the gut epithelium and the intestinal mucosal immune system to maintain gut homeostasis, thus forming a symbiotic relationship with the host.
Diet can disturb gut homeostasis by influencing the diversity, composition, and function of the gut microbiome. A nutritionally balanced diet is critical for maintaining a healthy gut microbiome, the integrity of the intestinal barrier, immune tolerance, and normal gut physiology, whereas an unbalanced diet, like the typical western diet, results in reduced diversity and dysbiosis of the gut microbiome, which can lead to a leaky gut and chronic inflammation, as seen in IBD. This article focuses on food and nutrition factors that affect gut health by influencing the interplay of the gut microbiome with the epithelium and intestinal mucosal immune system.
Undigested food components are metabolized to a diverse array of metabolites. Thus, what we eat shapes the structure, composition, and function of the gut microbiome, which interacts with the gut epithelium and mucosal immune system and maintains intestinal homeostasis in a healthy state. Alterations of the gut microbiome are implicated in many diseases, such as inflammatory bowel disease (IBD). There is growing interest in nutritional therapy to target the gut microbiome in IBD.
Investigations into dietary effects on the composition changes in the gut microbiome flourished in recent years, but few focused on gut physiology. This review summarizes the current knowledge regarding the impacts of major food components and their metabolites on the gut and health consequences, specifically within the GI tract. Additionally, the influence of the diet on the gut microbiome-host immune system interaction in IBD is also discussed.
Keywords: gut microbiome, gut microbiota, nutrition, foods, dietary fiber, dietary fats, dietary protein, intestinal health, colitis, IBD.
A new study from Washington University School of Medicine in St. Louis suggests the gut microbiome has an impact on how the body breaks down processed foods, such as cereals, pastas, chocolate and soda. The new knowledge could help in the development of healthier, more nutritious processed foods.
Reporting in the journal Cell Host & Microbe, scientists have identified a specific human gut bacterial strain that breaks down the chemical fructoselysine, and turns it into harmless byproducts. Some of these chemicals have been linked to harmful health effects.
“This study gives us a deeper view of how components of our modern diets are metabolized by gut microbes, including the breakdown of components that may be unhealthy for us,” said Jeffrey I. Gordon, MD, the Dr. Robert J. Glaser Distinguished University Professor and director of the Edison Family Center for Genome Sciences & Systems Biology.
Human gut microbial communities see foods as collections of chemicals. Some of these chemical compounds have beneficial effects on the communities of microbes living in the gut as well as on human health. For example, Gordon’s past work has shown that the gut microbiome plays a vital role in a baby’s early development, with healthy gut microbes contributing to healthy growth, immune function, and bone and brain development.
But modern food processing can generate chemicals that may be detrimental to health. Such chemicals have been associated with inflammation linked to diabetes and heart disease.
“Fructoselysine is common in processed food, including ultra-pasteurized milk, pasta, chocolate and cereals,” said first author Ashley R. Wolf, PhD, a postdoctoral researcher in Gordon’s lab. “This specific bacterial strain thrives in these circumstances,” Gordon said.
He added, “The new tools and knowledge gained from this initial study could be used to develop healthier, more nutritious foods as well as design potential strategies to identify and harness certain types of gut bacteria shown to process potentially harmful chemicals into innocuous ones.
Emphasizing the complexity of this task, Gordon, Wolf and their colleagues also showed that close cousins of Collinsella intestinalis did not respond to fructoselysine in the same way. These bacterial cousins, whose genomes vary somewhat, do not thrive in a fructoselysine-rich environment.
The Gut Epithelial Barrier
The human GI tract is covered by a single layer of epithelial cells held together by tight junction proteins such as claudins, occludins, and zonulae occudens (ZO). The intestinal epithelial cells form a physical barrier as they are impermeable to luminal contents. There are at least seven types of intestinal epithelial cells: enterocytes, goblet cells, Paneth cells, microfold cells, enteroendocrine cells, cup cells, and tuft cells.
Enterocytes are the most abundant cells responsible for nutrient uptake. Goblet cells, with more abundance in the distal direction, are responsible for producing mucus. Most Paneth cells reside in the small intestine and secret antimicrobial peptides.
The glycoprotein-rich mucus layer overlying the gut epithelium is the first line of defense against commensal microbes as well as pathogens. MUC2 is the major component of the gel-like mucins in the intestine. The large intestine has two layers of mucus, namely, a firmly attached bacteria-free inner layer and a loose outer layer. The inner layer is about 50 μm thick in mice and 200-300 μm thick in humans. The outer layer expands 4-5 times in volume, which creates a habitat for the commensal bacteria.
The mucus barrier is also a reservoir of antimicrobial peptides and IgA. The inner mucus layer is continuously renewed every 1-2 h in murine colonic tissue. Once the inner mucus layer is lost or becomes penetrable to bacteria, a large number of bacteria will reach the epithelial cells and trigger inflammation.
Bacterial stimulation is essential for the development and function of the intestinal barrier. In germ-free mice, the mucus layer is extremely thin. The permeability of the intestinal barrier is tightly regulated in a healthy gut. The commensal bacteria maintain the epithelial barrier by providing energy in the form of short-chain fatty acids and also releasing antimicrobial substances to inhibit pathogens. Some nutrients are important regulators of tight junction protein levels, which are critical in maintaining the epithelial barrier.
An increase in intestinal permeability, termed a "leaky" gut, can be induced by dietary factors and may trigger inflammatory responses. In a healthy gut, a balance exists between commensal bacteria and the mucus layer. Some gut bacteria, termed mucin specialists, specifically metabolize mucins and are the major mucin degraders when the diet is rich in dietary polysaccharides. There is a balance of production and degradation of mucus, which maintains the thickness of the mucus layer.
Dietary fiber-derived SCFAs promote the integrity of intestinal epithelium by inducing goblet cells to increase mucin production and enterocytes to secret IL-18, which is important for epithelial repair. SCFAs can also directly modify tight junctions to strengthen the gut barrier.
When the diet is devoid of dietary fibers, some mucin generalists switch metabolism from plant polysaccharides to host mucin glycans. Expansion of mucus-degrading bacteria and an increase in the metabolic activity in utilizing mucin glycans lead to erosion of the mucus layer. Reduced dietary fiber correlates with the thinning of colonic mucus. Different protein sources also affect the thickness of the mucus layer.
High saturated fats impair intestinal barrier integrity by reducing tight junction protein occludin and ZO-1. Simple sugars and emulsifiers negatively affect the intestinal barrier by inducing the expansion of mucin lytic bacteria such as Akkermansia muciniphila, which leads to a thinning of the mucus layer. Some food components (milk fat) promote the growth of Proteobacteria, which produces compounds that are toxic to the intestinal epithelial cells. A leaky gut is involved in the pathogenesis of many inflammatory diseases, including IBD.
The Intestinal Mucosal Immune System
Underneath the intestinal epithelial layer is the lamina propria, where most of the intestinal mucosal immune system resides. Here, various types of innate and adaptive immune cells are found: dendritic cells, macrophages, innate lymphoid cells (ILCs), CD4+ T cells (Th1, Th17, Treg cells), CD8+ T cells, and IgA-secreting plasma cells. These cells work in concert in defense against pathogen infection and in the maintenance of the intestinal mucosal barrier. Unrestrained inflammatory responses to food antigens or commensal bacteria are the main causes of chronic intestinal inflammation and tissue damage in human IBD patients.
Under normal conditions, the mucosal immune system is tightly regulated. Local Tregs play a critical role in colon homeostasis. Many bacterial metabolites induce colonic Tregs, such as SCFAs, certain secondary bile acid conjugates, and tryptophan metabolites. The commensal bacteria and the immune system evolve and interplay with each other. Normal development and function of the immune system depend on bacterial stimulation. Germ-free mice show defects in several immune cells and are more susceptible to infection.
In mice monocolonized with human gut microbes, immune responses show diversity and redundancy. Most microbes elicit distinct and shared responses at both transcriptional and cellular levels. The broad and redundant immune changes induced by gut microbes provide a consistent impact on the host and promote overall health. A recent human study showed that a diet rich in fermented foods leads to increased microbial diversity and decreases in numerous markers of inflammation.
It is well established that Foxp3+ Treg cells play a central role in the maintenance of immune homeostasis and particularly in the intestine. This is a subset of CD4+CD25+ T cells expressing the transcription factor Forkhead box P3 (Foxp3), which could suppress spontaneous multi-organ autoimmunity, including gastrointestinal inflammation induced by CD4+CD25− T cells.
Tregs represent around 10% of CD4+ T cells and were initially discovered to present only in lymphoid tissues; however, recent studies showed the existence of tissue Tregs. Two colonic Treg populations have been identified: one comes from the thymus and proliferates in the colon expressing Helios and Gata3; the other one newly differentiates from naïve Foxp3− CD4+ T cells and becomes Helios−RORγt+.
These colonic Tregs are as effective as lymphatic tissue Tregs in terms of suppression of effector T cells, thus controlling local inflammation. Another distinctive role of colonic Tregs is involved in local mucosal barrier repair. The commensal microbes play a major role in shaping the population of Foxp3+CD4+ T regulator cells in the colon. Colonic Tregs are reduced in germ-free mice or following antibiotic treatment.
A number of individual gut microbes strongly induce colonic Tregs, including Clostridia clusters IV, XIVa and XVIII, and some Bacteroides species. These bacteria produce SCFAs by fermentation of dietary fiber. The very low number of colonic Tregs in germ-free mice can be rescued by acetate, propionate, or butyrate, indicating these SCFAs work independently.
Different SCFAs induce colonic Treg population through multiple mechanisms. For example, acetate promotes the expansion of pre-existing colonic Tregs by activation of FFAR2 on T cells, whereas butyrate increases the de novo differentiation of colonic Tregs by inhibiting histone deacetylase (HDAC) activity. SCFAs also indirectly promote colonic Tregs expansion by affecting DC maturation through activation of GPR109A on DCs.
Dietary Fiber and the Gut Microbiome
The definition of dietary fiber dates back to the 1950s and has evolved in the last several decades. The same basis remains in carbohydrate polymers that are resistant to digestion and absorption in the human small intestine. Although dietary fibers are found in a wide range of plant-based foods such as cereals, legumes, nuts, tubers, vegetables, and fruits, fiber intake is far below the recommended levels in Western countries.
Dietary fiber is classified into different types based on chemical structures, including resistant starches (RS), nondigestible oligosaccharides, nondigestible polysaccharides, and chemically synthesized carbohydrates. Nondigestible polysaccharides include cellulose, hemicellulose, polyfructoses, gums and mucilages, and pectins. Not all dietary fibers are fermentable. Cellulose is not fermented by gut microbes and only has bulking effects. Most dietary fibers are fermentable.
Several terms are used to define subsets of dietary fiber with respect to their effects on the modulation of the gut microbiome. "Prebiotics" refers to a "nondigestible food ingredient that beneficially affects the host by selectively stimulating growth and/or activity of one or a limited number of bacteria already resident in the colon, and thus helps to improve host health". As more up-to-date knowledge builds up in terms of the health benefits of dietary fiber on the gut microbiota, the prebiotic concept is becoming considered outdated. Dietary fiber is the key nutrient for maintaining the diversity of gut microbiota.
Figure 1. Impacts of foods and nutrition on the microbiota-host interactions in the gut. The arrow indicates regulation. Food components and endogenous metabolites of nutrients directly modulate the gut epithelial barrier and mucosal immune system. Diet also determines microbiota-accessible nutrients, which play a critical role in the gut microbiota ecology. The interaction between the gut microbiota with host epithelium and the mucosal immune system determines intestinal homeostasis. IEC, intraepithelial lymphocytes; AMP, antimicrobial peptides; sIgA, secretory immunoglobulin A; DCs, dendritic cells; SCFAs, short-chain fatty acids; BCFAs, branched-chain fatty acids.
Gut Bacteria Evolution and Adaptation to Diet
Gut bacteria evolve rapidly in response to different diets, UCLA evolutionary biologists report in a new study. The researchers found that gene variants that help microbes digest starches found in ultra-processed foods have “swept” the genomes of some species of gut bacteria in industrialized parts of the world. Because these starches are industrially produced and have only been around for a few decades, scientists believe natural selection must have been acting strongly to make these genes dominant so quickly.
The study’s findings, published in Nature, scanned the genomes of almost three dozen species of gut bacteria using data from around the world and identified a process called horizontal gene transfer, in which bacteria transfer DNA from one strain to another, as the mechanism for this rapid evolution.
“The discovery that the ability to digest novel starches is a target of natural selection in gut bacteria is interesting, but we found an even more robust, stronger signal that there are different targets of selection across many genes and many species in industrialized and non-industrialized populations,” said UCLA doctoral student and paper first author Richard Wolff.
Wolff and corresponding author, UCLA professor of ecology and evolutionary biology Nandita Garud, developed a novel statistic that identifies locations in the DNA of 30 gut bacteria species where genes have risen to high frequency, or “swept,” in that species. “Different strains of E. coli, for example, have diverged from each other as much as humans have diverged from chimps, yet we call them the same species. Different genes appeared to be selected for in industrialized and non-industrialized populations, and one gene in particular was sweeping only in industrialized populations.
“We saw the adaptive signal very strongly, but we can’t say for sure yet if it’s specializing in maltodextrin or a broader class of starch derivatives. There might be intermediate steps as the bacteria adapt to different starch sources,” said Wolff. But humans have only a few strains of the same species of gut bacteria, and these strains typically stay with each person for many years.
“Each person might have a couple of different strains of E. coli,” said Garud. “If fragments of DNA are transmitted horizontally across different strains in different hosts, and these strains seemingly are faithful to their respective hosts, where do they recombine?