Good Bugs, Bad Bugs: Hacking the Gut

Bacteria, also known as bugs, are like family. Some you can’t live with and some you can’t live without. There are good bugs, bad bugs, and superbugs (super bad bugs). Bacteria coexist with the human body, taking up residence in the gut, vagina, mouth, and on the skin. Good bugs peacefully coexist, most notably in our gut where they play a role in digestion. However, they can also be minor nuisances like those malodorous conditions that can be treated with Listerine and Gas-X. Clinical research has established other more serious connections between resident bacteria and our bodies. There is an established connection between Porphyromonas gingivalis in the oral microbiome and Esophageal Cancer, and more recently with Pancreatic Cancer[1] as well, giving perhaps even more reason to brush and floss regularly.

Good bugs fly under the radar and are only conspicuous by their absence. For instance, in the gut there are tens of trillions of bacterial cells and hundreds of different species that cohabit symbiotically with our healthy cells. Gut bacteria account for about 70% of these commensal bacteria in our bodies. They provide us with nutrients, aid in digestion, and contribute to our immune function. They eat what we eat and they are affected by antibiotics as much as the ‘bad’ bugs. Gut flora has even been labeled as ‘the forgotten organ’. Friendly bacteria in the gut can be wiped out in about a third of patients on antibiotics, as good bacteria and bad alike are affected by the drugs. When antibiotics kill off the good bug, diarrhea ensues. Fortunately, a good dose of ‘friendly’ bacteria in a probiotic or in yogurt can help restore their population. An imbalance in the microbial population is called dysbiosis. Gut dysbioses have been implicated in inflammatory bowel disease and obesity. Since there is a mind-gut connection, it is no surprise that gut dysbioses have been implicated in anxiety disorders, autism spectrum disorder and obstructive sleep apnea-induced hypertension.

Bad bugs are responsible for unnecessary hospitalizations and excessive costs to the health care system and, at their worst, they kill. Bacteria are continually evolving and developing resistance to antibiotics. A major part of the problem with treating antibiotic-resistant bacteria infections is the lack of new antibiotics on the market. This is due to the lack of a profit motive for pharmaceutical companies to develop new antibiotics, and, as a consequence, the last new antibiotic to be introduced was Ceftaroline in 2010. The problem is the rise of superbugs that are resistant to many and potentially all antibiotics. The dangers of antibiotic-resistant bacteria like methicillin-resistant Staphylococcus aureus (MRSA) are well-publicized, but there are other emerging threats where we are running out of antibiotic drug options. According to the Centers for Disease Control (CDC), there are 23,000 deaths annually from 2 million infections caused by drug-resistant bacteria. The number one killer in the U.S. is diarrhea-causing C. difficile (Clostridium difficile). An emerging threat is the fearful superbug, carbapenem-resistant Enterobacteriaceae (CRE), which resists essentially all antibiotics according to CDC Director, Tom Frieden. Recently, a woman in Pennsylvania was diagnosed with a urinary tract infection caused by a mutant E. coli superbug, with a plasmid-borne gene called mcr-1, resistant to the last resort drug Colistin. This drug is used to treat CRE infections, but it can damage the kidneys so it is an option of last resort. Fortunately, the woman was successfully treated with the administration of a carbapenem.

Enter the good bugs. There are many strains of bacteria in the gut, so it is natural to suspect that they compete with one another, live alongside one another, or they may even work against one another. In the latter case, one could presuppose that these resident bacteria could be helpful in keeping dangerous disease-forming bacteria from establishing a foothold in our bodies. The trouble is, we don’t know a lot about them. In the 13th Edition (2016) of the highly respected textbook, Medical Physiology by Guyton and Hall, the digestive role of bacteria is relegated to less than 100 words in a single, sidebar text box in only one of five chapters on gastrointestinal physiology. Normal feces are about 75% water and 25% solid matter, 30% of which is dead bacteria, so it is easy to surmise that they might have a permanent place in our gut and an important role in digestion and maintaining homeostasis. Gut microbiota, good bugs aside, are also involved in lipid metabolism, the immune response, and in the regulation of moods and behavior.

Genome sequencing technology has allowed researchers to profile the microbiome associated with resident bacteria (the microbiota or flora). Bacteria are living cells and have a genome, as humans do. Mapping the genome of the microbiome is the broad task of the National Institutes of Health (NIH) Human Microbiome Project (HMP). The project is an important step toward understanding the genetics of newly emerging strains of antibiotic-resistant bacteria and aiding the development of new antibiotics. Dr. Curtis Huttenhower, Associate Professor of Computational Biology and Bioinformatics at the Harvard T. H. Chan School of Public Health, and 2015 winner of the Overton Prize from The International Society for Computational Biology (ISCB), said, “The microbiome represents an untapped new source of possible disease biomarkers and therapeutic interventions. In inflammatory bowel disease and type 1 diabetes, we're trying to determine which changes in the microbiome predict disease onset or inflammatory activity.”[2]

There are other strategies for dealing with new strains of superbugs. One strategy, besides developing new antibiotics, is to harness the ‘friendly’ bacteria to either compete with the superbugs for gut real estate and crowd them out, or to supplement or replace the gut with ‘friendly’ bacteria.

A group of researchers reported in the June 2015 issue of PLOS Computational Biology that they identified a normal strain of gut bacteria, Barnesiella intestinihominis that inhibited the growth of Clostridium difficile (C. difficle). The researchers measured and tracked changes in the relative amounts of gut bacteria populations and their susceptibility to C. difficile infection, as they responded to treatment with the antibiotic Clindamycin. A mathematical network model of the immune response of the gut was developed to model the interactive dynamic response of C. difficile to other gut bacteria and immune cells. They found that Barnesiella intestinihominis inhibited C. difficile growth, suggesting a role for B. intestinihominis as a potential probiotic.

So, what can one do when antibiotics don’t work and you have a recurrent, refractory, and relapsing Clostridium difficile infection (CDI)? Try a stool (fecal) transplant from a healthy donor. A study by Youngster, et al., published in 2014 in JAMA, reported the results of a study that effectively treated diarrhea in patients with CDI by giving them frozen fecal microbiota transplantation (FMT) capsules from unrelated donors. There are certainly safety questions and donor selection criteria to be nailed down, for sure. There is also the question of which disorders are candidates for FMT therapy? It has been tried in patients with metabolic syndrome with some success, and it has been tried in autistic children where it helped at least a few children with some intestinal problems. Then, there are the practical matters. How to capture, how much to capture, and how to process the feces? Fresh vs. frozen? How to shake, stir, or blend? How to filter? Coffee filters or steel strainers? How to administer? Down the hatch or up the alley via enema? Vomiting is an obvious risk with the former approach. These are all real concerns. The FDA is taking the issue head-on and the agency is classifying fecal transplants as drugs, not biologic tissue, and restricting its use to refractory C. diff. infections. What about the DIY crowd and the bio-hackers? Yes, that is also a concern with more to come on that front.

You can pick your battles or pick your poop. One thing is for certain, one man’s trash is another man’s treasure.

[1] Jacob, JA. Study Links Periodontal Disease Bacteria to Pancreatic Cancer Risk. JAMA. Published online May 31, 2016.

[2] http://journals.plos.org/ploscompbiol/article?id=10.1371/journal.pcbi.1004319