Guts and Glory: The Gut Microbiota
You are a superorganism.
Your cells work in glorious symbiotic harmony with trillions of microbes within your body and on your skin. Ten trillion of these organisms from up to a thousand different species reside in your gut. The microbiome – the collective genes of these microbes – is one hundred and fifty times larger than your genome. Your body provides these bacteria with a nutrient rich environment, and in return, these bacteria contribute to important functions that impact our everyday life.
Your gut can be anatomically divided into three major sections: the stomach, the small intestines, and the large intestines. Each of these anatomic areas have different compositions of the microbiota due to their distinct microenvironments. The stomach was long thought to be sterile and devoid of bacteria due to its harsh acidic nature. However, in the 1980s, acid-resistant bacterial strains were identified, including Streptococcus, Neisseria, Lactobacillus, Campylobacter pyloridis, and Helicobacter pylori. Since then, additional microorganisms have been identified in the stomach. As you move into the small intestines, the bacterial density and diversity remains fairly low due to the presence of bile acids and other antimicrobial secretions in the duodenum. The bacterial colonization rises as you move to the jejunum and reaches its highest point as you move into the ileum. As you travel through the large intestines, the main source of water absorption and fermentation of undigested food, the number of bacteria increases by magnitudes and is dominated by two bacterial phyla: Firmicutes and Bacteroidetes. Interestingly, research suggests that the ratio between these two phyla may be a predictive marker for health and disease.
The composition of our gut microbiota changes throughout our lives, being acquired at birth. While there is some debate around the idea of the microbiota being seeded in the womb, it is known that various maternal factors can impact the formation of the gut microbiota in newborns. Additionally, a newborn tends to have different microbiota composition depending on if the baby was delivered vaginally or by C-section. Similarly, breast-fed babies have different gut bacteria than formula-fed babies. The impact of these differences is not fully clear, though researchers have indicated that the lower bacterial diversity in a baby delivered by C-section may make the baby more susceptible to certain pathogens. When we’re around 3-5 years old, our microbiota differentiates and starts to resemble the composition of the adult microbiota. As adults, the composition of our microbiota is fairly stable, though dietary changes, antibiotics treatment, stress, and other factors can cause changes to the microbial makeup of the gut flora.
So, what do all of these microbes do for us? It turns out that they help us in four major functional areas: metabolic, protective, structural, and neurological.
Metabolically, our bodies are unable to fully digest everything we eat. We can digest approximately 85% of carbohydrates and 66-95% of proteins. Certain nutrients, like complex carbohydrates and dietary fiber, cannot be digested by our gut. In contrast, our gut microbiota produces enzymes that can break apart these compounds to make them more easily absorbed by our bodies. Similarly, our gut bacteria produce peptidases and proteases – enzymes that help break down undigested proteins and generate other nutrients. Our gut microbiota helps process other vital metabolic compounds, including bile acid, choline (an essential nutrient), and polyphenols (which can be processed into anti-inflammatory metabolites).
The gut microbiota also works in conjunction with our intestinal cells to protect our bodies from harmful pathogens. Our gut bacteria can outcompete pathogens for nutrients, thereby limiting the pathogens’ ability to proliferate. At the same time, the microbiota can act as a physical shield, forming a barrier that prevents pathogens from reaching and infecting our cells. The gut microbiota’s relationship with the immune cells in the intestines provides another mechanism for responding to pathogens. In healthy times, the microbiota produces signals that foster the generation of Treg cells, specialized immune cells that suppress the immune response and foster tolerance. These signals, along with other compounds that activate inhibitory immune cells, suppress inflammation and prevent the body’s immune system from attacking the resident, commensal bacteria. However, if pathogenic bacteria displace the resident microbiota, these inhibitory signals are reduced, dampening down the inhibitory environment and allowing the immune system to become activated and counterattack the invading pathogens.
The gut microbiota plays an important role in supporting the structure of the gut. The cells lining the intestines, the intestinal epithelium, are a single layer thick. They are held together by structures called tight junctions. These tight junctions are like molecular shoelaces that tightly seal the cells together. But these tight junctions can weaken and break when exposed to pathogenic bacteria, which can produce various toxins that destroy the tight junctions. The commensal microbiota, on the other hand, can produce compounds that increase the expression of the tight junction proteins, supporting the maintenance of the epithelial layer.
Lastly, the gut microbiota plays pivotal neurological roles. When I previously touched on the connection between gut and the brain, I didn’t discuss the importance of the gut microbiota. The gut microbiota is a major producer of serotonin and dopamine, two key neurotransmitters that can impact your mood, happiness, and possibly behavior. Interestingly, researchers have shown in animal studies that altering or eliminating the gut microbiota can reduce an animal’s sociability. When pregnant mice were given high-fat diets, the offspring had substantially altered microbiota and exhibited abnormal social behavior. Restoration of a conventional microbiota in these mice abrogated the social deficiencies. While the exact mechanism of these observations isn’t entirely clear, it may have to do with the specific composition of the microbiota. The gut microbiota may also play a role in how we perceive pain (nociception). The pain neurons can be activated by bacterially produced peptides. On the other hand, GABA, a pain inhibitor compound, can be produced by gut bacteria. More generally, animal studies have shown that the absence of the gut microbiota results in substantial changes in the brain, including gene expression differences and abnormal cellular maturation and function, highlighting the importance of the microbiota’s neurological roles.
As you can see, the gut microbiota plays important roles in our day-to-day lives. Unfortunately, perturbations to the microbiota can contribute to the progression of diseases. Due to its close relationship with the gut’s immune cells, changes to the microbiota have been linked to conditions like inflammatory bowel diseases (IBD), a group of chronic inflammatory diseases of the gut. Changes in the bacterial makeup have been closely associated with IBD, including a decrease in levels of Faecalibacterium, Clostridium, and Eubacterium, coupled with an increase in Enterobacteriaceae. The former three species produce compounds that down-regulate the immune response, and their decline may tilt the body toward a more pro-inflammatory stance. The changes to the gut microbiota may also contribute to Type 1 diabetes, as animal studies have shown that the absence of the microbiota contributed to the development of the condition. However, some attempts to translate this work to humans were unsuccessful, suggesting differences between humans and the animal models. Similar animal models were used to connect the gut microbiota to multiple sclerosis, finding that the absence of the microbiota increased the severity of the disease. In humans, the microbiota composition of patients with MS is dramatically different from healthy controls, supporting the connection between disease progression and the microbiota.
Due to its impact on behavior, the gut microbiota has been associated with neurobehavioral conditions, as well. Changes to the microbiota have been linked to autism spectrum disorder, anxiety, and depression, though it should be noted that a causative relationship hasn’t been demonstrated. Some of these connections are thought to occur through the microbiota’s ability to regulate inflammation, including neuroinflammation seen in these and other neurodegenerative diseases.
As mentioned above, high-fat diets can change the composition of the microbiota. These changes to the microbiota have been shown to be associated with obesity-related diseases in both animal models and in clinical studies. It was found that obese children had lower levels of Bacteroidetes and higher levels of Firmicutes, and obese patients possessed less microbial diversity than lean people. These observations may be connected to inflammation seen in obesity.
The gut microbiota can also influence the development of colon cancer. The microbiota of patients with colon cancer has been shown to be significantly different than the makeup of healthy controls. The mechanisms by which the gut microbiota affect the development of cancer remains unclear, but several potential mechanisms are thought to be related to the microbiota’s ability to regulate the immune system and its capacity to damage our cellular DNA.
We are superorganisms that have evolved with our gut’s inhabitants to form a carefully balanced, symbiotic relationship. Our gut microbiota helps us, and we help our microbial passengers. Disrupting the balance of this relationship can lead to dramatic health consequences, which underscores the vital importance of these microscopic and often overlooked organisms.
Special thanks to Qiagen and Todd Festerling for sponsoring the blog.
References and Further Reading:
Adak A and Khan MR. An insight into gut microbiota and its functionalities. Cell and Molecular Life Sciences. 2019. 76:473-493.
Brown EM, et al., Gut microbiota regulation of T cells during inflammation and autoimmunity. Annu. Rev. Immunol. 2019. 37:599-624.
Vuong HE, et al., The microbiome and host behavior. Annu. Rev. Neurosci. 2017. 40:21-49.
Quigley MM. Microbiota-Brain-Gut axis and neurodegenerative diseases. Curr. Neurol. Neurosci. Rep. 2017. 17:94.
Wu Y, et al., Interactions between food and gut microbiota: impact on human health. Annu. Rev. Food Sci. Technol. 2019. 10:389-408.
Brennan CA and Garrett WS. Gut microbiota, inflammation, and colorectal cancer. Annu. Rev. Microbiol. 2016. 70:395-411.