Research finds indole promotes liver health and reduces weight gain in offspring — Evidence Review
Published in eBioMedicine, by researchers from University of Oklahoma
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Table of Contents
Children exposed to a high-fat, high-sugar maternal diet may face increased risk of fatty liver disease, but a new mouse study suggests that supplementing mothers with indole—a compound produced by gut bacteria—can substantially reduce this risk. Related studies generally support the protective role of gut-derived indoles and microbiome modulation in liver health, as summarized in the original publication.
- Multiple animal studies have demonstrated that gut microbiota-derived metabolites, such as indole and its derivatives, provide protective effects against various forms of liver injury and metabolic dysfunction, supporting the new findings 2 4 6 7 10 11.
- Evidence indicates that maternal diet shapes the offspring's microbiome and metabolic risk, with research showing that Western-style diets in mothers disrupt tryptophan metabolism and reduce beneficial indole production in offspring 8 9.
- Related studies highlight the critical role of the gut-liver axis and microbiome in modulating liver disease risk, showing that interventions targeting microbiota composition or function can attenuate fatty liver and associated pathologies 1 3 4 5.
Study Overview and Key Findings
Fatty liver disease, now increasingly diagnosed as metabolic dysfunction-associated steatotic liver disease (MASLD), is rising among children, especially those born to mothers consuming high-fat, high-sugar diets. The University of Oklahoma study sought to determine whether supplementing pregnant and nursing mice with indole—a gut bacteria-derived compound—could alter this trajectory for their offspring. Notably, the research explored not only direct health outcomes in the offspring but also the underlying mechanisms involving gut microbiota and specific metabolic pathways, providing insight into possible preventive strategies for MASLD that begin before birth.
| Property | Value |
|---|---|
| Organization | University of Oklahoma |
| Journal Name | eBioMedicine |
| Authors | Jed Friedman, Karen Jonscher |
| Population | Pregnant and nursing mice |
| Methods | Animal Study |
| Outcome | Fatty liver disease rates, liver health, weight gain, blood sugar levels |
| Results | Offspring with indole had healthier livers and less weight gain. |
Literature Review: Related Studies
To place these new findings in context, we searched the Consensus paper database, which includes over 200 million published research papers. The following search queries were used to identify relevant studies:
Topics and Key Findings
| Topic | Key Findings |
|---|---|
| How does the maternal gut microbiome influence offspring liver health and disease risk? | - Maternal Western diet causes dysbiosis, reduces beneficial tryptophan metabolites (including indoles), and impairs offspring immune responses, increasing susceptibility to MASLD and liver injury 8 9. - Vertical transfer of altered microbiota can reduce protective indole metabolites in offspring, impacting immune tolerance and liver health 8 9. |
| Can gut-derived indoles and their derivatives prevent or ameliorate liver injury? | - Indoles such as indole-3-carbinol (I3C) and 3,3'-diindolylmethane (DIM) protect against various forms of liver injury, including fatty liver, through anti-inflammatory, antioxidant, and metabolic effects 6 7 10 11. - Indole derivatives activate signaling pathways (AhR, Nrf2) that reduce lipid accumulation and inflammation in the liver 2 11. |
| What is the broader role of the gut-liver axis and microbiome in modulating liver disease risk? | - The gut-liver axis, mediated by microbiota and microbial metabolites, is central to the development and progression of fatty liver disease and other liver conditions 1 4 5. - Therapies targeting the microbiome (probiotics, prebiotics, postbiotics) show promise in animal models for preventing or reducing liver injury 3 4 5. |
| What are the mechanisms underlying microbiome-derived compound protection in liver disease? | - Indoles and microbiome-derived compounds modulate immune responses, oxidative stress, and metabolic signaling (e.g., AhR, Nrf2, STAT3), resulting in reduced inflammation, improved barrier function, and decreased lipid accumulation 2 6 7 9 10 11. - These effects are linked to both direct hepatic signaling and modulation of the intestinal barrier 1 2 4 9. |
How does the maternal gut microbiome influence offspring liver health and disease risk?
Recent studies emphasize that maternal diet and gut microbiome composition have lasting impacts on offspring metabolic health, particularly in the context of MASLD and liver disease. The new University of Oklahoma study aligns with this evidence, demonstrating that increasing maternal indole levels can help counteract the negative effects of a Western diet by influencing the offspring's microbiome and metabolic outcomes.
- Maternal Western diet exposure leads to microbiome dysbiosis and decreased production of protective tryptophan metabolites, such as indoles, in offspring 8.
- Altered maternal microbiota can be vertically transferred to offspring, shaping their early immune responses and increasing susceptibility to liver disease 8 9.
- Maternal gut inflammation during lactation also exacerbates liver injury risk in offspring by reducing beneficial bacteria and microbial metabolites 9.
- Interventions that restore or enhance beneficial microbial metabolites in mothers may offer a preventive strategy for offspring liver health 8 9.
Can gut-derived indoles and their derivatives prevent or ameliorate liver injury?
A significant body of research supports the protective effects of indole compounds and their derivatives, such as I3C and DIM, in liver disease models. These compounds act through diverse mechanisms, including anti-inflammatory, antioxidant, and metabolic regulation—mirroring the effects seen in the new mouse study with indole supplementation.
- Indole derivatives like I3C and DIM have been shown to reduce hepatic inflammation and injury in animal models, including NAFLD and acute liver injury 6 7 10 11.
- These compounds suppress pro-inflammatory cytokine production and enhance apoptosis of activated immune cells, limiting liver damage 6 7.
- Activation of the aryl hydrocarbon receptor (AhR) and Nrf2 pathways by indoles mediates protection against lipid accumulation and oxidative stress in the liver 2 11.
- Both preclinical and mechanistic studies suggest that dietary or microbial sources of indoles may have therapeutic potential in preventing liver disease 10 11.
What is the broader role of the gut-liver axis and microbiome in modulating liver disease risk?
The integrity and composition of the gut microbiome, as well as its metabolic interactions with the liver, are now recognized as key modulators of liver disease risk. The current study's findings that manipulating the maternal microbiome can alter offspring liver outcomes are consistent with a wider literature highlighting the gut-liver axis as a therapeutic target.
- The gut-liver axis mediates the transport of microbial metabolites and immune signals that influence liver inflammation and metabolism 1.
- Disruption of the gut microbiome can increase liver exposure to microbial products, promoting inflammation and disease progression 1 4 5.
- Therapeutic strategies—including probiotics, postbiotics, and dietary supplementation—can improve microbiome balance and reduce liver injury in animal models 3 4 5.
- Gut microbiome interventions show promise for a range of liver diseases beyond MASLD, including autoimmune hepatitis and alcoholic liver disease 3 5.
What are the mechanisms underlying microbiome-derived compound protection in liver disease?
Mechanistic studies have clarified that gut microbiota-derived compounds such as indoles exert their hepatoprotective effects through multiple, interconnected pathways. The activation of immune-modulatory and metabolic signaling cascades is a recurring theme in this research area.
- Indole and its derivatives activate the AhR and Nrf2 signaling pathways, reducing liver inflammation, oxidative stress, and lipid accumulation 2 6 7 10 11.
- Restoration of beneficial microbial metabolites improves intestinal barrier function and reduces systemic exposure to inflammatory stimuli 4 9.
- These compounds can modulate immune responses both locally (in the gut) and systemically (in the liver), protecting against acute and chronic liver injury 6 9.
- The IAA-IL-22-STAT3 axis, influenced by specific bacterial populations and their metabolites, is implicated in limiting ferroptosis and promoting liver regeneration 9.
Future Research Questions
While this study provides new insights into the potential for early-life microbiome interventions to reduce liver disease risk, several important questions remain. Future research is needed to clarify the mechanisms in humans, assess long-term safety and efficacy, and explore broader applications for microbiome-targeted therapies.
| Research Question | Relevance |
|---|---|
| Can indole supplementation in pregnancy and lactation prevent fatty liver disease in humans? | Translating findings from animal models to human populations is essential to determine if indole supplementation could be a viable preventive strategy for MASLD in at-risk children 8 10 11. |
| What are the long-term effects of altered maternal microbiome on offspring metabolic health? | Understanding the persistence and breadth of microbiome-mediated metabolic programming in offspring will inform prevention and intervention strategies for metabolic and liver diseases 8 9. |
| How do gut-derived indoles interact with other microbial metabolites in modulating liver disease? | The interplay between indoles, short-chain fatty acids, and other microbial products may have synergistic or antagonistic effects on liver health, which remains poorly understood 1 2 7. |
| Are specific gut bacteria or microbial signatures required for the protective effects of indoles? | Identifying which bacterial taxa are most effective at producing beneficial indoles could guide targeted probiotic or prebiotic interventions for liver disease prevention 8 9 10. |
| What are the optimal dosing and timing parameters for indole or microbiome-targeted interventions in early life? | Establishing safe and effective protocols for timing and administration of indole or related interventions during pregnancy and lactation is critical for future clinical applications 7 10 11. |