Microbiome & Gut Health

Akkermansia muciniphila is a Gram-negative mucin-degrading bacterium that colonises the intestinal mucus layer and constitutes roughly 1–4 % of the healthy gut microbiota. By continuously digesting mucin glycoproteins it stimulates host renewal of the mucus layer, thereby reinforcing the physical barrier between luminal contents and the epithelium. Lower abundance is associated with obesity, insulin resistance and inflammatory bowel disease in multiple cross-sectional cohorts, though causation is not established. Depommier et al. (Nat Med 2019) demonstrated in a randomised trial that pasteurised — not live — A. muciniphila improved insulin sensitivity, reduced insulinaemia and attenuated body weight gain in overweight adults relative to placebo; the pasteurised form consistently outperformed the live preparation in murine models as well, with the outer membrane protein Amuc_1100 (identified in mechanistic work by Plovier et al., Nat Med 2017) as a key mediator signalling through TLR2. The bacterium is now available as a novel food supplement in the EU, but clinical evidence remains limited to early-phase trials.

The Bacteroidetes/Firmicutes ratio was prominently proposed in the mid-2000s as a functional biomarker of gut microbiome health, based on observations in obese mice and small human cohorts that obesity was associated with a relative reduction in Bacteroidetes and expansion of Firmicutes, and that weight loss reversed this pattern. The mechanistic hypothesis was that a high-Firmicutes microbiome extracts more energy from the same diet, thus promoting fat accumulation. However, this simplified narrative has not replicated reliably across diverse human cohorts: large subsequent studies found the ratio to vary substantially with sequencing methodology, diet, geography and cohort composition, and many found no consistent direction of association with obesity or metabolic health. The field has largely deprioritised this ratio as a clinically meaningful metric, recognising that the division of the gut microbiota into two phyla discards the vast functional diversity within each, and that species- or gene-level analyses provide much more informative resolution. It persists in popular science writing and supplement marketing, where it is frequently overstated.

Bifidobacterium is a genus of Gram-positive, anaerobic, non-motile, branched-rod bacteria belonging to the phylum Actinobacteria (Actinomycetota); it is among the first colonisers of the neonatal gut, particularly in breastfed infants, where strains such as B. longum subsp. infantis are uniquely equipped to metabolise human milk oligosaccharides (HMOs). Their core metabolic products include acetate and lactate (via the bifid shunt, a fructose-6-phosphate phosphoketolase pathway), acidifying the intestinal environment and suppressing pathogens. Abundance declines markedly after weaning, with a further sharp decline after the seventh decade of life; reduced Bifidobacterium abundance in older adults has been associated with frailty, increased intestinal permeability and heightened systemic inflammation, though causal interpretation remains challenging. Several species — particularly B. longum, B. lactis, B. bifidum and B. breve — are among the most extensively studied and commercially used probiotic organisms, with clinical evidence supporting modest benefits in antibiotic-associated diarrhoea, infant colic, irritable bowel syndrome and rotavirus-associated diarrhoea; effects in healthy adults are generally less pronounced.

Primary bile acids — cholic acid and chenodeoxycholic acid — are synthesised in the liver from cholesterol and conjugated to glycine or taurine before secretion into the small intestine. Gut bacteria transform them via deconjugation, 7α-dehydroxylation, epimerisation and oxidoreduction into a structurally diverse pool of secondary and tertiary bile acids, including deoxycholic acid (DCA), lithocholic acid (LCA), ursodeoxycholic acid (UDCA) and isoallo-lithocholic acid (isoallo-LCA). These secondary bile acids function as signalling molecules beyond their classical roles in dietary fat emulsification: they activate the nuclear receptor FXR and G-protein-coupled receptor TGR5, modulating glucose homeostasis, lipid metabolism, energy expenditure and innate immune tone. Isoallo-LCA is of particular interest in longevity research because it potently induces the differentiation of immunosuppressive RORγt⁺ regulatory T cells and is enriched in supercentenarians. The composition of the secondary bile acid pool is critically dependent on microbiota composition — notably species in Lachnospiraceae and Ruminococcaceae — and is substantially altered in ageing, obesity and inflammatory bowel disease.

Several studies of extreme longevity — notably the Italian group led by Biagi and Franceschi analysing semi-supercentenarians (105–109 years) and Sato and colleagues in Japanese centenarians — have identified microbiota features that distinguish long-lived individuals from healthy younger or elderly controls. Consistent observations include maintenance of relatively high alpha diversity into extreme old age, enrichment of Christensenellaceae and Akkermansia muciniphila, and a distinctive secondary bile acid profile characterised by elevated concentrations of isoallo-lithocholic acid (isoallo-LCA) produced by Odoribacteraceae family members, which potently induces regulatory T cells and may attenuate systemic inflammation. Whether these signatures are causal contributors to longevity, passenger effects of specific diets or genetics in long-lived populations, or results of survivor bias — those who reach 100+ have presumably already escaped the diseases that kill others earlier — cannot be determined from cross-sectional data. The findings are intriguing and point toward bile-acid–microbiota crosstalk and immune regulation as longevity-associated pathways, but should not yet be interpreted as actionable targets for the general population.

Dysbiosis describes a shift in the composition, diversity or metabolic output of the microbiota away from a configuration associated with host health, though it is an operational rather than precisely defined term because no single healthy reference community exists. It is characterised by loss of beneficial taxa such as short-chain fatty acid–producing Firmicutes, expansion of potentially pathobiontic species, reduced alpha-diversity, or altered functional capacity — changes associated with inflammatory bowel disease, metabolic syndrome, type 2 diabetes and colorectal cancer, among others. Causal directionality is difficult to establish in human studies, since most evidence is associative and dysbiosis may be both a driver of and a consequence of host inflammation. As a hallmark of ageing recognised in the 2023 update by López-Otín and colleagues, age-associated dysbiosis is increasingly considered a contributor to inflammaging and frailty.

Faecal microbiota transplant (FMT) is the transfer of processed stool from a healthy donor into the gastrointestinal tract of a recipient, with the aim of reconstituting a disrupted microbial community. Its only firmly established clinical indication is recurrent Clostridioides difficile infection (CDI), where it achieves cure rates exceeding 80–90 % and has superior efficacy to antibiotics alone, and it is now guideline-recommended for this purpose in most Western health systems. For all other indications — inflammatory bowel disease, metabolic syndrome, autism spectrum disorder, neurological conditions and ageing-related outcomes — the evidence base is investigational and results from randomised trials have been mixed, with some showing modest effects and others showing no benefit. Delivery methods include colonoscopy, nasogastric or nasoduodenal tube, enema and encapsulated freeze-dried preparations; donor screening is critical and complex, requiring testing for a broad panel of pathogens, and several serious adverse events including transmission of multi-drug-resistant organisms have been reported. The 'longevity' framing of FMT — informed by mouse studies showing life-extension after transfer from young donors — remains speculative in humans.

The gut microbiota comprises approximately 38 trillion bacteria — plus archaea, fungi, viruses and other microorganisms — that colonise the human gastrointestinal tract, with the highest density in the colon. Collectively they encode a gene catalogue roughly 150-fold larger than the human genome and perform functions the host cannot accomplish alone, including fermentation of dietary fibre into short-chain fatty acids, synthesis of certain B vitamins and vitamin K2, modulation of bile acid chemistry, and calibration of mucosal immunity. Compositional and functional differences between individuals are large — shaped by birth mode, infant feeding, diet, geography, antibiotics and age — and these inter-individual differences complicate the search for universal 'optimal' compositions. The term 'microbiome' technically encompasses both the organisms and their collective genetic material, but the two words are widely used interchangeably in the clinical literature.

The gut-brain axis is the bidirectional communication network linking the enteric nervous system, vagus nerve, hypothalamic-pituitary-adrenal (HPA) axis, immune signalling and blood-borne microbial metabolites between the gastrointestinal tract and the central nervous system. The gut microbiota participates in this network by producing neuroactive compounds — including serotonin precursors (roughly 90 % of whole-body serotonin is synthesised in enterochromaffin cells, stimulated partly by microbial metabolites), gamma-aminobutyric acid (GABA), short-chain fatty acids and secondary bile acids — that can reach the brain directly or modulate afferent vagal signalling. Animal studies have provided compelling evidence that germ-free or antibiotic-treated mice show altered stress responses, anxiety-like behaviour and neuroinflammation that can be partly reversed by specific microbiota reconstitution or probiotic treatment. Human evidence is more limited: proof-of-concept trials with specific psychobiotics have shown modest anxiolytic or antidepressant-like signals in some cohorts, but effect sizes are small and replication has been inconsistent, meaning clinical translation remains premature.

Lipopolysaccharide (LPS) is a structural component of the outer membrane of Gram-negative bacteria; when shed by bacteria at cell death or division, it is the most potent ligand for Toll-like receptor 4 (TLR4) and a primary driver of the inflammatory cascade in sepsis. In metabolic endotoxemia — a term coined by Cani and colleagues in a 2007 Cell Metabolism paper — low but chronically elevated circulating LPS levels (2- to 3-fold above fasting baseline) arise from impaired intestinal barrier function and increased chylomicron-mediated translocation of LPS after high-fat feeding. The resulting low-grade TLR4 activation on hepatocytes, adipocytes and macrophages promotes insulin resistance, adipose tissue inflammation and hepatic steatosis in rodent models. The phrase 'leaky gut' is a popular shorthand for increased intestinal permeability, but it is informal and mechanistically imprecise; barrier function is controlled by tight junction proteins (occludin, claudins, ZO-1) whose downregulation, along with reduced mucus layer thickness, is demonstrably altered by certain dietary patterns and dysbiosis. Human evidence for a causal metabolic endotoxemia–disease pathway is supportive but not conclusive, and circulating LPS is technically difficult to measure accurately.

Microbiome diversity describes the richness and evenness of microbial community composition within a single sample (alpha diversity) or across samples (beta diversity). The Shannon entropy index, which accounts for both species richness and relative abundance, is one of the most widely used alpha-diversity metrics; higher Shannon index values indicate a more complex community in which no single taxon dominates. Higher alpha diversity has been broadly associated with resilience, metabolic health and lower risk of conditions such as inflammatory bowel disease, though the relationship is not universal — some disease states feature increased diversity in anatomically inappropriate communities. Population studies consistently show that alpha diversity declines with age, particularly after the seventh decade, and that this decline correlates with frailty, hospitalisation and reduced survival. Diversity should be interpreted with caution as a standalone health proxy: functional redundancy means that a numerically diverse community can still lack critical pathways, and 16S rRNA sequencing depth and primers substantially affect measured diversity values.

The ISAPP 2021 consensus definition characterises a postbiotic as a preparation of inanimate microorganisms and/or their components that confers a health benefit on the host. The key distinction from probiotics is that postbiotics contain non-viable organisms or isolated microbial components — including cell wall fragments, teichoic acids, exopolysaccharides, secreted proteins, metabolites and extracellular vesicles — without requiring colonisation or survival through the gastrointestinal tract. This gives postbiotics practical advantages in formulation stability, safety in immunocompromised individuals, and defined composition. Pasteurised Akkermansia muciniphila (discussed separately) is one example that fits the ISAPP postbiotic framework. Evidence for specific health effects varies substantially by preparation; most clinical data come from heat-killed Lactobacillus and Bifidobacterium preparations, primarily in infant colic, allergy and mild gastrointestinal complaints. The field is emerging and regulatory frameworks for postbiotic health claims are still developing in most jurisdictions.

According to the International Scientific Association for Probiotics and Prebiotics (ISAPP), a prebiotic is defined as a substrate that is selectively utilised by host microorganisms conferring a health benefit. This definition is deliberately broad — encompassing not only fermentable dietary fibres (such as inulin, fructooligosaccharides and galactooligosaccharides) but also non-carbohydrate compounds and applications beyond the gut — and requires evidence of both selective utilisation and a demonstrated health outcome, not merely substrate availability. Well-characterised prebiotics reliably increase populations of Bifidobacterium and Lactobacillus species, enhance SCFA production, and improve stool consistency; effects on harder clinical endpoints such as glycaemic control and immune function have been shown in some trials but are modest and context-dependent. The prebiotic concept should be distinguished from dietary fibre generally: fibre is broadly fermented by many taxa, whereas the selectivity criterion for prebiotics is more stringent and differentiates them from general substrate provision.

Short-chain fatty acids — principally acetate, propionate and butyrate — are produced when anaerobic gut bacteria ferment dietary fibre and resistant starch that reaches the colon undigested. Butyrate is the preferred energy substrate for colonocytes, strengthens tight junctions and maintains mucosal barrier integrity, inhibits histone deacetylases (acting as an HDAC inhibitor) and signals via free fatty acid receptors GPR41, GPR43 and GPR109A to modulate immunity, appetite hormones and insulin secretion. Propionate travels primarily to the liver where it participates in gluconeogenesis and lipid regulation, while acetate enters systemic circulation. Reduced SCFA production — from low dietary fibre intake or loss of key producers such as Faecalibacterium prausnitzii and Roseburia intestinalis — is consistently associated with inflammatory bowel conditions, obesity and impaired glycaemic control, though translating this association into effective dietary or therapeutic interventions remains an active area of research.

Trimethylamine-N-oxide (TMAO) is a small organic compound produced when gut bacteria convert dietary choline, phosphatidylcholine and L-carnitine — abundant in red meat, eggs and fish — into trimethylamine (TMA), which is then oxidised to TMAO in the liver by flavin-containing monooxygenases (mainly FMO3). Elevated circulating TMAO has been associated with increased risk of major adverse cardiovascular events, atrial fibrillation and all-cause mortality in multiple large prospective studies, and mechanistic work in mice points to inhibition of reverse cholesterol transport and promotion of foam-cell formation. However, the relationship is complicated by the fact that fish consumption, which is generally cardioprotective, also raises TMAO, and that TMAO levels vary markedly with gut microbiota composition, genetics (FMO3 polymorphisms) and renal clearance — making TMAO a biomarker of exposure and microbial metabolism rather than a straightforward causal risk factor.