The gut–brain–immune triad in neurodegeneration: an integrated perspective

Xia & He Publishing Inc.

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Neurodegenerative diseases (NDs), such as Alzheimer’s disease (AD), Parkinson’s disease (PD), amyotrophic lateral sclerosis (ALS), and multiple sclerosis (MS), represent a growing global health burden, particularly in aging populations. While traditional research has focused on neuronal mechanisms like protein misfolding and oxidative stress, recent evidence underscores the critical role of the gut-brain-immune axis in disease pathogenesis. This review synthesizes current knowledge on how gut microbiota dysbiosis influences neuroinflammation, blood-brain barrier (BBB) integrity, and immune homeostasis through microbial-derived metabolites, including short-chain fatty acids (SCFAs), lipopolysaccharides (LPS), and bacterial amyloids. We explore the communication pathways linking the gut, immune system, and central nervous system (CNS), and highlight disease-specific mechanisms and therapeutic opportunities. Despite promising preclinical findings, significant challenges remain in establishing causality and translating these insights into clinical practice.

Introduction
The rising prevalence of NDs and the limited efficacy of neuron-centric therapies have prompted a paradigm shift toward a systems biology approach. The gut-brain-immune triad offers a holistic framework to understand neurodegeneration, integrating signals from the gut microbiota, immune responses, and CNS function. This review aims to unify recent discoveries and emphasize the translational potential of microbiome-targeted and immunomodulatory interventions.

Toward a Systems Biology Framework for NDs
Moving beyond reductionist models, a systems perspective acknowledges the contributions of glial dysfunction, chronic neuroinflammation, and metabolic dysregulation. This approach may reveal novel therapeutic targets and explain the failure of neuron-focused treatments.

Gut Microbiota as a Neuroregulatory Hub
The gut microbiome, often termed the "second brain," regulates brain function through neural, endocrine, immune, and metabolic pathways. Dysbiosis can disrupt these pathways, leading to systemic inflammation and CNS dysfunction, positioning the gut as a central modulator of neurodegeneration.

Communication Pathways in the Gut–Brain–Immune Triad
Bidirectional communication occurs via:

• Neural pathways: Vagus nerve and enteric nervous system.

• Endocrine signals: Gut hormones like GLP-1 and ghrelin.

• Immune mechanisms: Cytokine signaling and immune cell trafficking.

• Metabolic routes: Microbial metabolites such as SCFAs and tryptophan catabolites.
  These pathways collectively influence neuroinflammation, synaptic function, and neuronal survival.

Dysregulation of the Gut–Brain–Immune Axis in NDs

• AD: Gut dysbiosis promotes amyloid-β aggregation and tau hyperphosphorylation via LPS and reduced SCFA production.

• PD: α-Synuclein aggregation originates in the gut and propagates to the brain via the vagus nerve, exacerbated by SCFA depletion and immune activation.

• ALS: Altered Firmicutes/Bacteroidetes ratio and reduced butyrate producers correlate with neuroinflammation and motor neuron loss.

• MS: Dysbiosis drives Th17/Treg imbalance and molecular mimicry, fostering autoimmunity and demyelination.

Neuroinflammation: A Converging Mechanism
Neuroinflammation serves as a central integrator of gut-brain-immune crosstalk. Microbial metabolites, immune cell infiltration, and epigenetic modifications (e.g., miRNA regulation) sustain inflammatory cycles, contributing to synaptic dysfunction and neuronal damage.

Limitations of the Study
Key challenges include:

• Establishing causality from correlation.

• Interindividual variability in microbiome composition.

• Methodological inconsistencies in microbiome research.

• Overreliance on cross-sectional and preclinical data.

• Bidirectional feedback loops complicating therapeutic targeting.

Significance of the Review
This review integrates overlooked elements such as epigenetic regulation, non-GLP-1 gut hormones, and bidirectional gut-brain feedback. It advocates for a multidisciplinary approach to develop personalized, mechanism-based therapies.

Future Directions
Priority areas include:

• Longitudinal human studies with multi-omics integration.

• Development of brain-gut organoid models.

• Standardization of microbiome research protocols.

• Exploration of vagal and epigenetic mechanisms.

• Clinical trials of probiotics, postbiotics, and dietary interventions.

Conclusions
The gut-brain-immune triad is a pivotal, though underrecognized, axis in ND pathophysiology. Microbial metabolites, particularly SCFAs, play key roles in modulating neuroinflammation and BBB integrity. While microbiome-based interventions hold promise, their clinical translation requires robust, longitudinal studies and personalized approaches. A systems-level understanding of this triad is essential for advancing ND prevention and treatment.

 

Full text

https://xiahepublishing.com/2994-8754/JTG-2025-00027

 

The study was recently published in the Journal of Translational Gastroenterology.

Journal of Translational Gastroenterology (JTG) dedicates to improving clinical diagnosis and treatment, advancing understanding of the molecular mechanisms, and promoting translation from bench to bedside of gastrointestinal, hepatobiliary, and pancreatic diseases. The aim of JTG is to provide a forum for the exchange of ideas and concepts on basic, translational, and clinical aspects of gastroenterology, and promote cross-disciplinary research and collaboration.

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Journal

Journal of Translational Gastroenterology

DOI

10.14218/JTG.2025.00027 

Article Title

The Gut–brain–immune Triad in Neurodegeneration: An Integrated Perspective

  

New multisociety guidance strengthens infection prevention and control in nursing homes

Society for Healthcare Epidemiology of America

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The Society for Healthcare Epidemiology of America (SHEA), in collaboration with the Association for Professionals in Infection Control and Epidemiology (APIC), the Infectious Diseases Society of America (IDSA), the Post-Acute and Long-Term Care Medical Society (PALTmed), and the American Geriatrics Society (AGS), today released Multisociety Guidance for Infection Prevention and Control in Nursing Homes.

The new guidance updates earlier guidance, published as the SHEA/APIC guideline: infection prevention and control in the long-term care facility, July 2008.  The updated guidance provides a framework to help nursing homes prevent and control infections while maintaining the social and rehabilitative goals of residential care.

Why Now

• COVID-19 lessons: Devastating morbidity and mortality underscored the urgent need for stronger infection prevention to protect nursing home residents.
• Evolving resident population: More complex medical needs and higher exposure to devices increase infection risks in nursing home residents.
• Expanding services: Growth of ventilator-dependent units further raises infection challenges.
• Regulatory priority: CMS has made infection prevention in nursing homes a national focus.

Key Recommendations from the Updated Guidance

• At least one dedicated infection preventionist per facility (full-time for >100 beds; 0.5 FTE for smaller facilities).
• Stronger support and accountability from administrative and medical leadership.
• Improved healthcare personnel vaccination rates that support workforce illness prevention.
• Clear outbreak management strategies, including precautions, PPE, and visitation policies.
• Infection prevention input on environmental systems such as water, air handling, and cleaning practices.
• Collaboration with public health and infectious diseases experts as part of routine operations.

“Nursing homes are unique. Vulnerable people live and receive medical care, but it’s also important for the environment to feel homelike. This guidance offers practical, evidence-informed strategies to keep both short-stay and long-stay residents safe while supporting the comfortable environment they deserve,” said Lona Mody, MD, MSc, lead author of the guidance.

About the Document

Multisociety Guidance for Infection Prevention and Control in Nursing Homes was developed by experts in geriatrics, infectious diseases, infection prevention, and epidemiology, and has been reviewed and endorsed by leading professional societies.

The full guidance is published in Infection Control & Hospital Epidemiology (ICHE), SHEA’s flagship scientific journal.

Media Contact:
Julia Russo
jrusso@shea-online.org

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Journal

Infection Control and Hospital Epidemiology

DOI

10.1017/ice.2025.10252 

Article Title

Multisociety guidance for infection prevention and control in nursing homes

Article Publication Date

28-Oct-2025

 

Reducing use of sleep drugs could improve quality of life and longevity in older adults

New USC Schaeffer Center modeling demonstrates the benefits of reducing prescriptions for medications that carry serious risks for older adults

University of Southern California

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Millions of older Americans suffering from insomnia regularly use prescription sleep medications, despite the risk of serious side effects—such as falls, broken bones, cognitive impairment and dependence—and warnings from leading medical societies against their use.

A new study from the USC Schaeffer Center for Health Policy & Economics finds that reducing prescriptions of sleep medication in older adults could provide substantial health and economic benefits.

Avoiding use of these medications among older adults would reduce lifetime incidence of falls by 8.5% and cognitive impairment by 2.1%, researchers found. It would also increase life expectancy by 1.3 months, which translates to 1.7 million life-years gained across the population—most of which would be spent in good health.

“Our results show reducing use of sleep medications could help older adults live healthier lives with fewer limitations,” said lead author Hanke Heun-Johnson, a research scientist at the Schaeffer Center.

The study appears in The Lancet Regional Health - Americas.

Improved Quality of Life

An estimated 15.3 million American adults ages 50 and older take prescribed sleep medications, including benzodiazepines and “Z-drugs” such as Ambien. Use of these medications tends to increase with age and is more common among women and white adults.

While medical guidelines discourage long-term use, doctors often prescribe these drugs long-term. For some patients, the primary benefit becomes the avoidance of withdrawal, which in a clinical setting is easily misconstrued as ongoing effectiveness.

Insomnia itself carries serious risks for older adults, including depression, heart disease and cognitive decline. But while many people take sleep medications hoping to improve their quality of life, long-term use appears to do more harm than good.

For the new study, researchers leveraged a dynamic microsimulation model developed at the Schaeffer Center, the Future Elderly Model, to project the impacts of sleep medication use in older adults. They compared current use of the drugs with a scenario in which no one uses them, examining various outcomes such as cognitive decline, fall risk, nursing home use, medical costs and lifetime earnings.

People ages 65 to 74 saw the largest potential benefit in cognitive function and physical health from avoiding these drugs, suggesting that efforts to reduce prescribing should focus on this age group.

In addition to the health benefits of avoiding these drugs, researchers found it would mean lifetime savings of $6,600 per person, or about $101 billion across the United States. Most of the savings come from improvements in quality of life. 

Encouraging Safer Prescribing Practices

Professional organizations such as the American Academy of Sleep Medicine recommend cognitive behavioral therapy for insomnia (CBT-I), rather than sleep medication, as a first-line treatment. The treatment is structured to help people adopt better sleeping habits and can be delivered in-person, virtually or through an app (for example, the Department of Veterans Affairs’ CBT-I Coach). CBT-I is just as effective as sleep medication in the short term and is more effective in the long run, without the side effects.

Previous Schaeffer Center research identified practical interventions to reduce inappropriate prescribing of antibiotics, opioids and other medications. Researchers said some of these methods could likely be used to reduce prescriptions of sleep medications and steer physicians toward recommending safer options.

For example, it’s possible that electronic health record systems could prompt physicians to justify prescriptions for older patients and provide information about cognitive behavioral therapy. Physicians could also receive periodic reports comparing their prescribing patterns with those of their peers.

“Insomnia is a serious issue for many older adults, but regular use of sleep medication can pose real risks. Supporting physicians in reducing prescriptions and promoting safer, proven alternatives will ultimately benefit patients and society,” said co-author Jason Doctor, a senior scholar at the Schaeffer Center and the Norman Topping Medical Enterprise Chair in Medicine at the USC Price School of Public Policy.

About the Study
Other co-authors are Johanna Thunell, Jonathan Cloughesy and Bryan Tysinger of the USC Schaeffer Center; Jeffrey Linder and Stephen Persell of Northwestern University; and Mark Sullivan of the University of Washington.

The authors received support from the National Heart, Lung & Blood Institute (R01HL167023), and the USC-Yale Roybal Center for Behavioral Interventions in Aging (P30AG024968). The funding sources had no role in the design and conduct of the study; the collection, management, analysis, and interpretation of the data; the preparation, review, or approval of the manuscript; and the decision to submit the manuscript for publication.

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Journal

The Lancet Regional Health - Americas

DOI

10.1016/j.lana.2025.101284 

Article Publication Date

22-Oct-2025

What drives sleep problems in long-term care facilities?

University of Waterloo researchers find that residents’ poor sleep can trigger problematic medication use, falls and delirium

University of Waterloo

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Sleep problems affect more than one in five residents in long-term care facilities, with pain, daytime napping and certain medications emerging as key contributors.  
 
An international team led by University of Waterloo researchers analyzed health records from more than 21,000 residents aged 65 and older living in 228 long-term care homes across New Brunswick and Saskatchewan between 2016 and 2021, using data from the standardized interRAI assessment system. 

The researchers tracked who developed – or recovered from – sleep disturbances over time. At the start, nearly 22 per cent of residents had trouble sleeping, although facility rates varied widely, from three to 56 per cent. Within a year, about 10 per cent of residents who had been sleeping well developed new sleep issues, while half of those with existing problems saw improvements. 

The study identified several predictors of new or persistent sleep problems, including pain, chronic conditions such as heart or lung disease, moderate cognitive impairment, daytime napping and the use of sedative or antipsychotic medications. 

“Poor sleep is strongly associated with adverse health outcomes, including an increased risk of cardiovascular disease, cognitive decline and depression,” said Dr. John Hirdes, professor in Waterloo’s School of Public Health Sciences and senior author of the paper. “It also often leads to greater medication use, which can in turn raise the risk of falls, delirium and other complications.” 

Hirdes said the findings highlight opportunities to improve resident well-being. “Many of the risk factors we identified are modifiable. Improving pain management, reviewing medication use and promoting better sleep routines could make a real difference.” 

Dr. Sophiya Benjamin, a geriatric psychiatrist and researcher at McMaster University and an adjunct professor at Waterloo, noted that poor resident sleep doesn’t just affect individuals – it also takes a toll on caregivers and the broader health-care system. “When residents sleep poorly, it can heighten stress and burnout among staff, ultimately affecting quality of care,” she said. 

Benjamin added that long-term care homes should make sleep quality a routine part of health monitoring and, where possible, explore non-drug strategies to improve rest. “Facilities should also pay attention to environmental factors like noise, lighting and nighttime routines – elements that can have a major impact on residents’ sleep but weren’t part of this particular study.” 

The paper, “Predictors of change in sleep disturbance in Canadian longterm care facilities: a longitudinal analysis based on interRAI assessments,” was published in European Geriatric Medicine. 

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Journal

European Geriatric Medicine