Dr Ashok Kumar, President,CRD, IPCA Laboratories, explains how a focussed research on microbiomebased interventions can help to understand the mechanism of action for developing a more rational and scientific approach and clinical efficacy data,before giving it as a therapy to patients

Compassion or an act of kindness with selfless motive makes people ‘feel good deep inside,’ difficult to express in words. Some of those having routine to yoga or physical exercise may have also found themselves in relaxed or euphoric state (at least sometime) after the workout. This ‘feeling good’ was earlier believed to be related to the endorphins (endogenous opioids) surge, but has, of late, been found to be linked to the release of endocannabinoids, such as Anandamide, a Small Chain Fatty acid Amide (SCFA), known to participate in our body’s endocannabinoid system (ECS) by interacting with cannabinoid receptors. These receptors are also activated by compounds, such as THC (Tetrahydrocannabinol) and CBD (Cannabidiol), found in Cannabis (Psychoendocrinology, 126, 105173, 2021).

The striking feature of the other paper published in the same year (Gut Microbia 1997559, 2021) was the finding that exercise leads to noticeable change in the composition of gut microbiota producing anti-inflammatory substances (SCFAs) and lower levels of pro-inflammatory genus Collinsella, on the constant basis; and this shift is linked to the spike in the release of endocannabinoids. The latter are also known to possess potent anti-inflammatory activity, and, therefore, also help in managing conditions such as cancers, and even heart diseases, by reducing chronic inflammation. For those curious to know the origin, the name ‘Anandamide’ is taken from the Sanskrit word Ananda, which means ‘Bliss’ or ‘Joy’ (DOI:10.180/19490976.2021). The gut microbiome/microbiota: The large intestine, also commonly known as colon, has surface area touching 350 sq. ft. and hosts ~ 95 per cent of the total human microbiome (~100 trillions in numbers) and account for -> 0.2 kg of the body weight of a normal human adult.

The microbiota of a human is quite diverse and constitutes approximately 4,000 different strains of bacteria, viruses and fungi. We possibly know a bit about bacteria, but probably lack almost complete knowledge of the viruses that inhabit in a human gut. In 1885, Pasteur promulgated that “animals lacking bacteria would die,” but until the beginning of the 21st century, microbes were considered to produce toxins and also the cause for the poor mental health of patients. ‘All diseases begin in the gut,’ as proclaimed by Hippocrates over 2,000 years ago, may not be completely true, but, today, scientists believe that gut microbes play an important role in keeping the human health in shape.

We are what we eat and think: Mounting evidence illustrates that diet plays an important role in shaping the gut microbiome, but there are good number of reports suggesting that close, yet sustained relationship (e.g. marital), harbour microbial communities of greater diversity and richness relative to those living alone (Scientific Reports 9, 703, 2019). Higher levels of wisdom, compassion, social support and lower levels of loneliness are found to have strong link to more diverse and rich gut microbiome, as reported by researchers from the University of California, San Diago (Front Psychiatry 2021,12,648475). These findings suggest that not only food, but the social interactions are also critical in maintaining quality gut microbiome (Labroots 30/3/2021). Gut microbiome and mental health: Apart from providing home to microbes, our gut also hosts Enteric Nervous System (ENS) also known as second brain because it seems to act autonomously, without involvement of CNS.

And, if one remembers the emotions like having butterflies in the stomach, when excited or nervous, it is because of the sensitivity of the ENS. Gut-brain is the key to maintain two-way biochemical signalling between GI tract and the CNS through vagus nerve, but it was the report published by Sudo et al in J Physiology in the year 2004, which, for the first time, brought a new dimension to the existing knowledge that the germ-free mice are more susceptible to stress compared with those having intact microbiota and the finding published by Cryan’s group in PNAS- USA, 2011 confirming that vagus nerve is involved in providing connection between microbiota and the brain. Four week intake of yogurt with probiotics (Bifidobacterium, Streptococcus, Lactobacillus and Lactococcus), for example, modulating the brain regions that control the central processing of emotions and sensations,

observed in the randomised controlled trials (Gastroenterology, 2013, 1394-401); and the confirmation of the consistent depletion of bacteria (Coprococcus and Dialister), known to have correlation with human health in the individuals suffering with depression, found from the studies conducted under Flemish Gut Flora Project (Nat.Microbial.2019, DOI:10.1038/s41564-018-0337- x) can be considered as evidence for substantiating the link between gut microbes and human brain health. Microbiome therapy: A hope So far, there is no knowledge on the underlying mechanism how gut microbes influence or modulate human health. However, it is more than evident from the above discussion that there is a microbiagut-brain-axis and many disorders such as anxiety, depression, schizophrenia, etc have some connection with this axis.

However, once we believe in the said hypothesis, many questions which come spontaneously to our mind include: 

◆ is it possible to use microbes for disease treatments? 

◆ is it possible to prevent diseases in general and even the neurodegenerative diseases such as Alzheimer’s and Parkinson’s (for which there is no treatment available so far) by improving or manipulating the microbiomes of the patients? 

◆ could it be possible to restrict the ageing process or reverse it via microbiome therapy, as demonstrated using mice model where scientists found rejuvenation of some aspects of brain and immune functions of the animals (Nature Aging 1. 666-67, 2021)? The answer of these questions is more likely to be – may be – ‘yes’ ! – because lots of studies are going on across the globe to translate the existing knowledge into treatments. Fecal Microbial Transplantation (FMT), however, has already shown some promising results, as highlighted below: FMT and Parkinson’s disease:

The finding of the study published in the journal Cell suggests that feeding the mice with the microbes taken from the gut of the people suffering with Parkinson’s made the animals’ symptoms worse in the mouse model of Parkinson’s disease. However, since FMT from healthy donors did not show any observable impact on the animals’ symptoms, one can believe that gut bacteria are indeed linked to neurodegeneration (Cell 167. 1469-1480, 2016). One should, however, not conclude that we are anywhere close to find a treatment for Parkinson’s disease. FMT and insulin sensitivity: A recently published work (Nature Medicine 27, 1272-1279, 2021), however,

takes us to a higher level of confidence which provides the Proof of Concept for the use of single-dose oral FMT generated from healthy donors to increase insulin sensitivity in patients suffering with severe obesity and metabolic syndrome in a randomised double-blind placebo controlled phase-II trial FMT. FMT and cRDi: The treatment of recurrent infections caused by Clostridium difficile (rCDi) using FMT, supported by several randomised clinical trials with a high success rate, is not only stabilised, but, is now considered as a second-line treatment (Clin. Endosc 52,137-143,2019); doi:5946/ce.2019.009).

The same approach is also being considered for other GI diseases as well such as IBD, IBS and hepatitis encephalopathy. FMT and cognition: Based on the findings that FMT from young mice to aged one helps increase their cognition, the Motion Study, sponsored by Quadram Institute Biosciences has started tracking the gut microbiome and cognitive function of people aged 60 years living in East Anglia, with an aim to identify how microbiome changes correlate with the cognitive decline, and also finding a solution for, atleast, controlling the further decline, if possible, in the affected people.

FMT and cancers therapy: A more recent paper appeared in Nature reports that microbiome can have effect on the progression of distant tumours, the side effects of the treatments and the ability of the immune system to pickoff cancer cells. The paper also reports that FMT has already helped some people to overcome resistance to immunotherapies and at least 30 FMT trials are currently underway around the world, being conducted by academic institutions and pharma companies (Nature, 607, 436-439, 2022). Dr Boursi, an oncologist at the Sheba Medical Centre who has already treated 30 people, believes that this approach could open the door to a “new era of ecological oncology,” in which understanding of tumour, host, the immune system and resident microbes will lead to better cancer treatment. COVID-19: The findings of the paper published last year (Gut 70, 698-706, 2021) suggest that depletion of immunomodulatory gut microorganisms contribute to severe COVID-19 disease and bolstering of the beneficial gut species, otherwise depleted in COVID-19, could serve as a novel avenue to mitigate severe disease, underscoring the importance of managing patients gut microbiota during and after COVID-19.

The way forward FMT demonstrating improvements in the insulin sensitivity of patients suffering with metabolic syndrome and clinically proven success in treating recurrent rCDi substantiated by the findings compiled in the text can be considered as a reasonable support to believe that maintenance, improvement or manipulations of gut microbiota may one day provide us a healthy solution for treating or managing many diseases, and also maintaining good health without the medicinal intervention. However, more focussed research to understand the mechanism of action to develop a more rational and scientific approach and clinical efficacy data to support the findings is critical, before microbiome-based interventions could be given to patients as approved therapies.

It is difficult to predict the time frame within which the microbiome-related approach could see, even if it does, the light of the day, as far as the availability of the proven treatments are concerned. However, one thing which is almost clearly evident from the above discussion is that diet has significant impact on the quality of gut microbial flora, on the gut health and mental wellbeing, and, therefore, it is important to make note of what we eat. Since higher levels of wisdom and compassion have shown to help maintaining quality microbiome, a lifestyle fortified with the virtues of humility and gratitude will surely lead us to an Anand-maya life! Let’s give it a try !!