Monday, December 10, 2018

Priming the Gut: How Organisms Inside Us Can Fight Our Battles

by Nicholas James Walsh

             Microorganisms live almost everywhere imaginable, from the bottom of the ocean, to outer space, to deep inside our bodies. They even play roles in protecting ourselves, inside and out. Microbes live on our skin, hair, mouths, and between our toes, and these miniature creatures often staves off other dangerous microbes that could potentially infect us. This competition puts these “good microbes” on our side, defending us like a small army, who get the benefit of our nutritious micro-environments. Even in the seeming inhospitable environment that is our gut, these microbes, from yeast to bacteria, can flourish and compose what is deemed the “microbiome.” Controlling everything from our weight to our mental health (1), these microorganisms play a larger role in the daily functioning of human beings than previously believed. Imbalances in the usually robust gut microbiome can result in fluctuations in body fat percentage and even alter the signals coursing through our brains.
             It is no surprise, then, that new data constantly emphasizes the importance of retaining a healthy, balanced gut microbiome. One of the main players in the well-being of the gut environment is the microbe Cryptosporidium parvum. C. parvum is a eukaryote, which means it is arguably more similar to human cells compared to the other bacteria in the gut. However, certain infections with C. parvumcan result in an enteric disease called cryptosporidiosis, which causes small intestine disturbance and watery diarrhea. The infection process is common in malnourished individuals, since low-protein diets can lead to a decreased immune response to certain infections—notably cryptosporidiosis (2). It is these populations that tend to have incomplete diets who are most likely to experience dangerous infection with C. parvum. 
             This may seem paradoxical, because the same organism that is vital in maintaining the well-being of the gut can also cause a potentially fatal infection. This phenomenon is seen in many different organisms in the gut, notably in the notoriousEscherichia coli, or E. coli. Various circumstances can lead certain microbes to become infectious, as many strains of these organisms can produce different levels of beneficence or toxicity. For instance, E. coli is abundant in the gut, but a certain strain that has a unique antigen, or small protein, causes massive food poisoning, even to the point of death. This “O antigen” strain is very similar to healthy E. coli, but are different in this small, extracellular protein, which causes the human body to react very negatively to the bacterium when it proliferates in the small intestine (3).
             How then, do we use this to our advantage? Studies have shown that “priming”, or preparing, the gut with helpful bacteria or protozoa can stave off certain common gut infections. A novel technique, called the fecal microbiota transplant, can transfer healthy microorganisms into our guts, where they will take hold and produce a desired result. This can be conducted through both oral and anal methods, which have shown to be approximately equal in efficacy. 
             A famous study showed that when skinny mice were given high-dosage antibiotics (to clear the gut of bacteria), and quickly administered a fecal microbiota transplant of “obese mice” gut flora, the skinny mice develop mild-to-severe obesity, as seen in the figure below (4). From these studies, and others like it, we have gained an understanding of the processes that are heavily controlled by the microorganisms that live inside us. Not everything is determined purely through genetic luck of the draw, but our environment, including the small beings that live within us, can have strong impacts on our physical and mental well-being.
Figure 1. The scheme above shows the process by which a fecal transplant
 can affect the body fat percentage of mice. The microbiome of obese mice can
cause lean mice to accumulate large amount of fat when their microbiomes
 are placed in a sterile lean mouse microbiome.
             In the case of cryptosporidiosis, low-dosage exposure to C. parvumto the human gut is showing promise as a new method to alleviate Cryptosporidium-specific diarrhea in patients, particularly affected children in generally poorer populations.
             To conduct these pseudo-surgeries, the human gut is “blasted” with antibiotics. This kills off a strong portion of the microbiome, which creates gut vacancy that can quickly be occupied by the first organism that can find a niche in it. Though this may seem like a dangerous process, considering the aforementioned importance of maintaining a healthy microbiome in the gut, studies have shown that the composition of the gut is generally very robust, even in responses to stressors like antibiotic hits and diets containing high quantities of sulfur. After disturbance, the makeup of the gut is elastic, and “whips” back to its normal composition in a matter of days, like a slow rubber band. These transplants work by taking advantage of the time window available during this period, where niches in the gut are free, and instead of reverting back to the original gut composition, it becomes slightly modified (5).
             Even in the last ten years, new fecal microbiota transplant techniques have alleviated diseases such as Clostridium difficile infection and diabetes. Though it seems strange, these fecal transplants involve using one of the most unlikely substances to improve your heath—poop. In fact, thousands of labs arounds the United States are using fecal samples to improve the health of individuals. A fecal transplant is similar to a liver or lung transplant: a “defective” gut microbiome is fully or partially replaced with the gut microbiome of a healthy, non-infected individual. Often a general fecal sample is taken from a young, healthy individual with a balanced diet and fully replaces the gut microbiome of the patient, as seen in the image below. This is the method being used to treat C. difficile infection and the like. It is the standard, less risky method to cure generalized gut infection, yet not all enteric diseases can be tackled in the same exact simple manner.
Figure 2. The general process by which a fecal microbiota transplant (FMT) occurs.
Simply, the microorganisms in the gut of healthy individuals is placed in a
sterile gut of a patient with a gut-affecting condition.
             The case of C. parvum infection is slightly different—its treatment involves giving low-dosage C. parvum gut injections, which seems counterintuitive. However, the logic applies here is similar to that of your garden variety flu shot. Many shots involve injecting a harmless/modified, or dead, version of the virus or bacterial toxin into the human bloodstream, and the immune system goes through a process of developing memory immune cells to tackle a future infection that mimics that of the flu shot. Because the infection does not pose a biological threat, the immune system can take care of it efficiently and prevent future infection (6). 
The microbiome priming technique follows a similar line of logic. Most infections occur in those with low-protein diets, which leads to a decrease in certain immune responses. Here, these responses are called Th-1 responses and cytokine responses. These interactions by the immune system are critical in halting C. parvum infection. Restoring these responses is key in stopping lethal cryptosporidiosis (6).
            With this in mind, two routes appear feasible in ridding infection: the first is reestablishing a protein-heavy diet, and the second is priming via C. parvuminjection. Many neglected or lower socio-economic populations are unable to maintain a balanced diet, and many lifestyle choice involve low-protein intake, as well. This leads many groups of people to be susceptible to potentially fatal protozoan infection by C. parvum. Often these diets changes are not possible or are otherwise rejected. Therefore, a pragmatic approach to reducing the incidence of cryptosporidiosis is fecal transplantation in these populations. So, use of fecal microbiota transplantation can be a plausible option for those who cannot alter their diets to fit a protein-heavy intake. 
             Not only are these findings about C. parvum infection clinically applicable, but it may pave a new common route for treating gut infections that are tied to microbiota imbalances. Traditional methods to improving gut health usually involve dieting techniques, medication, or other lifestyle changes. These prescriptions may be effective in cases, but disturbances in the gut microbiome are extremely difficult to fix due to their elasticity. With the case of dieting, studies in the past have shown that most diet changes do not permanently alter the gut composition. Even high dairy or sulfur diets over the course of weeks hardly change the organisms abundant in the gut, and when they do change, it seems to be temporary. Exercise and other anti-inflammatory lifestyle approaches are also common route in treating gut infection, particularly related to colitis. Yet these methods are not necessarily a permanent or even effective way to ameliorate gut disturbance symptoms. New evidence related to cryptosporidiosis infection is showing that these “gut vaccines” may be a route for reducing gut disease incidence. Most vaccines are typically seen as bloodstream injections involving dead or broken viruses, but gut priming appears to follow a similar logic and could be just as valid of a medical treatment.
             Because the impact that the gut microbiome has on the human body—which is a growing library of knowledge recently—is seems to be possible to manipulate the makeup of the gut to improve many conditions. Here, it is intriguing that priming the intestines with C. parvum leads to alleviation of the lethal infection caused by the same protozoan. This could pave the way to treating other gut infections related to common microbiome species, like E. colior C. difficile, which appear to be more commonplace in the wake of an aging, susceptible population (figure 3).
Figure 3. The rate by which individuals in the USA are affected with gut-related diseases appears to be increasing with time, particularly in older populations. Because many treatments to other diseases, like cancer, involve unintentional gut dysbiosis, colitis rate seem to increase, which makes FMTs a popular and effective solution to gut dysbiosis.

Works Cited:

1)     Mangiola F, Ianiro G, Franceschi F, Fagiuoli S, Gasbarrini G, Gasbarrini A. Gut microbiota in autism and mood disorders. World J Gastroenterol 2016; 22(1): 361-368
2)     Cryptosporidium Pathogenicity and Virulence; Maha Bouzid, Paul R. Hunter, Rachel M. Chalmers, Kevin M. Tyler; Clinical Microbiology Reviews Jan 2013, 26 (1) 115-134; DOI: 10.1128/CMR.00076-12
3)    Sarkar S, Ulett GC, Totsika M, Phan M-D, Schembri MA (2014) Role of Capsule and O Antigen in the Virulence of Uropathogenic Escherichia coli. PLoS ONE 9(4): e94786. doi:10.1371/journal.pone.00947861. 
4)    Kulecka M, Paziewska A, Zeber-Lubecka N, Ambrozkiewicz F, Kopczynski M, Kuklinska U, Pysniak K, Gajewska M, Mikula M, Ostrowski J. Prolonged transfer of feces from the lean mice modulates gut microbiota in obese mice. 2016;13(1):57.
5)     Kelly CR, Khoruts A, Staley C, Sadowsky MJ, Abd M, Alani M, et al. Effect of Fecal Microbiota Transplantation on Recurrence in Multiply Recurrent Clostridium difficile Infection: A Randomized Trial. Ann Intern Med. ;165:609–616. doi: 10.7326/M16-0271
6)   Bartelt LA, Bolick DT, Kolling GL, Roche JK, Zaenker EI, Lara AM, et al. (2016) Cryptosporidium Priming Is More Effective than Vaccine for Protection against Cryptosporidiosis in a Murine Protein Malnutrition Model. PLoS Negl Trop Dis 10(7): e0004820. doi:10.1371/journal.pntd.0004820