In the realm of metabolic diseases, metabolic dysfunction-associated steatotic liver disease (MASLD) has emerged as a pervasive health challenge, intimately tied to obesity and the broader spectrum of metabolic syndrome. Despite its growing prevalence and clinical significance, the intricate microbial landscapes implicated in MASLD have remained largely enigmatic. A recent landmark study has fundamentally reshaped our understanding by harnessing the power of multi-omic technologies to disentangle the complex transkingdom microbial interactions within the gut ecosystems of MASLD patients. This investigation, conducted on an unprecedented scale within a large cohort of female nurses, delves deep into the viral and bacterial constituents that may influence the pathophysiology of this disease, illuminating pathways hitherto obscured in the shadow of metabolic dysfunction.

MASLD is classically recognized for its hallmark feature of fatty accumulation in the liver, typically correlated with insulin resistance, altered lipid metabolism, and systemic inflammation. However, unraveling the precise microbial interactions and their metabolic repercussions has been challenging, partly due to the multifaceted nature of the gut microbiota and its diverse cross-kingdom components. The present study leverages cutting-edge metagenomic, metatranscriptomic, and metabolomic profiling, providing a comprehensive lens through which to view not only bacterial populations but also viral inhabitants, thereby characterizing MASLD as a condition defined by profound transkingdom dysbiosis.

The cohort under investigation represents one of the largest and most rigorously characterized populations studied in this context, comprising 211 individuals diagnosed with MASLD and 502 healthy controls, all female nurses drawn from a well-controlled epidemiological background. This demographic specificity allows for minimized confounders related to sex and lifestyle, enhancing the fidelity of observed microbial and metabolic signatures. Such a large dataset facilitated high-resolution profiling of gut microbial species, unraveling nuanced shifts with statistical robustness, thereby enabling insights into how microbiome perturbations interface with MASLD phenotypes.

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One of the most striking findings emerging from this study is the pronounced shift in the abundance of 66 distinct gut bacterial species linked with MASLD status. A conspicuous trend toward enrichment of microbes typically associated with the oral cavity within the gut environment was observed. This ectopic colonization phenomenon raises compelling questions about microbial translocation and adaptation, challenging traditional compartmentalized views of microbiota biogeography. The presence of oral-typical bacteria in the gut milieu could potentially drive or exacerbate inflammatory cascades, contributing to liver fat accumulation and dysfunction through immunomodulatory and metabolic pathways.

Further stratification of MASLD patients revealed intriguing distinctions based on body composition, most notably the differential abundance of Streptococcus species in non-lean versus lean MASLD subtypes. This dichotomy underscores the heterogeneity within MASLD, particularly with lean MASLD representing a paradoxical entity where hepatic steatosis and metabolic impairment occur in the absence of overt adiposity. The expansion of Streptococcus spp. in non-lean MASLD perhaps signals a microbial signature intertwined with obesity-associated inflammation and metabolic derangements, while the lean phenotype may harbor distinct microbial and host interactions that merit focused investigation.

Beyond bacterial profiling, the study’s transkingdom approach uncovered a landscape of viral dysbiosis that parallels bacterial alterations. Notably, a marked expansion of bacteriophages targeting oral-typical bacteria was documented, suggesting a dynamic viral-bacterial interplay that may influence microbial community structure and function. Bacteriophages, as modulators of bacterial populations, wield considerable impact over microbial composition, diversity, and metabolite production. Their expansion in MASLD underlines the potential for viruses to contribute actively to the disease milieu, either through direct effects on bacterial hosts or via modulation of immune responses and metabolic pathways.

Indeed, the metatranscriptomic analyses shed light on functional consequences aligned with these microbial shifts. The study demonstrated altered expression patterns of microbial genes implicated in key metabolic processes, signaling a recalibration of gut microbial activity in MASLD. This functional perturbation dovetails with metabolomic findings, where notable increases in polyamines and acylcarnitines were observed, accompanied by reductions in secondary bile acids. Polyamines, linked to cell proliferation and inflammation, and acylcarnitines, associated with mitochondrial fatty acid oxidation, hint at disturbed metabolic fluxes that could aggravate hepatic lipid accumulation and oxidative stress.

Secondary bile acids hold a central role in regulating host lipid metabolism, gut barrier integrity, and systemic immunity. Their depletion in MASLD participants intimates a disruption of host-microbial co-metabolism, potentially contributing to metabolic endotoxemia and hepatic injury. These metabolic fingerprints provide a functional context that ties microbial community alterations with host metabolic dysregulation, reinforcing the notion of the gut microbiome as an active participant in MASLD pathogenesis rather than a passive bystander.

The research not only maps these microbial and metabolic changes but also offers a comprehensive resource, capturing multi-omic datasets that enable future interrogation and hypothesis generation. This repository holds promise for the identification of microbial biomarkers and therapeutic targets, particularly as the field moves toward precision medicine approaches in metabolic liver diseases.

Importantly, this investigation highlights MASLD as a disease unconfined to bacterial dysbiosis but rather one shaped by interkingdom interactions, encompassing bacterial species, bacteriophages, and metabolic networks. This holistic viewpoint challenges prior assumptions derived exclusively from bacterial taxa and spotlights viruses as key players in disease modulation.

The enrichment of oral-derived microbes and their phages in the gut microbiome points toward potential pathways of microbial migration, colonization, and community restructuring in MASLD. Such findings provoke broader questions regarding lifestyle, dietary influences, oral health, and their systemic repercussions, opening novel avenues for integrative research spanning multiple organ systems.

Moreover, the dissection of lean MASLD subtypes reveals the necessity for nuanced diagnostic criteria and personalized therapeutic strategies that consider microbial and metabolic heterogeneity. Understanding the mechanistic underpinnings in lean individuals, who do not fit the traditional obesity-linked MASLD mold, could unlock novel prevention and treatment modalities that are currently underappreciated.

In conclusion, this pioneering multi-omic study elucidates the gut microbial ecosystem as a complex, transkingdom community that undergoes profound dysbiosis in MASLD, implicating both bacterial and viral agents along with their metabolic footprints. These insights not only extend our comprehension of MASLD aetiopathogenesis but also lay a conceptual and practical foundation for the development of microbiome-targeted diagnostics and therapeutics.

As metabolic diseases continue their global ascent, such integrative microbial investigations become indispensable in translating biological complexity into clinical innovation, potentially transforming patient outcomes through precision microbiome medicine.

Subject of Research:
Metabolic dysfunction-associated steatotic liver disease (MASLD) and its association with gut microbiota and virome dysbiosis.

Article Title:
Multi-omic analysis reveals transkingdom gut dysbiosis in metabolic dysfunction-associated steatotic liver disease.

Article References:
Kim, H., Nelson, P., Nzabarushimana, E. et al. Multi-omic analysis reveals transkingdom gut dysbiosis in metabolic dysfunction-associated steatotic liver disease. Nat Metab (2025). https://doi.org/10.1038/s42255-025-01318-6

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Tags: female nurses cohort studygut dysbiosis in fatty liverimplications of gut microbiota on metabolisminsulin resistance and liver healthmetabolic dysfunction and liver diseasemetagenomic profiling in microbiota studiesmicrobial interactions in MASLDmulti-omic technologies in metabolic diseasesobesity and metabolic syndrome correlationspathophysiology of fatty liver diseasesystemic inflammation in MASLDviral and bacterial constituents in health