Listen to your gut – it may be telling you something about your heart | Explained

The human microbiome is a community of trillions of microorganisms that reside in our body, especially in the digestive tract. It is a dynamic community that plays a pivotal role in regulating our health and diseases.

These microbes influence various aspects of our well-being, including the way we digest food, absorb nutrients, metabolise key metabolites, develop immunity, and keep good mental health. This is why scientists have been immensely interested in understanding the intricate relationship between the human genome and the body’s microbial inhabitants.

Genomic technologies have been central to our knowledge of the human microbiome. Many microorganisms of the microbiome aren’t amenable to being studied in a scientist’s traditional way: by culturing them in a lab.

In 2012, an international consortium of scientists launched the Human Microbiome Project that provided the first glimpses into the human body’s complex microbial makeup using genome sequencing. Advancements in this technology in the last decade allowed scientists at greater revolutions than possible previously.

The microbiome and human health

Today, scientists widely accept that a healthy human microbiome is essential for healthy living. For example, we know that the human gut microbiome contributes to essential physiological functions like digesting food and absorbing essential nutrients. The microbes involved in these activities also produce some of the enzymes the human body requires to function normally.

Conversely, if the population of one microbe becomes excessive or the composition of a community of microbes changes, the body can develop a variety of health conditions.

The human microbial communities also change over time. When sick people take antibiotics to treat an infection, their gut microbial compositions change significantly – and return to their ‘original’ state after some time.

Some medical researchers also artificially change the human microbiome composition in order to achieve some clinical outcomes. For example, researchers have used a treatment called faecal, or intestinal, microbiota transplant – i.e. transplanted microbiota from a healthy to a sick individual – to control infections of a bacterium called Clostridium difficile. Researchers have also used faecal microbial transplants from donors to people with extreme obesity to improve their sensitivity to insulin and ‘resolve’ other metabolic syndromes.

In sum, we have lots to gain from knowing the optimal composition of the human microbiome and the ways in which it influences our health.

From the gut to the heart

Scientists have published numerous studies on how the environment, diseases, and our diets affect the composition of our gut microbiome. But there’s been increasing evidence of late to suggest differences in our genetic make-ups could also affect the diversity of gut microbes as well as the abundance of specific microbe populations.

In fact, how exactly an ‘effect’ could travel from our genes to the microbes in our gut has been an enigma until now. In a large study – involving 9,015 individuals from four Dutch cohorts – published on January 3, researchers from institutes in Australia, Germany, Italy, Romania, Tanzania, the Netherlands, and the U.S. investigated the link between human genetic variations and the genes of gut microbes.

Specifically, they identified a link with variants of a gene cluster in organisms involved in metabolising an amino-sugar molecule called N-acetylgalactosamine. The organisms with this gene cluster had more individuals with specific genetic variants in the ABO blood group locus (a locus is a place on a chromosome where a gene is located). The ABO blood group in humans is determined by specific variations in the human genome.

Genetic variants in ABO blood group loci, and consequently ABO blood groups, have been previously associated with a number of cardiometabolic traits, including lipid levels and blocks in blood vessels. More recently, scientists have also unearthed links with the risk of severe COVID-19 infections.

The researchers’ experiments also revealed that microbial strains that possessed this gene cluster could use an amino-sugar called N-acetylgalactosamine as their sole sugar source.

The strong association of the ABO locus in the human genome and the gene cluster associated with the metabolism of N-acetylgalactosamine in specific microorganisms – like in Faecalibacterium prausnitzii and Collinsella aerofaciens, which scientists have studied extensively in the context of cardiovascular risk – suggests that the association of ABO and risk for cardiovascular disorders could in part be modulated through the microbiome.

Potential links to cancer and neurons…

Scientists have also been probing a link between gut microbes and human cancers. In a recent article published on January 2, researchers found that the development of colorectal cancer could be mediated by a molecule called trans-3-indoleacrylic acid (IDA). That is, administering IDA – or implanting the microbe Peptostreptococcus anaerobius – in the gut of mice caused them to develop colorectal cancer.

(Older studies had found the bacterium P. anaerobius to be enriched in the gut of people with colorectal cancer.) The researchers also found the effects of IDA could be abolished by deleting two human genes – AHR or ALDH1A3 – thus revealing a new opportunity for cancer therapy.

Evidence is also mounting that the human microbiome can be associated with how neurons ‘talk’ to each other. Gut microbes produce vitamin B12 – and in a recent paper, also published on January 2, researchers from the University of Massachusetts suggested the vitamin could influence neuronal signalling by influencing the availability of free choline, a molecule neurons use to make a neurotransmitter called acetylcholine.

… and even to urine

We’ve known for many decades that the yellow colour of urine comes from a pigment called urobilinogen. Urobilinogen is produced in the body when the body metabolises bilirubin. And bilirubin is produced when the body metabolises haemoglobin in the blood. This is why a high level of bilirubin – seen in the yellowing of the eyes – is associated with jaundice.

In a January 3 paper, University of Maryland researchers suggested that the human microbiome could be involved in the metabolism of urobilinogen. Using biochemical analyses and comparative genomics, they identified a bacterial enzyme, called bilirubin reductase (BilR), to be responsible for reducing bilirubin to urobilinogen, a pivotal step in this process that has so far remained out of sight.

Through genome sequencing, the researchers observed that microorganisms belonging to the species Firmicutes predominantly encode the gene that teaches cells to make BilR. They also found that BilR is nearly ubiquitous in healthy human adults – but is less prevalent in newborns and people with inflammatory bowel disease. Their findings emphasise the importance of the gut-liver axis in maintaining bilirubin levels.

In this way, human genomic studies will shape healthcare of the future by personalising interventions.

The authors are senior consultants at Vishwanath Cancer Care Foundation and adjunct professors at IIT Kanpur. All opinions expressed here are personal.

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