Gut Dysbiosis Module

Aging Module gut_dysbiosis 2 disorders Pathograph 11

A conserved mechanism module for the hallmark of aging (Lopez-Otin et al., 2023) termed dysbiosis: the age-associated alteration of the gut microbiome and its downstream contribution to systemic aging. With age the composition of the intestinal microbiota drifts - older people show greater inter-individual variation and increasingly individual-unique communities - and this is coupled to increased intestinal permeability. Loss of barrier integrity permits microbial products to translocate, driving age-associated systemic inflammation and macrophage dysfunction; germ-free and cohort studies indicate the microbiota is causally involved in the age-related rise in circulating inflammatory mediators. Gut-microbiome patterns track healthy aging and even predict survival. Dysbiosis is thus an integrative hallmark feeding inflammaging and broader age-related morbidity. Individual disorder entries declare conformance via conforms_to on their pathophysiology nodes, substituting the disease-specific microbiome or barrier context while preserving the conserved microbiota-shift -> barrier-failure -> systemic-inflammation -> age-related-decline chain.

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Pathophysiology Nodes

4 shared nodes are defined in this module.

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Cell Types

No cell types are annotated for this module.

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Biological Processes

Notes

This is a mechanism module, not a specific disease. Disorder entries reference individual nodes via conforms_to (e.g., "gut_dysbiosis#Intestinal Barrier Dysfunction and Microbial Translocation"). Conforming nodes in disorder files should include the corresponding biological processes and causal edges, specialized to their disease context. Dysbiosis is an integrative hallmark that feeds the inflammaging module (systemic inflammation is the shared interface); route the systemic-inflammation consequences there rather than re-deriving them. Key conformance target: "gut_dysbiosis#Intestinal Barrier Dysfunction and Microbial Translocation". One non-animal model is attached under experimental_models: an anaerobic human intestine-on-a-chip that holds a complex living human gut community against human intestinal epithelium and reads out barrier function in the same device. Both of its links are MEASURES rather than recapitulation claims, because the study compares oxygenation conditions and not aged with young donors; it supplies the assay this module's trigger-to-effector step would be tested with, not evidence for that step. Conforming disorder entries do not inherit those links. It is typed ORGAN_ON_CHIP because the oxygen-gradient device is what makes it informative here; the sibling non-animal model on inflammaging is typed CO_CULTURE by the same reasoning applied to a different distinctive feature, and that entry's notes carry the rationale for the divergence.

Discussions and Knowledge Gaps

Which summary of the gut microbiota, if any, is the aging readout? Alpha diversity is the usual assumption and does not survive contact with longitudinal data.

KNOWLEDGE GAP OPEN knowledge_gap_which_microbiome_measure_reports_aging

Attached to: Age-Associated Gut Microbiota Alteration

Both markers curated in this module report the barrier and the host response to translocation. The first node, the compositional shift itself, has no curated marker, and the reason is that it is unclear what to measure. Reduced alpha diversity is the conventional summary, but in a longitudinal centenarian cohort followed to death there was no significant alpha-diversity difference between the period before death and earlier follow-up, while ten individual species did change significantly. If the signal is carried by particular taxa rather than by a diversity index, then the readout is a high-dimensional composition and not a number, which raises the same representational problem recorded in the decision register for composite indices. A further obstacle specific to this hallmark: the same paper found the centenarian microbiome in Hainan differs from that in northern Italy, so a taxon-level marker may not transfer between populations even if it is real within one.

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Experimental Models

Anaerobic human intestine-on-a-chip with complex gut microbiome coculture ORGAN_ON_CHIP namo:OrganOnChip

A two-channel microfluidic intestine-on-a-chip in which living human intestinal epithelium and its overlying mucus are held in direct contact with a complex living human gut microbial community. The device controls and reports a transluminal oxygen gradient, so the anaerobic luminal environment that obligate anaerobes require can be maintained while the epithelium stays oxygenated from the basal side. Establishing that physiological hypoxia gradient, rather than culturing aerobically, both raised intestinal barrier function and sustained a community whose diversity and Firmicutes to Bacteroidetes ratio approach those of human faeces. For this module the platform is the host-microbe interface itself: it makes microbial community composition a manipulable variable measured alongside barrier function in the same human tissue.

Organism

human NCBITaxon:9606

Tissue

intestine UBERON:0000160

Cell source

Living human intestinal epithelium with an overlying mucus layer. MEDLINE indexes the study under Caco-2 Cells, so at least part of the work used a colorectal adenocarcinoma line rather than primary or organoid-derived epithelium.

Culture

Microfluidic two-channel intestine-on-a-chip with real-time control and assessment of a transluminal oxygen gradient, supporting extended coculture of aerobic and anaerobic human gut microbiota against the epithelium

Publication

PMID:31086325

Pathograph links

Age-Associated Gut Microbiota Alteration measures fidelity: low The chip sustains and profiles a complex living human gut community directly against human intestinal epithelium, reported as over 200 operational taxonomic units from 11 genera with an abundance of obligate anaerobes and faeces-like Firmicutes to Bacteroidetes ratios. That makes microbial community composition, the entity this node asserts is altered with age, an experimentally measurable and manipulable variable in a human system rather than one inferred from stool sequencing alone.

Limitations: Fidelity is LOW because the inoculum is not age-stratified and the study makes no young-versus-aged comparison: the platform measures community composition but does not itself reproduce the age-associated drift this node describes. The coculture also runs over days, against the decades across which the human compositional shift develops, so nothing here speaks to the timescale of the trigger.

Readouts

Sustained gut microbial diversity and community composition

Interpretation: Taxonomic profiling of the on-chip community establishes that a physiologically representative human gut microbiota can be held against human epithelium and read out, which is the measurement capability this node's trigger would be tested with. No direction is recorded because no aged-versus-young community comparison was made.

Evidence: 1

Intestinal Barrier Dysfunction and Microbial Translocation measures fidelity: moderate Barrier function is assayed in human intestinal epithelium while a complex living gut community sits on its luminal face, which is the host-microbe interface this node's translocation claim depends on and the configuration a conventional monolayer cannot provide. Barrier function in this system is responsive rather than fixed: establishing the physiological transluminal hypoxia gradient increased it relative to aerobic coculture, so the same conditions that determine which community can be sustained also move the barrier readout.

Limitations: The measurement is made under a healthy-donor community at physiological oxygenation, so it establishes the assay rather than the age-associated barrier failure this node asserts; no dysbiotic or aged community was tested. Translocation of microbial products across the epithelium is not itself reported in the cached abstract, so the second half of this node's claim is unaddressed here. MEDLINE indexes the study under Caco-2 Cells, so at least part of the work used a colorectal adenocarcinoma line rather than primary or organoid-derived epithelium.

Readouts

Intestinal barrier function under complex microbial coculture, anaerobic versus aerobic

Direction: INCREASED

Interpretation: Barrier function rose when the physiological transluminal hypoxia gradient was established, measured against aerobic coculture. The direction is relative to that oxygenation comparator, not to an aged or dysbiotic condition.

Evidence: 1

Notes

The cached reference is abstract-only, so snippets quote the abstract and figure-level detail is summarized in prose. This is a non-animal human system attached to this module for its host-microbe interface, not a model of aging: no arm of the study compared aged with young donors, which is why the trigger-node link is MEASURES at LOW fidelity rather than a recapitulation claim. The same platform is the natural place to test whether an aged-donor community reproduces the barrier failure this module asserts.

Evidence: 1

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Animal Models

Young-donor gut microbiota transfer in turquoise killifish (Nothobranchius furzeri) Naturally short-lived vertebrate aging model

This is the causal experiment behind the module. Rather than correlating an aged microbiome with poor outcomes, Smith and colleagues transferred the gut community of young killifish into middle-aged recipients and measured what happened. Recipients lived longer, declined behaviorally more slowly, retained microbial diversity, and kept a young-like community composition. Because the host is a vertebrate with a months-long lifespan, the whole intervention and its survival readout fit inside a single experiment.

Species

Turquoise killifish (Nothobranchius furzeri)

Genotype

Wild type

Background

Middle-aged fish whose gut was recolonized with bacteria from young donors, compared against age-matched controls, with 16S community profiling, survival, and behavioral endpoints.

Publication

PMID:28826469

Pathograph links

Age-Associated Gut Microbiota Alteration recapitulates fidelity: moderate Killifish lose gut microbial diversity as they age and shift away from a young-like community composition, reproducing the module's upstream node in a vertebrate host.

Limitations: The taxa that mark a young-like killifish community are teleost gut genera and do not correspond to the human commensals whose loss defines age-associated dysbiosis in people, so the composition finding is directional rather than taxon-transferable. Fish gut communities are strongly shaped by the aquatic environment, which has no counterpart in the mammalian gut.

Readouts

Gut microbial diversity and community composition with age

Microbial diversity and community composition of the killifish gut across age, and in middle-aged recipients of a young-donor transfer.

Direction: DECREASED

Interpretation: Diversity falls with host age and is held up by the transfer, which is what establishes the shift as a modifiable state rather than a fixed correlate of age.

Evidence: 1

Age-Related Health Decline and Reduced Survival rescues fidelity: moderate Recolonizing middle-aged fish with a young-donor gut community extended lifespan and delayed behavioral decline. This is the module's strongest causal claim in any model: an intervention on the microbiota alone, applied after the host is already middle-aged, moving a survival endpoint.

Limitations: The mechanism connecting the transferred community to host survival is not resolved by this study; the module's intervening barrier-dysfunction and systemic-inflammation nodes are inferred, not measured here. The intervention is a whole-community transfer, so no individual taxon is established as causal. Lifespan effects in a fish with an annual life history and an environmentally coupled gut community should not be assumed to transfer quantitatively to mammals.

Readouts

Lifespan after young-donor recolonization

Survival of middle-aged fish recolonized with young-donor gut bacteria versus age-matched controls.

Direction: RESTORED

Interpretation: A survival benefit from a microbiota-only intervention started in middle age is what makes this a causal rather than correlative result.

Evidence: 1

Behavioral decline after young-donor recolonization

Age-associated behavioral decline in recolonized fish versus controls, measured alongside survival.

Direction: RESTORED

Interpretation: A functional healthspan endpoint moving with survival is what distinguishes this from a lifespan-only result.

Evidence: 1

Curated as part of a tranche adding turquoise killifish models across the hallmarks-of-aging modules. Note what this model does and does not cover: it supports the module's first and last nodes with a causal intervention, but says nothing about the intervening barrier-dysfunction and systemic-inflammation nodes, which are recorded as a limitation rather than silently assumed.

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Computational Models

AGORA Gut Microbiome Genome-Scale Metabolic Reconstructions SBML COBRA Toolbox GENOME_SCALE_METABOLIC

Resource of genome-scale metabolic reconstructions semi-automatically generated for 773 human gut bacteria (assembly of gut organisms through reconstruction and analysis). Interactions among modelled species depend on both each species' metabolic potential and the nutrients available, so a community's metabolic output can be predicted from its composition. Reconstructions integrate metagenomic or 16S rRNA sequencing data and are compatible with the human reconstruction Recon 2, allowing host-microbiome metabolic coupling to be simulated.

PMID:27893703

Pathograph links

Age-Associated Gut Microbiota Alteration measures fidelity: moderate Turns a compositional shift into a predicted metabolic-output shift, so an age-associated change in taxa can be expressed as a change in the community's metabolite production rather than as taxonomy alone.

Limitations: A general-purpose reconstruction resource, not an ageing model: it carries no age-specific parameterization, and any age contrast has to be supplied as input composition from a cohort.

This is the piece of tooling that makes the module's first node quantitatively connectable to its downstream inflammation node - short-chain fatty acid and other metabolite output is the mechanistic currency between them.

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Module Collections

Hallmarks of Aging as Dysbiosis

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Used By Disorder Entries

Idiopathic Pulmonary Fibrosis via Gut dysbiosis and microbial metabolite dysregulation → Age-Associated Gut Microbiota Alteration

Parkinson's Disease via Gut Microbiome Dysbiosis → Age-Associated Gut Microbiota Alteration , Intestinal Inflammation and Barrier Dysfunction → Intestinal Barrier Dysfunction and Microbial Translocation

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Pathograph

Use the checkboxes to hide or show graph categories. Hover nodes for evidence-backed metadata.

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Pathophysiology

Age-Associated Gut Microbiota Alteration

trigger

With age the composition of the gut microbiota shifts: older individuals display greater inter-individual variation than younger adults and, from mid-to-late adulthood, increasingly unique individual microbiome compositions. This age-associated compositional drift is the initiating alteration of the hallmark.

Used by disorders

Idiopathic Pulmonary Fibrosis as Gut dysbiosis and microbial metabolite dysregulation

Parkinson's Disease as Gut Microbiome Dysbiosis

Downstream

Intestinal Barrier Dysfunction and Microbial Translocation

Show evidence (2 references)

PMID:22797518 SUPPORT Human Clinical

"The microbiota of older people displays greater inter-individual variation than that of younger adults."

Documents the greater compositional variation of the elderly gut microbiota, the age-associated drift modeled here. Evidence source is HUMAN_CLINICAL (elderly cohort study).

PMID:33619379 SUPPORT Human Clinical

"starting in mid-to-late adulthood, gut microbiomes become increasingly unique to individuals with age"

Shows progressive individualization of the gut microbiome with age across large cohorts, supporting the microbiota-drift trigger. Evidence source is HUMAN_CLINICAL (multi-cohort human study).

Intestinal Barrier Dysfunction and Microbial Translocation

central effector

Age-associated dysbiosis is coupled to loss of intestinal barrier integrity (increased permeability), allowing microbial products to translocate across the gut wall. This barrier failure is the conserved central effector that links a shifted microbiota to systemic consequences.

Used by disorders

Parkinson's Disease as Intestinal Inflammation and Barrier Dysfunction

Downstream

Dysbiosis-Driven Systemic Inflammation

Show evidence (1 reference)

PMID:28407483 SUPPORT Model Organism

"Age-Associated Microbial Dysbiosis Promotes Intestinal Permeability, Systemic Inflammation, and Macrophage Dysfunction."

States that age-associated dysbiosis promotes intestinal permeability (and downstream systemic inflammation), the barrier-failure effector modeled here. Evidence source is MODEL_ORGANISM (germ-free and aged mouse experiments).

Dysbiosis-Driven Systemic Inflammation

amplifier

Translocating microbial products drive the age-associated increase in circulating inflammatory mediators and macrophage dysfunction. Germ-free studies indicate this age-related inflammation is causally dependent on the microbiota. This node is the amplifying interface at which gut dysbiosis feeds inflammaging.

Inflammatory Response GO:0006954 ↑ INCREASED

Downstream

Age-Related Health Decline and Reduced Survival

Show evidence (2 references)

PMID:28407483 SUPPORT Model Organism

"when maintained under germ-free conditions, mice do not display an age-related increase in circulating pro-inflammatory cytokine levels"

Germ-free mice lack the age-related rise in circulating pro-inflammatory cytokines, showing the microbiota is causally required for dysbiosis-driven systemic inflammation. Evidence source is MODEL_ORGANISM (germ-free mouse study).

PMID:22797518 SUPPORT Human Clinical

"Alterations in intestinal microbiota composition are associated with several chronic conditions, including obesity and inflammatory diseases."

Links altered microbiota composition to inflammatory and metabolic disease, supporting the inflammation-driving role of dysbiosis. Evidence source is HUMAN_CLINICAL (human cohort study).

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Treatments

Metformin (Microbiome and Barrier Restoration)

Pharmacotherapy NCIT:C15986

Agent: metformin CHEBI:6801

Platform: Small molecule

Beyond its glucose-lowering action, metformin reshapes the aged gut microbiota and restores the mucus barrier, increasing goblet cell mass and mucin production and thereby reducing intestinal permeability and the systemic inflammation it drives. This targets two nodes of the module in sequence - the microbiota shift and the barrier defect - rather than treating the downstream inflammation alone.

Mechanism target:

MODULATES Age-Associated Gut Microbiota Alteration — Metformin shifts the composition of the aged gut microbiota; the effect is modulatory rather than a restoration of a defined youthful community, so no unidirectional claim is made.

INHIBITS Intestinal Barrier Dysfunction and Microbial Translocation — Metformin increases goblet cell mass and mucin production in the aged gut, reducing the permeability that permits microbial translocation.

Evidence: 2

Acarbose (Starch-Flux Redirection to Colonic Fermentation)

Pharmacotherapy NCIT:C15986

Agent: acarbose CHEBI:2376

Platform: Small molecule

Acarbose is an alpha-glucosidase inhibitor that blocks host starch digestion, increasing the flux of starch to the colon where bacterial fermentation yields short-chain fatty acids. The microbiome effect is therefore a consequence of the drug's primary pharmacology rather than a separate activity, which is what makes it an unusually clean test of whether microbiome modulation contributes to lifespan extension. Ranked third of nine (9/12) by Kulkarni et al.

Mechanism target:

MODULATES Age-Associated Gut Microbiota Alteration — Acarbose alters the taxonomic composition of the gut microbiota and raises fecal short-chain fatty acid concentrations, notably propionate, by redirecting undigested starch to colonic fermentation.

INHIBITS Age-Related Health Decline and Reduced Survival — Acarbose extends median lifespan in genetically heterogeneous mice, and fecal short-chain fatty acid concentrations independently predict longevity in the same animals - the observation that links this module's microbiota node to its survival outcome.

Evidence: 3