Microbiome-targeted-interventions (MBTI) and the immune system: translating gut ecology into clinical practice Original paper

What was reviewed?

This review synthesizes evidence on microbiome-targeted-interventions (MBTIs) that modulate gut ecology and immune function from the perinatal period through adulthood, integrating mechanistic data from animal models, human trials, and in vitro systems. The authors summarize how various strategies, including diet, fermented foods, prebiotics, probiotics, fecal microbiota transplants (FMT),phage therapy, and microbial metabolites (postbiotics), reshape gut community structure, metabolic output, and host immune responses. The introductory sections emphasise the ecological complexity of the gut microbiome, strain-level heterogeneity, biogeography along the gastrointestinal tract, and the particular vulnerability and plasticity of the perinatal microbiome, providing the ecological context required to interpret intervention outcomes.

Who was reviewed?

The review draws on a broad corpus of preclinical and clinical literature that spans healthy term and preterm infants, pregnant women, adults with chronic inflammatory or metabolic diseases, patients with recurrent Clostridioides difficile infection, ulcerative colitis, Crohn’s disease, obesity, non-alcoholic fatty liver disease, epilepsy, end stage renal disease, multiple sclerosis, and solid-organ cancers receiving immune checkpoint inhibitors. Human data include small, deeply phenotyped dietary and probiotic trials, larger epidemiologic cohorts linking diet and fiber intake to incident inflammatory bowel disease, and early phase trials of fecal microbiota transplantation in infection, inflammatory bowel disease, and cancer immunotherapy. These are complemented by mechanistic mouse models and cell culture systems that dissect immune pathways, such as short-chain fatty acid (SCFA)-mediated T regulatory cell induction, bile acid receptor signalling, and epithelial barrier modulation.

Most important findings

A central conclusion is that targeted manipulation of gut ecology can reproducibly shift both microbiome composition and immune tone, but effects are highly context and host-dependent. Table 1 of the article (pages 4–5) organizes microbiome-based interventions by rationale, including infection prevention and treatment, chronic disease modification, early-life immune programming, improved nutrition, vaccine enhancement, and modulation of drug efficacy. Early life homeostasis is linked to Bifidobacterium longum subsp. infantis and Bifidobacterium breve, which metabolise human milk oligosaccharides into indole-3-lactic acid and other aromatic lactic acids that signal via the aryl hydrocarbon receptor and promote tolerogenic T cell and monocyte profiles. Akkermansia muciniphila is repeatedly associated with improved metabolic status, tighter epithelial barrier function, and enhanced response to PD-1 based checkpoint blockade; the outer membrane protein Amuc_1100 and pasteurised cells can be considered candidate postbiotic effectors. In fiber and prebiotic interventions, resistant starch robustly enriches Ruminococcus bromii and Eubacterium rectale, while complex arabinoxylans drive Bifidobacterium longum, Prevotella copri, and other saccharolytic taxa, shifting SCFA production toward butyrate or propionate in a structure-specific manner.

Western-style diets and high-fat feeding favour pathobionts such as Bilophila wadsworthia and Crohn’s disease-associated adherent invasive Escherichia coli, while Mediterranean pattern diets enrich Akkermansia and SCFA producers and reduce Fusobacterium. Figure 1 on page 6 schematically depicts how each intervention class primarily introduces new species, depletes selected taxa, or selectively enhances the growth of resident strains, with inevitable secondary network effects. Phage therapy and bacteriophage-rich fecal filtrate transplantation illustrate species depletion approaches that can reduce C. difficile or adherent invasive E. coli, yet still propagate indirect shifts in non-target taxa. Postbiotic strategies, including butyrate, propionate, and specific secondary bile acids such as ursodeoxycholic acid, modulate Treg expansion, Th17 differentiation, macrophage antimicrobial programmes, epithelial tight junction expression, and mucus secretion, as visualised in the mechanistic summary diagram on page 11 (Figure 2).

Key implications

The review underscores that microbiome-based interventions should be conceptualised as ecosystem engineering rather than simple single target therapies, with strain level resolution and host context critical for predicting outcomes. For clinicians, Bifidobacterium dominated, HMO driven infant microbiomes, Mediterranean pattern, fiber rich diets, and carefully selected probiotics or next generation probiotics such as A. muciniphila and Faecalibacterium prausnitzii represent promising tools to restore beneficial Major Microbial Associations in immune mediated and metabolic diseases. However, examples of high dose soluble fiber exacerbating colitis or promoting cholestatic liver cancer in mice highlight that interventions can be harmful when applied without ecological and disease specific nuance. For microbiome signatures databases, this paper provides mechanistically anchored associations between specific taxa (for example Bifidobacterium infantis, Ruminococcus bromii, Akkermansia muciniphila, Bilophila wadsworthia, Bacteroides fragilis complex, and Enterococcus hirae), distinct dietary or therapeutic exposures, and defined immune phenotypes such as Treg expansion, Th17 suppression, checkpoint inhibitor responsiveness, or epithelial barrier reinforcement. The authors conclude that future clinical translation will depend on integrating ecological design principles, precise chemical characterisation of substrates and postbiotics, and prospective trials that link defined microbial shifts with hard clinical endpoints, moving from associative signatures toward rational, condition specific microbiome based therapies.

Citation

Hitch TCA, Hall LJ, Walsh SK, Leventhal GE, Slack E, de Wouters T, Walter J, Clavel T. Microbiome-based interventions to modulate gut ecology and the immune system. Mucosal Immunology. 2022;15(6):1095-1113. https://doi.org/10.1038/s41385-022-00564-1