LOW oxygen levels (Hypoxia) can be a problem but surprisingly also beneficial at times. New medical research has revealed that antibiotics, essential to combat bacterial infections, can inadvertently promote potentially lethal fungal overgrowth in the gut due to low oxygen levels. This also highlights the influence of the molecular environment on drug action. Antibiotics disrupt the gut's delicate microbial balance, leading to low oxygen levels and promoting the expansion of disease-causing fungi like Candida albicans. Earlier Soviet scientists had also shown how hypoxia can be handled and the medical benefits possible.

HYPOXIA

Hypoxia, a state where there is a reduction in the oxygenation level presented to or used by body tissue, involves a decrease in oxygen delivery. In the gut, hypoxia, a state of reduced oxygenation, helps maintain microbes in homeostasis (in balance and in a healthy state). Although the history of hypoxia research began in the mid-19th century, scientists initially employed terms like "anoxia" or "anoxemia." The word "hypoxia" was first used in 1938.  Soviet scientists began to examine hypoxia, specifically intermittent hypoxic training (IHT), systematically in the 1930s as a way to use it in military and space exploration applications. Researchers like Nikolai Sirotinin and Oleg Gazenko experimented with the use of altitude chambers and hypoxic gas mixtures to acclimatise pilots and cosmonauts to withstand low-atmospheric oxygen pressures at high altitudes. Their research made it possible for Yuri Gagarin of the Soviet Union to be the first man in space.

Therapeutic applications of hypoxia have evolved over the years. Soviet research found that controlled hypoxia was therapeutic for conditions as diverse as bronchial asthma, hypertension, neurological pathologies, and radiation toxicity. Early experiments revealed that hypoxia produced adaptive physiological responses, such as increased ventilatory sensitivity, activation of antioxidant defense, and mitochondrial efficiency. Ukrainian Professor Tatiana V Serebrovskaya, who succumbed to COVID-19 in 2021, was instrumental in introducing Soviet success to the global scientific community. Later studies have expanded on these findings, investigating intermittent and continuous chronic hypoxia (CCH) for a range of therapeutic applications. CCH can potentially cure mitochondrial and neuroinflammatory disease.

However, there exists a dark side to hypoxia revealed by recent research on the gut microbiome. Derek Bays at the University of California in the US recently demonstrated the risk of fungal infection caused by antibiotics. Antibiotics wipe out beneficial bacteria in the gut, which keep the low-oxygen environment under control. This provides a window for fungi like C. albicans to grow with potentially fatal consequences, as invasive C. albicans infection has a 49 per cent mortality rate. Bays and colleagues found that high oxygen tension in the gut after antibiotic treatment provokes growth of C. albicans, and prevention may be central to preserving hypoxia. He observed this phenomenon in cancer patients who subsequently developed life-threatening Candida albicans infections despite antifungal and prophylactic antibiotic treatment. This was a failure of "colonisation resistance," the process by which normal gut bacteria prevent pathogen colonisation.

Antibiotics wipe out the bacteria, increasing oxygen levels by disrupting the gut's mechanisms for maintaining hypoxia. The scientists figured that restoring hypoxia could be a good strategy. They experimented with 5-aminosalicylic acid (5-ASA), which they knew would reinstate anaerobic conditions in the intestine. They discovered that 5-ASA triggered colonisation resistance and blocked C. albicans growth by reinstating a low-oxygen environment. Microbiota transplantation from 5-ASA-treated antibiotic mice conferred maximum resistance to C. albicans in recipient mice, suggesting 5-ASA as an effective surrogate for missing beneficial bacteria. This approach, which targets the environment rather than the fungus, presents a promising direction for the prevention of C. albicans overgrowth in susceptible individuals because the fungus cannot develop resistance to a low-oxygen environment.

IN INDIA

These findings have significant implications, particularly in countries like India where misuse of antibiotics is rampant. India has generic drugs, which are cheaper than branded antifungals, unlike the US. Antifungal drugs like Nystatin, Fluconazole, Itraconazole, and numerous others are made available at lower costs as generics. This route or generics has been facilitated by Section 3(d) of the Indian Patent Act, which restricts the patenting of new forms of known substances unless they demonstrate substantially enhanced efficacy. This is to prevent the "evergreening" of patents and to allow generic medicines to be made available.

The inclusion and safeguarding of this section was facilitated mainly through the initiatives of Amit Sengupta and others of the People's Health Movement. They argued that strict patent regimes, which were adverse to medicine access could lead to the "plunder" of people. Prabir Purkayastha, points in his book "Knowledge as Commons: Towards Inclusive Science and Technology," to the privatisation of knowledge. He shows how capitalist structures, under the pressure of profit, are increasingly seeking to privatise knowledge in the form of patents, copyrights, and other IPR regimes. He describes how this is a new form of "enclosure," like the ancient enclosure of common land, that shuts off access and retards progress.

Researchers are also investigating other forms of treatment as the antifungal pharma market in India as a whole is large and expanding due to the fact that fungal infections are so common.

These include bacteriophage therapy (using viruses to treat disease-causing bacteria), fecal microbiota transplantation (FMT), and probiotics. Probiotics, which are helpful bacteria that are sometimes administered along with antibiotics, attempt to restore the microbiota of the gut. While promising in certain situations, additional research is necessary to determine if they can avert invasive fungal infections. Fecal microbiota transplantation (FMT), or the transfer of fecal material from donor to recipient, is a more invasive means of restoring microbial harmony to the gut. FMT has been very successful in the management of recurrent Clostridioides difficile infection and is being investigated for other uses. Its application in suppressing fungal overgrowth must be investigated.

Increasing antibiotic resistance has witnessed renewed interest in bacteriophage therapy. Bacteriophage therapy was routinely employed in the Soviet Union for treating bacterial infections. Although bacteriophages do not infect fungi, they can selectively kill invading bacteria that disrupt gut ecology, and this will indirectly affect the pattern of fungal growth. They need to be investigated further.

COVID 19

Hypoxia is so a key factor in COVID-19 pathology. Many will remember the measurements of SpO2 during Covid done to check the oxygen concentration in the blood. They may also recollect how a doctor in UP was punished for providing much needed oxygen to his patients with COVID-19 using his money. In COVID-19, hypoxia is due to inflammation and swelling in the lungs that impair the exchange of oxygen and make oxygen levels in the blood decrease. This lead to symptoms like breathlessness, confusion, and fatigue, though many others did not experience obvious symptoms – a condition known as "silent hypoxia". If left untreated, hypoxia leads to organ failure and death.

In India, the impact of COVID-19, and thus hypoxia, has been particularly devastating. Though official reports cite approximately 533,570 deaths from COVID-19, recent data has confirmed that the actual number is much higher. Excess deaths in 2020 and 2021 have been estimated to be in the range of 2.1 to 2.2 million based on government reports, indicating massive underreporting. Evidence exists that hypoxia, especially silent hypoxia, was one of the main causes of deaths, and 40–50 per cent of the Indian hospital deaths attributed to COVID-19 could have been linked to hypoxia complications. The many-sidedness of hypoxia – from therapeutic applications as being explored early by Soviet scientists to its implication in COVID-19 and now in antibiotic-induced fungal infections – testifies to the power of scientific research and the need to investigate therapies relating to hypoxia.