For Gut’s Sake

Imagine your gut as a hilly terrain where some terrorists (harmful bacteria) are hiding among the mountains. To eliminate them, you take antibiotics, which has a ‘carpet bombing’ effect. Not only does it wipe out all the harmful bacteria, it results in collateral damage inside the gut as the good bacteria essential for microbiome balance too get wiped out. The end result — a health disaster in the making, inside you. As researchers across the globe are beginning to recognise the benefits of protecting the human gut microbiome — which is directly linked to metabolic influences on mental and physical health of humans — is it possible to come up with antibiotics that would be effective without killing the good bacteria?

The Lolamicin step

Renowned Gastroenterologist

Dr D Nageshwar Reddy says it has long been a topic of scientific deliberation how antibiotics that can do a targeted job of only killing or inhibiting the harmful bacteria and not affecting the good ones inside our gut, can be made. Only recently, informs Dr Reddy, researchers at the University of Illinois Urbana-Champaign, USA led by Prof. Paul Hergenrother developed a new antibiotic called the Lolamicin which can take down harmful bacteria, leaving the friendly gut microbes unharmed. “The experimental studies conducted on mouse models showed that Lolamicin targeted the bad guys (like E. coli, K. pneumoniae, and E. cloacae) and spared the good bacteria in the gut. However, we're still a long way from human trials but this is a huge step forward,” says an optimistic Dr Reddy.

Good Vs bad bacteria

Describing the gut as a complex warehouse consisting of a diverse set of microorganisms that play a significant role in our overall health, the Chairman of the Asian Institute of Gastroenterology (AIG) says in terms of numbers, bacterial cells in the gut are 10 times greater than the number of human cells in our entire body. “There has been quite a bit of advancement in understanding the role of these bacterial phyla, mainly Bacteroidites and Firmicutes which constitute approximately 90% of the gut microbiota. It is the balance of these two that helps us maintain good gut health,” he points out.

Dr Reddy says various studies have shown that altering the balance of these bacteria can have multiple effects on our body. “The good bacteria help in treating metabolic diseases like obesity, impact brain functions, and enhance our ability to extract energy from food. If they get wiped out, it can even change the circadian rhythm (human body’s 24-hour cycle of physical, mental, and behavioural changes).” He says there are harmful bacteria in the environment that cause disease when they enter our body like Escherichia coli (E. Coli) can cause urinary tract infections, gastroenteritis or Salmonella can cause food poisoning, typhoid fever, etc.

“To treat these diseases, antibiotic medications were invented which either kill or inhibit the growth of these bacteria. But when the good bacteria too is killed in the process, it impacts several body functions,” he adds. The human body contains 30 trillion human cells, but also has about 38 trillion microbes – mostly bacteria, majority of them in the gut and their weight is about 0.2 kg!

Dysbiosis

“Antibiotics create havoc in the gut leading to disruption and imbalance – what is called gut dysbiosis. There is a race to understand dysbiosis and ways to prevent it,” says Professor R Shyama Prasad Rao from the Centre of Bioinformatics, NITTE University, Manguluru. He says that our gut microbiome is shown to profoundly affect various cancer development, cardiovascular, neurological as well as generative diseases. What’s more, food and gut microbiome are also shown to affect behavior, mood, and mental health. “A super cool bottom might really be the secret to our cool head. Yet, we mindlessly meddle with it by abusing antibiotics,” says the bioinformatician.

It is not an exaggeration to say that we humans have outsourced our health and well being to the bacteria in the backend – the gut microbiome, says Prof Rao. “Bacterial cells are complex systems that behave differently under diverse conditions and when challenged using antibiotics. This is where the need of continued research is required to understand their biology, combat infections, and avoid antibiotic-resistance pandemic,” he says.

Gram Positive

Prof Rao says the good old method – a balanced diet with fiber supplementation was shown to protect from antibiotic-induced gut microbiome dysbiosis. “While there is exciting progress to keep our gut healthy, antibiotic use is always fraught with danger,” he points out. Prof Rao says that common disease-causing multi-drug resistant bacteria such as Escherichia coli, Klebsiella pneumoniae, Acinetobacter baumannii, Pseudomonas aeruginosa, etc. are all gram negative, while bulk of the gut microbiome such as Bacillota and Actinomycetota are gram positive.

He says the gram staining of bacterial cell wall differentiates them into positive or negative, and it was developed by a Danish bacteriologist Hans Christian Gram in 1884. “Gram positive bacteria such as Enterococcus faecium and Staphylococcus aureus commonly found in gut as harmless commensals can be opportunistic pathogens and increasingly known to be drug resistant,” explains Prof Rao. Referring to the ongoing research at the University of Illinois, Prof Rao says the new antibiotic Lolamicin is a gram-negative bacteria-specific antibiotic effective against over 130 multi-drug resistant clinical isolates. “Using the mouse model, they showed that in comparison to broad-spectrum and gram-positive-only antibiotics, Lolamicin spared the beneficial gut microbiome.”

Genetic Engineering

Dr Shiva Raju, Sr. Consultant Physician & Diabetologist, KIMS Hospital says presently, some antibiotics in combination with probiotics are in the market ( lactobacillus), like amoxycillin and clavulanic acid and Doxycycline.

“Only some companies are manufacturing this combination. But it may be of limited use, as this combination may not cover all possible good bacteria in the gut. At least important gut microbes have to be covered or protected with usage of antibiotics,” he says. He says antibiotics that work without killing the good bacteria in the gut is possible to some extent. “But we have to understand the mechanisms of antibiotics, causing damage to good bacteria. At least, some genetic engineering or technology may have a role in protecting good bacteria,” he feels. In future, says Dr Shiva Raju, the doctors will have to combine antibiotics with probiotics.

That Gut Feeling

• In 2018, Dr Mireille Nishiyama and colleagues from Genentech identified a novel pyrrolopyrimidinedione compound called G0507 effective against Escherichia coli. As demonstrated in the same study, bacteria can acquire resistant-mutations in the target protein rendering the antibiotics useless. Thus, magic and miracles are short-lived in the bacterial world.

• In 2022, researchers led by James Collins from Massachusetts Institute of Technology engineered Lactococcus lactis, a beneficial or probiotic bacteria commonly found in fermented milk products such as buttermilk and curd, to degrade broad-spectrum antibiotics ß-lactams. They have shown that it minimized gut dysbiosis, and can be used as a live biotherapeutic to protect gut microbiome when in antibiotic course.

• Dr. Jean de Gunzburg and others from Da Volterra biopharmaceutical showed in a 2018 phase-1 clinical study that coadministration of antibiotics with DAV132, a novel colon-targeted adsorbent, effectively prevented antibiotic-induced perturbations on gut microbiota.

• Bacteria, fungi, viruses and other microscopic organisms — trillions of them — together form the microbiome.

The experimental studies conducted on mouse models showed that Lolamicin targeted the bad guys (like E. coli, K. pneumoniae, and E. cloacae) and spared the good bacteria in the gut.” — Dr D Nageshwar Reddy, Gastroenterologist

Antibiotics create havoc in the gut leading to disruption and imbalance – what is called a gut dysbiosis.” — Professor R Shyama Prasad Rao, Centre of Bioinformatics, NITTE University, Manguluru