“Cells at Work!” is a manga and anime series that explains what cells, represented by anthropomorphised human beings, do in a healthy human body and how they respond to disease. Coming off the success of the first anime season, the second season of the anime is currently airing across most anime streaming platforms. The second season will continue to talk about how the human body responds to different infectious diseases. The season will also cover the important role of the gut microbiota, the collection of commensal bacteria in the human gut, in human health and disease with a particular focus on lactic acid bacteria. However, the manga and anime series overemphasise the role of lactic acid bacteria in human health. A healthy gut microbiota is more than just lactic acid bacteria; different commensal bacteria contribute to the varied functions of the gut microbiota. In addition, alterations in the composition of the gut microbiota can adversely affect human health and increase the risk of developing infectious and chronic diseases. In this blog post, I will outline the structure and functions of the gut microbiota and how its composition can be changed by a myriad of external factors. By the end of this blog post, I hope to provide you with a lot of background information on the gut microbiota to fill in some of the gaps in the anime series, enhancing your appreciation of the gut microbiota in human health.
What is the gut microbiota?
In the first anime season, all the bacteria depicted are bad as they are capable of causing infections around the body. To prevent and remove these infections, white blood cells constantly detect and eliminate pathogenic bacteria around the body. It is important to realise; however, that there are a lot of commensal bacteria living in the human body that do not cause harm. In particular, a lot of commensal bacteria reside in the colon, making up the gut microbiota that provides nutrients and signals to the human body. Up to 2172 different bacterial species reside in the gut microbiota, split into 12 different phyla or groups of bacteria. Most of the gut microbiota consist of bacteria in the Firmicutes (Lactobacillus, Bacillus, Clostridium, Enterococcus, and Ruminicoccus) and Bacteroidetes (Bacteroides and Prevotella) phyla. Besides these two phyla, the Actinobacteria phylum is noteworthy for having Bifidobacterium bacteria which have been shown to provide a lot of health benefits.
Lactic acid bacteria, the main bacteria showcased in the anime, are a group of bacteria that convert carbohydrates to lactate or lactic acid. These bacteria produce lactate as they cannot conduct cellular respiration to produce ATP (carriers of cellular energy). This is because they cannot produce haem which is an essential component of cytochromes that are used to conduct cellular respiration. Lactobacilli are a prime example of lactic acid bacteria, but there are other lactic acid bacteria such as lactococci, enterococci and streptococci.
| Microscopic | Anime |
 |  |
Did you know? Lactic acid bacteria are most well-known for being present in Yakult, a fermented milk drink containing the unique Lactobacillus casei Shirota strain. It is a very popular probiotic drink, selling over 40 million bottles/day globally.
The functions of the gut microbiota
The gut microbiota produces essential chemicals that the human body alone cannot synthesise. Without the gut microbiota, the functioning of the human body would diminish. The gut microbiota has four main functions in the human body: metabolic, protective, structural and communicative.
Metabolic
The gut microbiota possesses a unique set of enzymes that the human body cannot produce, allowing it to break down undigested food products that enter the colon. The microbiota is well-known for fermenting dietary fibres from fruits, vegetables and wholegrains such as cellulose and lignin that the human body alone cannot break down. The gut microbiota breaks down the fibre into energy and various by-products. The most notable of these by-products is short-chain fatty acids (SCFAs) such as acetate, propionate and butyrate that provide a wide array of health benefits to the human body. Their functions will be explained in later blog posts. The gut microbiota is also essential for synthesising B vitamins such as folate and niacin that are essential for the optimal functioning of the human body.
Protective
A healthy gut microbiota is able to prevent pathogenic bacteria from proliferating in the gut to cause disease. It does this by successfully taking up adhesion sites and nutrients against pathogenic bacteria and stimulating the gut epithelium to release antimicrobial peptides that inhibit the growth of pathogenic bacteria. Depletion of the gut microbiota such as during antibiotic treatment liberates adhesion sites and nutrients for pathogenic bacteria to survive and divide in the gut, increasing the susceptibility of the human body against infectious diseases.
The gut microbiota is essential for the normal development and functioning of the mucosal immune system in the gut. During development, the gut microbiota trains the mucosal immune system to distinguish commensal bacteria from pathogenic bacteria. This allows the immune system to direct an appropriate immune and inflammatory response against pathogenic bacteria while ignoring the commensal bacteria. The essential role of the gut microbiota in developing the mucosal immune system can be seen in germ-free mice which do not have a gut microbiota. These mice do not develop the cells and structures of the mucosal immune system within the gut.
The gut microbiota is also required for controlling immune function in the gut such as modulating neutrophil migration and function and influencing the differentiation and function of helper T cell subsets. In particular, specific commensal bacteria in the gut microbiota can interact with the immune system to maintain immune function. For example, segmented filamentous bacteria (SFB) can closely interact with epithelial cells in the gut to release serum amyloid A1, a chemical that attracts white blood cells, and trigger an IgA antibody response to neutralise bacteria trying to invade the epithelium.
Structural
The gut microbiota maintains the integrity of the epithelial barrier in the gut. The gut epithelium consists of a single layer of epithelial cells that are tightly bound by various junctional proteins. This prevents pathogenic bacteria from breaching the epithelium to enter the body and cause infection. It also prevents bacterial proteins in the colon such as lipopolysaccharide (LPS) from leaking into the body to promote inflammation, contributing to chronic diseases such as Alzheimer’s disease. The gut microbiota, by releasing microbial by-products such as SCFAs, can maintain the integrity of the gut epithelium by controlling the proliferation and repair of epithelial cells. SCFAs also control the apoptosis or death of epithelial cells to prevent the development of tumours and cancers.
Communicative
By-products produced in the gut microbiota can establish communication channels with organs in different body systems to affect their function. The most noteworthy of these communication channels is the gut-brain axis (GBA). In the GBA, the gut microbiota produces a wide array of neurotransmitters such as serotonin and dopamine that can spread around the bloodstream to modulate the activity of the central nervous system. Consequently, the GBA is able to affect different aspects of human thinking such as behaviour, stress and appetite.
The role of the gut microbiota in human disease
A healthy human body possesses a stable, diverse gut microbiota that can maintain an active mucosal immune system and a strong epithelial barrier while producing by-products that can optimise human health. Perturbations in the composition of the gut microbiota, known as dysbiosis, are associated with a large number of infectious and chronic diseases. For instance, Clostridium difficile infection, a bacterial infection that causes diarrhoea, abdominal cramping and inflammation of the colon, arises when the gut microbiota is depleted, often due to antibiotic consumption. Normally, a healthy gut microbiota reduces the chances of colonisation by Clostridium difficile bacteria. Depletion of the gut microbiota; though, frees up nutrients and adhesion sites for Clostridium difficile to divide and grow, allowing it to colonise the colon and cause disease.
In the last two decades, medical research has revealed a number of chronic diseases that are linked to dysbiosis. These diseases include type II diabetes, inflammatory bowel disease (IBD), allergy, obesity and cancer. These chronic diseases are associated with reduced diversity of bacteria in the gut microbiota and increased prevalence of certain bacterial species. For instance, obese people tend to have increased amounts of Eubacterium ventriosum and Roseburia intestinalis bacteria compared to lean individuals. The gut microbiota itself may partially contribute to the disease as transferring gut microbiota from diseased mice into healthy or germ-free mice can recapitulate the disease. Research is underway to understand the mechanisms that specific bacteria in the gut microbiota can exacerbate or prevent chronic disease in humans. Later blog posts will point out the specific bacteria in the gut microbiota that are more prevalent in specific diseases and the known mechanisms that they utilise to cause disease.
Factors affecting the composition of the gut microbiota
The composition of the gut microbiota varies among individual people. This variation arises from a number of external factors that can favour one group of bacteria over another.
- Method of birth: how a baby is delivered has a huge influence on the composition of the gut microbiota. Babies delivered naturally via the vagina have a gut microbiota that is enriched in bacteria from the mother’s vagina such as Bacteroides, Bifidobacterium and Escherichia. In contrast, babies delivered via a C-section (Caesarean-section) have a gut microbiota that is enriched in skin bacteria such as Enterobacteria, Haemophilus and Staphylococcus.
- Breast feeding: the milk that an infant feeds on in the first months of life can affect the composition of the gut microbiota. Infants that are breast-fed have a gut microbiota that is enriched in Bacteriodetes bacteria compared to formula-fed infants that have a gut bacteria mostly composed of Firmicutes bacteria.
- Ageing: the composition of the gut microbiota remains relatively stable throughout late childhood, adolescence and adulthood. Ageing is associated with a less diverse gut microbiota that is linked to increased frailty and reduced cognitive performance.
- Antibiotics: oral antibiotics, which kill bacteria in the colon, can drastically alter the composition of the gut microbiota. Not only do antibiotics reduce the diversity of the gut microbiota but they also favour antibiotic-resistant bacterial strains, reducing the responsiveness of the human body to antibiotics.
- Diet: the human diet has a huge influence on the composition of the gut microbiota. This can be seen in the composition of the gut microbiota between children from Italy, Europe and Burkina Faso, Africa. Children in Burkina Faso consume a high-fibre diet which is associated with a larger Bacteroidetes population able to digest fibre. In contrast, children in Europe consume a high-fat, high-sugar diet which is linked to a bigger Enterobacteriaceae population. The presence of these bacteria is associated with an increased risk of developing IBD.
- Exercise: exercise can alter the composition of the gut microbiota, particularly in lean individuals. This can alter the production of some biomolecules such as butyrate from the gut microbiota.
Supplementing the gut microbiota
Just as various external factors can affect the composition of the gut microbiota, consuming exogenous substances can also affect the gut microbiota. These substances either add bacteria into the gut microbiota or favour the growth of beneficial bacterial in the gut microbiota. Some of these substances are readily available over the counter while faecal microbiota transplantation is an emerging medical treatment that has been shown to cure an infectious disease.
Probiotic supplements
Some bacterial strains, most notably lactic acid bacteria such as lactobacilli, can be ingested as a probiotic supplement. These bacteria are able to augment the gut microbiota, providing a health benefit. These supplements are designed so that the bacteria can be kept alive as it passes through the gastrointestinal tract to the colon. Probiotic supplements can be used to treat various symptoms and diseases. These include gastrointestinal symptoms such as diarrhoea and constipation as well as gastrointestinal diseases such as IBD and infections such as gastric ulcers (caused by Helicobacter pylori) and urinary tract infections. However, the efficacy of probiotics in treating gastrointestinal symptoms and diseases is debatable due to huge differences in how various studies were conducted and publication bias favouring positive results over negative results. Further studies still need to be conducted before potential bacterial strains can be identified that are shown to provide a health benefit in humans.
Fermented foods
Some foods are produced via fermentation, where bacteria break down or metabolise carbohydrates within food in the absence of oxygen. Fermenting food not only preserves it but may also confer health benefits. These bacteria are kept alive by the time the food is consumed, with some bacteria ending up in the colon to supplement the gut microbiota. Examples of fermented foods that contain live bacteria include dairy products such as yoghurt and kefir (drinkable yoghurt), preserved vegetables such as kimchi and sauerkraut, seasonings such as miso (made by fermenting soybeans) and drinks such as kombucha (fermented sweet tea).
Prebiotic supplements
Prebiotics are ingested substances that can be used by beneficial bacteria in the gut microbiota to provide a health benefit. Prebiotics are most often associated with soluble fibres such as inulin but can also encompass other substances, including indigestible oligosaccharides (short-chain carbohydrates) such as galacto-oligosaccharides and fructo-oligosaccharides that are often found in human breast milk. Prebiotics can be taken as a supplement, but they can also be found in foods such as beans, lentils, barley, rye, onions and peas. The ingestion of prebiotics can influence the composition of the gut microbiota which can potentially treat some diseases such as type I diabetes. Again, further studies need to be conducted to assess the efficacy of these prebiotics in affecting human health.
Faecal microbiota transplantation
Faecal microbiota transplantation describes the transfer of faecal material containing the microbiota from a healthy donor to a diseased recipient. Stools are taken from a healthy donor, suspended in water or saline and administered to the recipient’s colon via the nose (via a nasoduodenal tube) or the anus (via colonoscopic delivery). The bacteria in the transplanted stools are then allowed to colonise in the colon, completely replacing the recipient’s gut microbiota. Faecal microbiota transplantation is commonly used to treat Clostridium difficile infection, particularly when the healthy gut microbiota is depleted. Restoring a healthy microbiota in the colon makes it more difficult for C. difficile to proliferate, curing the infection in 90% of cases.
Conclusion
This blog post gives an overview of what the gut microbiota is and how it is important to human health. Hopefully, you gain an appreciation that it is not just lactic acid bacteria that is important to human health. Other bacteria in the gut microbiota also play key roles in maintaining human health and in contributing to disease. Later blog posts will provide more detail on particular aspects of the gut microbiota and specific commensal bacteria to supplement what is shown in the anime episodes. I hope that these blog posts will give you a greater appreciation of the gut microbiota and how it is important to human health and disease.
Hello author!
I have a question, did you already make a blog post about how purines can form into uric acids? I hope you will notice this comment and also thank you for sharing your knowledge.
There was a completed spin-off of cells at work called Bacteria at work! that goes over the resident bacteria of the intestines and other areas of the body.