Our gut: A hidden world

“Death sits in the bowels,” and “bad digestion is the root of all evil,” proclaimed Hippocrates, the Greek philosopher and “father of medicine”, in the fourth century BCE. These quotes resonate profoundly in modern science as researchers continue to unveil the critical role the gut plays in both maintaining health and contributing to disease. Far from being just a digestive bowel, our gut harbors a complex and dynamic microbial ecosystem that influences nearly every aspect of our health.

The anatomy

The gut or gastrointestinal (GI) tract spans from the mouth to the rectum, and is crucial for digestion and nutrient absorption. However, its significance goes far beyond breaking down food. The gut is home to approximately 100 trillion microbes—bacteria, archaea, fungi and viruses—that outnumber human host cells by ten-fold. This bustling microbial metropolis, known as the gut microbiome, is often considered an “essential organ” due to its indispensable functions. 

Weighing roughly two kilograms—comparable to the human brain size—the gut microbiome contains 150 times more genes than the human genome. Over millennia, these microbes have co-evolved with humans, establishing a symbiosis that profoundly influences our physiology, immune system and even mental health.

A landmark study (Almeida et al 2020) published in Nature Biotechnology highlighted the staggering gut microbiome diversity. The study cataloged 204,938 reference genomes and 170m protein sequences from 4,644 bacterial species found in the human gut. Despite these advances, much of the gut microbiome remains an uncharted territory, with 70 percent of its microbial populations still uncultured in the laboratory and poorly understood.

Diverse, complex microbiota

The gut microbiota (GM) is a highly diverse and intricate microbial community, comprising over 1,000 heterogeneous species dominated by six major phyla, Firmicutes (Clostridium, Lactobacillus, Enterococcus), Bacteroidetes (Bacteroides), Actinobacteria (Bifidobacterium), Proteobacteria (Escherichia coli), Fusobacteria, Verrucomicrobia, and Cyanobacteria. Of these, Firmicutes and Bacteroidetes dominate adult gut microbiota, accounting for 80-90 percent composition.

The dominant fungal species are Candida, Saccharomyces, Malassezia and Cladosporium. Meanwhile, the gut virome, the viral counterpart of the microbiome, is vast and largely uncultivated. Enteroviruses, parechoviruses, and sapoviruses are common residents. A Journal of Clinical Microbiology 2012 case report highlighted the gut virome diversity in stools collected from two healthy infant siblings during their first year of life, identified 15 enteric genera Adenovirus, Aichivirus, Anellovirus, Astrovirus, Bocavirus, Enterovirus, Parechovirus, Picobirnavirus, and Rotavirus. Additionally, the gut DNA viromes of Malawian one-year-old infant twins, with severe acute malnutrition, revealed Anellovirus, Picobirnavirus, and HPeV-1/-6 as the most frequently observed viruses.

Archaea are less diverse but highly conserved, with Methanobrevibacter smithii being the most frequently observed species across all six continents.

Each individual’s GM is a unique microbial signature, shaped by genetics, immune function, diet, lifestyle, environment, epigenetics and early microbial exposure during birth and breastfeeding. These microbes colonize different GI tract sections, with the highest biomass found in the caecum and proximal colon.

Health guardians 

GM performs crucial functions for maintaining health. In digestion and metabolism, gut microbes break down complex carbohydrates, synthesize vitamins such as B and K (via Bifidobacterium, Lactobacillus, Salmonella, Streptococcus, Clostridia, and Listeria), and produce short-chain fatty acids (SCFAs) like butyrate, which nourish colonic cells and regulate inflammation.

While humans cannot digest fiber, bacteria possess glycoside hydrolases/ polysaccharide lysases that ferment plant polysaccharides. Gut bacteria Eubacterium, Roseburia, Faecalibacterium and Coprococcus ferment indigestible fibers like resistant starches, and cellulose, generating butyrate, provides energy to colonocytes. Butyrate enhances bowel health by regulating colonic motility, improving blood flow and preventing pathogen overgrowth. GM Bacillus subtilis and E. coli synthesize riboflavin (vitamin B2), essential for cellular metabolism. With 70 percent of the immune system in the gut, microbes train immune cells to differentiate pathogens, ensuring immune balance. Furthermore, they strengthen the intestinal barrier, preventing harmful pathogens and toxins from entering the bloodstream.

Through the gut-brain axis, they influence mood, cognition and behavior, impacting conditions like anxiety and depression. Maintaining a healthy balance of GM, known as ‘normobiosis’, is crucial for overall well-being. Disruptions to this balance, ‘dysbiosis’, fosters pathogen overgrowth triggering health issues.

Declining diversity

Modern lifestyles and urbanization have significantly reduced GM diversity, impacting health. Processed diets, irrational antimicrobial use, sedentary lifestyles, high salt/protein intake and limited exposure to natural environments have caused a multigenerational loss of beneficial microbial signatures, key for immune resilience. A 2024 study in Kazakhstan revealed stark differences in gut diversity between urban and rural populations. Urban microbiomes showed reduced diversity, elevated Firmicutes/Bacteroidetes ratios and higher prevalence of Coprococcus and Parasutterella. Rural populations exhibited greater microbial diversity, with abundant Ligilactobacillus and Paraprevotella, correlating with their fiber-rich diets. Interestingly, a Nepali study (Jha et al 2018) found traditional Himalayan populations (Chepang, Raute, Raji, and Tharu) had distinct microbiome signatures compared to Americans, emphasizing lifestyles impact on gut diversity.

This GM diversity depletion is linked to autoimmune diseases and chronic inflammation. Dysbiosis is implicated in obesity where excessive Firmicutes enhance fat absorption. Inflammatory bowel disease (IBD) (Crohn’s disease, Ulcerative colitis), features reduced alpha diversity and shifts favoring pathogenic Gamma-proteobacteria. Colorectal cancer patients exhibit harmful bacteria, such as Fusobacterium nucleatum, genotoxic E. coli, Enterotoxigenic Bacteroides fragilis, produce metabolites fostering tumorigenesis. Dysbiosis also influences metabolic disorders (diabetes) and neurodegenerative diseases (Alzheimer’s, Parkinson's) through inflammation and the gut-brain axis.

Advancements

Advancements in gut microbiome research herald a new era of personalized medicine. Probiotics/prebiotics restore microbial balance by enhancing beneficial GM, while fiber-rich diets and healthy lifestyles promote gut health reducing inflammation. Conversely, ultra-processed foods, artificial sweeteners and emulsifiers disrupt this balance, decreasing diversity and driving inflammation. Innovations like fecal microbiota transplant treat C. difficile infections and hold promise for IBD.

Despite progress, gut microbiome research is still in its infancy, with challenges in decoding complex host-microbe interactions. Investigating gut microbial signatures of exceptional mountain climbers, like Sherpas, and ethnic Nepali communities could lead to personalized therapies. Technologies like metagenomics/metabolomics offer breakthroughs in diagnostics and therapies. Deepening our understanding of this hidden world within us can unlock new avenues to enhance well-being and resilience.