How often do patients ask you about the probiotics they should be taking? What about interpreting microbiome tests directly to consumers? Gastroenterologists are often considered the most appropriate doctors to address these questions, but due to rapid developments in this field and a lack of adequate educational resources, many of them may feel less up-to-date and confident in providing advice to patients in this area.
Gastroenterologists need to have a basic understanding of the current microbiome science and how to apply it in everyday practice. While microbiome research is still in its early stages, there is already a substantial body of literature to guide gastroenterologists in understanding what is often considered the most fascinating living organ and ecosystem in our bodies – and potentially a cornerstone of future therapies.
What Is the Gut Microbiome?
The gut microbiome consists of trillions of microorganisms (bacteria, archaea, fungi, and viruses, including bacteriophages) and their genomes/gen. Bacteriophages (viromes) outnumber bacteria and can shape the composition of the gut bacterial community. Fungi (mycobiomes) are the least abundant, with Candida being the dominant genus.
When discussing the organisms that make up the microbiome, they are categorized by phylum, class, order, family, genus, and species. Gut microbiota varies among individuals, reflecting differences in the abundance of four dominant phyla: Bacteroidetes, Firmicutes, Proteobacteria, and Actinobacteria. Firmicutes and Bacteroidetes represent 90% of the gut microbiota. Within the Firmicutes phylum, the Clostridium genus accounts for 95% of that group; Lactobacillus, Bacillus, Enterococcus, and Ruminicoccus are among other genera in the Firmicutes phylum.
While the primary focus is on the bacteria that make up the microbiome, mycobiomes and viromes also play significant roles. Mycobiomes are influenced by the environment and a diet high in carbohydrates and are associated with immune compromise. Antibiotic use can lead to an overgrowth of fungi, reflecting a competitive relationship between fungi and bacteria. Mycobiomes have been implicated in immune response changes, such as in inflammatory bowel disease (IBD), with the Crohn’s biomarker anti-Saccharomyces cerevisiae directed at fungal cell wall epitopes with cross-reactivity against Candida albicans.
Viromes are one of the most diverse biological systems and consist primarily of bacteriophages, which are viruses that can infect bacterial cells. Bacteriophages can directly affect the immune system in various ways, such as stimulating the production of macrophage interleukin-1b and tumor necrosis factor-alpha. Viromes also respond to dietary changes.
Components of the Gut Microbiome
The composition of microbiota varies along the gastrointestinal tract, differing in each part from the mouth to the colon. The highest bacterial density is found in the colon, with greater nutrient availability and slower transit times. The small intestine, on the other hand, has lower microbiota abundance and diversity due to shorter transit times, the influx of digestive enzymes and bile, and intermittent food substrate availability.
The human oral cavity is home to abundant and diverse microbial communities collectively known as the oral microbiome. The oral microbiome typically exists in the form of biofilms, and common oral bacteria include Streptococcus mutans, Porphyromonas gingivalis, Staphylococcus, and Lactobacillus. Streptococcus mutans is a major component of the oral microbiota and is associated with dental plaque and tooth decay. Lactobacillus is capable of producing lactic acid by fermenting sugars, contributing to tooth decay. Besides oral diseases like cavities and periodontitis, the oral microbiome is associated with systemic conditions such as esophageal, colorectal, and pancreatic cancer, diabetes, Alzheimer’s disease, cardiovascular diseases, cystic fibrosis, and rheumatoid arthritis. The oral microbiome can also be a target for disease treatment, with probiotics like Streptococcus A12 able to stabilize the acidic pH in biofilms contributing to tooth decay.
The esophagus has been found to have a diverse microbiome, including Streptococcus as the most common bacterial genus, as well as Haemophilus, Neisseria, Prevotella, and Veillonella. Gram-negative bacteria like Prevotella are more frequently found in the context of diseases like gastroesophageal reflux disease and Barrett’s esophagus. Changes in esophageal microbiome composition can be caused by acid reflux, inflammation, and exposure to proton pump inhibitors (PPIs), alcohol, and smoke.
The stomach contains five major phyla (Firmicutes, Bacteroidetes, Actinobacteria, Fusobacteria, and Proteobacteria); at the genus level, Prevotella, Streptococcus, Veillonella, Rothia, and Haemophilus are the most common. The gastric microbiota is influenced by diet, medication use like PPIs and antibiotics, gastric mucosal inflammation and atrophic gastritis, and Helicobacter pylori infection. The interaction between the existing gastric microbiota and H. pylori can impact the risk of certain conditions such as gastric cancer.
The small intestine is the longest part of the gastrointestinal tract, approximately 22 feet in length, and has its own microbiome. Common bacterial genera found in the small intestine include Lactobacillus, Clostridium, Staphylococcus, Streptococcus, and Bacteroides. In the small intestine, bacterial populations increase from about 104-105 CFU/mL in the duodenum to 107-108 CFU/mL in the distal ileum, where transit time slows. The proportion of gram-positive to gram-negative bacteria and facultative anaerobic and strict anaerobic species increases from the proximal to distal small intestine due to oxygen usage. Small intestinal bacterial overgrowth (SIBO), a developing condition associated with up to 78% of irritable bowel syndrome cases, involves an overabundance of bacteria in the small intestine leading to abnormal nutrient fermentation, excessive gas production, and bloating.
The colon hosts the most robust and abundant microbiome, primarily composed of obligate anaerobes; the most abundant bacteria in the colon are members of the Bacteroides genus, with gram-positive anaerobic cocci such as Peptostreptococcus, Eubacterium, Lactobacillus, and Clostridium. Through fermentation, absorption, and the metabolism of metabolites like short-chain fatty acids, the colonic microflora plays a vital role in the host’s digestion process, especially in terms of fiber, which is not broken down in other parts of the digestive system. Many microbiota studies use stool samples, reflecting the “lumen” colon microbiome. Additionally, colonic mucosa-attached microbiota interacts more directly with the host immune system and requires biopsy during colonoscopy for research.
Healthy vs. Abnormal Microbiomes
A healthy gut microbiome is characterized by a diverse microbiota that develops from birth. By the age of 3, a person’s microbiome resembles that of an adult, but it continues to change and develop functions like vitamin synthesis. Although the relative abundance of microbes may change, the overall community and functions remain relatively intact and stable. Likewise, detrimental microbial communities can be stable and eventually contribute to chronic diseases. Resilience is a critical property of the microbiome, reflecting how much disturbance a microbial community can tolerate before shifting to a new steady state. A single dose of antibiotics can temporarily alter the microbiome but often returns to the initial state. More persistent disruptions, such as long-term dietary changes, repeated antibiotic use, or perturbations during vulnerable periods like infancy or the peripartum period, can lead to a reassembly of the microbiome into states promoting disease.
Studies have identified specific indicators of a healthy gut microbiome. For example, alpha diversity, a measure of microbiome diversity, has been associated with human health, with lower diversity levels linked to certain acute and chronic diseases. Another indicator is the Firmicutes-to-Bacteroidetes (F/B) ratio. More generally, some species have stood out for their benefits, such as Faecalibacterium prausnitzii. F. prausnitzii has consistently been reported as a major producer of butyrate in the gut, with protective properties against colorectal cancer and inflammatory bowel diseases, as well as the ability to reduce mucosal inflammation. Another important bacterium is Akkermansia muciniphila. A. muciniphila has been shown to contribute to a healthy gut barrier, regulate immunity, and control inflammation, and low abundance of this organism has been linked to several diseases.
What Shapes the Adult Microbiome?
Several factors influence the adult gut microbiome, with diet appearing to have the most prominent effect. Given the role of diet, gastroenterologists can provide essential counseling points during visits to help patients understand their ability to modify and optimize their microbiome.
Diet: Both short-term and long-term dietary habits influence the microbiome. Short-term dietary changes can lead to rapid shifts in the microbiome, often reversible with occasional digestive symptoms. Fiber is a key nutrient for the microbiome, especially carbohydrates accessible to gut microbiota (MACs) that nourish gut microbes. As microbes ferment MACs, they produce short-chain fatty acids with various health benefits, including improving bowel transit through serotonin pathways. Low MAC diets can lead to unfavorable microbiome shifts, which can mostly be reversed with high MAC diets, unless low MAC diets persist across generations and cause irreversible microbial diversity loss. Low-fiber diets essentially “starve” gut microbes, forcing them to switch to host epithelial cells and mucus for sustenance, compromising the epithelial barrier and increasing the risk of gut inflammation. Additives such as emulsifiers and artificial sweeteners can also have negative effects on the gut microbiome, increasing the risk of metabolic and inflammatory disorders. Offering guidance to patients on optimizing their fiber and MAC intake and minimizing processed food consumption can offer significant benefits to their health.
Exercise: Athletes have been found to have a more diverse gut microbiome and lower levels of inflammatory markers. In animal research, exercise-related gut microbiome changes reduce susceptibility to inflammation and weight gain. Gut microbiota changes associated with exercise can be of similar magnitude to dietary changes, which is why even though exercise is used for weight loss, it’s challenging to achieve sustainable weight loss without altering one’s diet as well. Engaging in moderate to high-intensity exercise for 30 to 90 minutes at least three times a week (or between 150 and 270 minutes per week) for a minimum of 8 weeks is likely to bring about changes in the gut microbiota.
Medications: Antibiotics, PPIs, laxatives, metformin, statins, hormones, benzodiazepines, antidepressants, NSAIDs, and antihistamines are just a few examples of medications associated with changes in gut microbiota composition. This information can assist gastroenterologists in making decisions such as using PPIs for a limited duration and being more cautious in antibiotic use.
Other Exposures: Smoking, alcohol consumption, and psychological stress have been linked to changes in gut microbiota. Offering advice on smoking cessation, reducing alcohol consumption, and modulating the gut-brain axis are essential components of patient care.
Studying the Microbiome
Methods of studying the microbiome have evolved in recent years. Microbiome research began with microbial culture techniques that relied on specific growth media to identify particular microbes. Culture techniques are highly limited, and the field shifted to 16S rRNA gene sequencing. This approach relies on sequencing a single gene (16S). Each organism has its own 16S signature, which provides information at the genus but not species or strain level. More recently, shotgun metagenomic sequencing techniques have been used. This approach, which evaluates DNA from entire genomes rather than a single gene, provides more information at the species level and insights into microbial functions.
The microbiome plays a critical role in many aspects of health, from metabolic diseases like obesity and type 2 diabetes to cardiovascular diseases and GI conditions like non-alcoholic fatty liver disease (NAFLD), IBD, celiac disease, and cancer. It also affects how the body responds to specific drug therapies like chemotherapy. Not only does the microbiome impact so many aspects of health, but there is an increasing body of evidence that targeting the gut microbiome for therapeutic manipulation will be a cornerstone of GI and broader disease treatments in the future.
