The findings, published in Cell Reports Medicine, suggest that specific gut microbes and metabolites can serve as biomarkers to help diagnosing depression and guide treatment.

While it’s known that certain microbes and metabolites can influence depression by affecting brain pathways and neurotransmitters, it’s unclear whether they could reliably help diagnose the condition.

Researchers led by Mingliang Zhao at Shanghai Jiao Tong University School of Medicine in China conducted a study analyzing gut bacteria and blood metabolites in dozens of people with depression, before and after treatment.

Metabolic patterns

By comparing blood and stool samples from non-depressed individuals with samples from people with depression, the researchers found that people with depression showed alterations in their blood metabolites. An analysis of more than 200 metabolites revealed 34 molecules that differed between depressed and non-depressed people.

Many of these changes were reversed after treatment, showing that medications can restore certain metabolic patterns. Animal experiments confirmed similar trends, supporting the connection between gut microbes, metabolism, and depression.

Using data from one group of participants, the researchers found that certain metabolites mediate the effects of specific gut microbes on depression. For example, the amino acid L-tyrosine mediated some of the effects of one bacterial species on depression, and homovanillic acid partly mediated the effects of another. 

Identifying depression

Key bacteria and metabolites, such as Bifidobacterium longum, Roseburia intestinalis, serotonin, and homovanillic acid, were linked to lower depression risk, while others, such as Blautia obeum and 2-hydroxybutyric acid, were linked to higher risk, the researchers found. 

Building on these findings, the team developed a machine-learning model using 34 metabolites that could reliably identify depressed individuals.

Although more research is needed to confirm these results, the findings “highlight metabolites as key mediators linking microbiota to depression and as valuable indicators for its identification,” the authors say.

The researchers set out to answer a fundamental question: to what extent do age-related shifts in the microbiota causally contribute to memory decline? To address this, they separated host age from microbiota age. First, they co-housed young 2-month-old mice with old 18-month-old mice and found that, after one month, the young animals developed a microbiota more similar to that of the older mice. At the same time, they showed impaired performance in short-term memory and spatial learning tests. The same effect was reproduced by transplanting fecal microbiota from aged donors into germ-free young mice, whereas it did not occur in germ-free conditions or when the microbiota had been depleted with antibiotics. Notably, antibiotic treatment improved not only the “microbiota-aged” young mice, but also the old animals themselves, suggesting that the microbial contribution to cognitive impairment may be at least partly reversible.

A key suspect: Parabacteroides goldsteinii

To identify the microbial drivers of the phenotype, the team followed the mouse microbiota longitudinally across the lifespan, integrating metagenomics and fecal proteomics. Among the taxa that increased with age and were transmissible to young animals through co-housing or fecal transfer, Parabacteroides goldsteinii emerged as the strongest candidate. Colonizing young germ-free or antibiotic-treated mice with this bacterium was enough to induce cognitive impairment, whereas other microbes that also changed with ageing did not reproduce the same effect.

This is an important conceptual point. The study does not simply report a dysbiosis associated with ageing; it isolates a specific microbial change with measurable functional consequences for the brain. In other words, it moves the discussion from the broad observation that “the microbiota changes with age” to the more rigorous conclusion that certain age-associated microbial shifts may directly contribute to memory decline.

From the gut to the hippocampus: the role of the vagus nerve

One of the most original aspects of the study is its reconstruction of the gut–brain circuit involved. The authors showed that an “aged” microbiota and P. goldsteinii reduce the activation of immediate early genes in the hippocampus and blunt neuronal responses to novel object exposure, suggesting a lower capacity for memory encoding. The effect did not appear to result primarily from major alterations in hippocampal neurogenesis or dendritic spine morphology in the young co-housed mice, but rather from a defect in signal transmission.

The crucial relay in this pathway was the vagus nerve. Silencing TRPV1-positive sensory neurons, particularly the PHOX2B-positive vagal component, reproduced the memory deficit. By contrast, pharmacological or chemogenetic activation of these neurons restored cognitive performance. Imaging of the nodose ganglion further showed that young mice exposed to an aged microbiota had reduced vagal responses to intestinal nutrient stimuli. Together, these findings support the idea that ageing may involve not only a reduced perception of the external world, but also a reduced perception of internal signals arising from the gastrointestinal tract.

This interpretation is also central to the accompanying editorial, which frames the findings as a form of “internal sensory decline” in ageing: just as older age often brings poorer vision and hearing, it may also bring a diminished capacity of the brain to receive and interpret gut-derived signals.

The metabolic mediator: medium-chain fatty acids

The next step in the study was to identify the molecular mechanism. Analysis of P. goldsteinii showed that the bacterium produces high levels of medium-chain fatty acids (MCFAs), including 3-hydroxyoctanoic acid, decanoic acid, and dodecanoic acid. Oral administration of these metabolites reproduced the phenotype seen with the bacterium itself: reduced vagal activation, weaker responses in the nucleus tractus solitarius and hippocampus, and poorer performance in novel object recognition. Luminal MCFA levels increased with age in conventional mice, but not in germ-free or antibiotic-treated animals, and they were transmissible from old mice to young ones.

For clinicians, this is particularly relevant because it shifts attention from the microbe itself to its metabolites. From a translational perspective, a metabolic target may prove more manageable than an entire microbial ecosystem.

Peripheral inflammation, GPR84 and macrophages

The MCFAs exerted their effects through GPR84, a receptor expressed mainly by myeloid cells. Mice lacking GPR84 were protected from the cognitive impairment induced by MCFAs, whereas a GPR84 agonist mimicked the detrimental effects. Conversely, the GPR84 inhibitor PBI-4050 restored both hippocampal activation and memory performance, including in old mice and in animals colonized with P. goldsteinii.

The study then clarified that the critical target of this signalling pathway is peripheral macrophages, rather than the central nervous system itself. Depletion of myeloid cells or blocking their recruitment protected mice from memory impairment, while pro-inflammatory cytokines such as TNF and IL-1β appeared to play a key role. Neutralizing TNF or IL-1β improved memory in aged mice and in mice exposed to an aged microbiota; moreover, IL-1β signalling on PHOX2B-positive vagal neurons seemed to contribute directly to circuit dysfunction. Overall, the data point to a localized peripheral inflammatory response capable of interfering with vagal function and, through that, with hippocampal memory encoding.

What therapeutic perspectives does this open?

The study highlights several potentially actionable levels of intervention. In aged mouse models, the authors observed cognitive benefits after treatment with antibiotics, a bacteriophage active against Parabacteroides, GPR84 inhibition, and reactivation of vagal signalling through capsaicin, cholecystokinin, GLP-1, or liraglutide. These results should, however, be interpreted with caution. This is not a ready-to-use clinical strategy, but a robust proof of concept in an animal model.

The accompanying editorial emphasizes exactly this point. If the circuit identified in mice is conserved in humans, gut-targeted therapies could one day become a way to counter physiological cognitive decline. But substantial translational work remains. It will be necessary to determine whether P. goldsteinii also increases with age in humans, whether its metabolites are associated with specific cognitive phenotypes, whether the GPR84–macrophage–vagus pathway operates in older adults, and above all whether modulating it can produce clinically meaningful benefits.

What this study adds to microbiome medicine

For a medical audience, the value of this work lies in three main aspects. First, it provides experimental evidence that age-related cognitive decline can be shaped by peripheral intestinal signals. Second, it identifies a defined biological axis — P. goldsteinii, MCFAs, GPR84, macrophages, cytokines, vagus nerve, hippocampus — that goes well beyond the descriptive associations often found in microbiome research. Third, it introduces the concept of “interoceptive dysfunction” as a component of brain ageing.

Naturally, important limitations remain. The study was conducted entirely in mice; the polysynaptic route linking the gut to the hippocampus is not yet fully mapped; and it is still unclear how much this pathway contributes relative to other determinants of cognitive ageing. Still, the direction is clear: the gut appears not only as a mirror of brain health, but also as a possible active regulator of cognitive ageing trajectories.

If confirmed in humans, these findings could open a new chapter in the biology of ageing, one in which the loss of memory is shaped not only by what happens inside the brain, but also by what happens in the intestine.

The findings, published in iScience, suggest that the microbiota could be one of the ways through which owning a dog supports adolescents’ social development and mental well-being.

“Raising dogs has beneficial effects, especially for adolescents, and these effects may be mediated through symbiosis with microorganisms,” says study co-author Takefumi Kikusui at Azabu University in Japan.

Studies have suggested that living with a dog can change a person’s gut bacteria, but it is unknown whether the microbes acquired from living with dogs could affect adolescents’ social behavior or mental well-being. So, Kikusui and his team studied 343 adolescents, some of whom owned a dog, and assessed their microbiota and mental health.

Bacterial differences

Teens who owned a dog at age 13 showed better mental and behavioral health at age 14 than those who did not: they had fewer social problems and less social withdrawal, even after accounting for factors such as family income and size. 

When the researchers analyzed saliva samples from the teens, they found that while overall oral bacteria diversity was similar between groups, certain bacteria were more common in dog owners. 

Some of these bacteria, particularly in Streptococcus strains, were linked to fewer behavioral and attention problems, the researchers found.

Promoting well-being 

To explore whether bacteria from dog-owners could influence social behavior, the researchers transferred saliva microbes from these teens into germ-free mice. 

Compared with mice receiving microbes from teens who didn’t own a dog, those receiving microbes from dog-owning teens showed increased sociability, approaching unfamiliar mice more often. However, these mice also showed more avoidance of new objects. Specific Streptococcus strains were linked to increased sociability in mice, the researchers found.

“The most interesting finding from this study is that bacteria promoting prosociality, or empathy, were discovered in the microbiomes of adolescent children who keep dogs,” Kikusui says. “The implication is that the benefits of dog ownership include providing a sense of security through interaction, but I believe it also holds value in its potential to alter the symbiotic microbial community.”

Now, a Perspective article published in Neuron concludes that there is currently no robust evidence of a causal link between the gut microbiota and autism. 

“I don’t think it’s warranted to spend further time and funding on this topic,” says Kevin Mitchell at Trinity College Dublin, who led the work. “We know that autism is a strongly genetic condition, and there’s still loads to be worked out there.”

Mitchell and his colleagues reviewed the scientific literature on autism and the gut microbiota, evaluating study designs, sample sizes, statistical methods, and behavioral assays in mice.

Inconsistent findings

The research examining the role of gut microbiota in autism includes observational studies, experiments in mice, and clinical trials. Observational studies in humans have reported differences in gut microbial composition between autistic and non-autistic people, but findings are inconsistent and often based on small sample sizes. 

Mouse experiments, which aim to model autism-like behaviors and assess microbiota interventions, face challenges related to the validity of behavioral assays and differences between human and mouse gut microbiotas. 

While some studies report behavioral effects following microbiota manipulation, these results are limited by small sample sizes, methodological variability, and limited replication, the authors say.

Methodological concerns 

Clinical trials in humans have mostly been small, open-label studies without control arms, making it difficult to distinguish treatment effects from placebo responses.

Randomized controlled trials, which provide more rigorous evidence, have so far not shown consistent or meaningful effects of microbiota interventions, such as probiotics or fecal microbiota transplants, on autism-related traits. 

Meta-analyses of these trials also reported limited evidence of benefit and noted methodological concerns including small sample sizes and potential biases, including the influence of financial conflicts of interest, the authors say.

Future work

Future studies should have clearly defined hypotheses, adequate sample size, standardized protocols, and replication using multiple independent approaches. This would help ensure that findings are robust and reproducible, the authors say.

Overall, there is no strong evidence that the gut microbiota causally influences autism, they add. Similarly, claims that microbiota interventions can prevent or treat autism should be interpreted with caution.

Although the review focused on autism, the gut microbiota has been linked to many other conditions, including mental health conditions and neurodegenerative diseases, the authors note. “Given that the same methods have been used for most of these studies, it seems likely that they may suffer from the same methodological shortcomings.”

The findings, published in Science Advances, indicate that combining data about gut-brain–related disorders with genetic and other information provides a powerful approach for predicting these neurodegenerative diseases.

Recent studies suggest that disorders of the gut-brain axis influence the risk of developing Alzheimer’s and Parkinson’s disease. However, more work is needed to understand the connection between disorders of the gut-brain axis and neurodegeneration.

Mohammad Shafieinouri at the National Institutes of Health in Bethesda, Maryland, and his colleagues set out to look for patterns linking gut-brain–related disorders, genetics, and blood-based biomarkers to the risk of developing Alzheimer’s and Parkinson’s disease. 

To do so, they analyzed data from more than 500,000 participants across three large biobanks: the UK Biobank, the Secure Anonymized Information Linkage databank, and FinnGen. These biobanks collect and link large-scale health, genetic, and clinical data from hundreds of thousands of participants.

Gut-brain axis

The researchers identified specific conditions within the gut-brain axis that are linked to increased risk for Alzheimer’s and Parkinson’s disease. For Alzheimer’s, disorders including gastritis, gastroenteritis and colitis were associated with higher hazard ratios years before diagnosis. For Parkinson’s, associations were observed for functional intestinal disorders, pancreatic internal secretion disorders, and deficiencies in B group vitamins. 

These findings were robust across multiple datasets and time intervals, demonstrating that risk can be elevated up to 15 years before diagnosis. Genetic analyses revealed that people with Alzheimer’s or Parkinson’s disease who also had co-occurring gut-brain axis–related conditions often had less genetic risk for the disease compared to those who developed Alzheimer’s or Parkinson’s without such conditions. 

This suggests that non-genetic factors, including metabolic and digestive disorders, may play a role in disease development, the researchers say.

Predicting disease

Further analyses supported the relevance of the gut-brain axis in neurodegeneration. Specific blood-based biomarkers were increased in people with Alzheimer’s or Parkinson’s disease, reflecting underlying neuronal damage. Other proteins showed altered levels in people with co-occurring metabolic or digestive conditions.

By combining clinical, genetic and other types of data into models, the researchers could predict who was more likely to develop Alzheimer’s or Parkinson’s disease. Age and molecular biomarkers were the strongest predictors of these neurodegenerative diseases, while traditional clinical features contributed relatively little, the team found. 

“This endeavor illuminates the interplay between factors involved in the gut-brain axis and the development of Alzheimer’s and Parkinson’s disease, opening avenues for therapeutic

targeting and early diagnosis,” the authors say.

Recent studies have explored microbiome-targeted interventions, such as prebiotics, probiotics, and faecal microbiota transplantation (FMT), showing potential for improving both gut and behavioral symptoms. In particular, strains such as Lactobacillus rhamnosus GG, L. plantarum, and Bifidobacterium longum have shown positive effects on gut health, microbiota balance, and anxiety-like behavior. The prebiotic fiber partially hydrolyzed guar gum (PHGG) has also shown efficacy in reducing GI symptoms in both DGBI and autistic individuals. Additionally, GDH has demonstrated success in managing GI-related anxiety in DGBI, although it remains untested in the context of autism.

Mitchell and colleagues conducted a study published in Journal of Autism and Developmental Disorders to evaluate the effectiveness of a synbiotic supplement (containing PHGG and a probiotic mixture of Humiome® L. rhamnosus GG, Humiome® L. plantarum DSM 34532, Humiome® B. lactis DSM 32269 and B. longum DSM 32946) alone versus the same synbiotic combined with GDH in improving gastrointestinal symptoms in autistic children. Moreover, changes in behavior, anxiety, and gut microbiota composition were assessed. 

The trial, conducted in Brisbane (Australia) and supported by dsm-firmenich, revealed that synbiotic supplementation, both alone and combined with GDH, is safe and effective in reducing gastrointestinal discomfort in autistic children with comorbid DGBI. Both interventions also led to beneficial shifts in gut microbiota. 

Improvements of gastrointestinal outcomes following treatment 

A total of 36 children were randomly assigned to the trial (18 in the synbiotic treatment group, SYN group, and 18 in the combined treatment group, synbiotic + GDH, COM group). The intervention period lasted 12 weeks with an additional 12-week follow-up. Both the SYN group and the COM group experienced statistically and clinically significant reductions in gastrointestinal symptom severity over the 12-week intervention period. These improvements were also sustained at the 24-week follow-up, even when controlling for sex, baseline anxiety levels, and antibiotic exposure.

Further analysis revealed significant improvements in both groups for pain and stool smell after 12 weeks. The SYN group also showed a significant reduction in diarrhea frequency and improved stool consistency, whereas the COM group demonstrated a significant reduction in flatulence. 

Notably, at follow-up, only the COM group maintained the improvements observed in pain and flatulence, suggesting that while both interventions were effective in the short term, the addition of GDH may help sustain certain GI symptom improvements over time.

Other Gut-Based Outcomes

After 12 weeks, 73% of participants in the COM group showed improvements in stool consistency, compared to 50% in the SYN group. Similarly, a higher proportion of participants in the COM group were classified as “responders” post-intervention (75%) compared to the SYN group (66.7%). This trend persisted at the 24-week follow-up, with 90.9% of the COM group and 63.6% of the SYN group classified as responders. While these findings were not statistically significant, they suggest a possible clinical advantage of the combined intervention in improving stool-related outcomes.

Treatment effects on behaviour and anxiety

Following the 12-week intervention, the COM group showed statistically and clinically significant improvements in behavior and anxiety. Notably, children in this group were less irritable, more cooperative, and less socially withdrawn. Their anxiety levels also dropped significantly.

In contrast, the SYN group showed some improvement, mainly in social behavior and hyperactivity, with hyperactivity being the only change that was also clinically meaningful. There was a slight improvement in irritability, but it wasn’t strong enough to be considered significant. Anxiety levels in the SYN group did not change. Overall, these results suggest that combining the synbiotic with hypnotherapy had a greater and wider effect on behavior and anxiety.

Changes in microbiome composition 

Analysis of the stool microbiome revealed changes in microbial composition following the 12-week intervention. Both groups experienced a significant rise in Bifidobacterium animalis and Dialister, whereas the COM group showed increases in Faecalibacterium, a strain linked to gut health and lower anxiety levels. These findings suggest that both interventions led to beneficial and distinct microbial shifts associated with improved gut health. 

The present study is the first to evaluate a combined gut-brain approach—oral synbiotic supplementation paired with GDH—in autistic children with disorders of DGBI. While both the synbiotic-only and combined interventions were safe and significantly reduced gastrointestinal symptoms, the COM group exhibited added benefits. Notably, behavioural improvements are clinically relevant given the bi-directional relationship between anxiety, irritability, and GI symptoms in autistic individuals. The study supports the emerging view that targeting the microbiome may help modulate brain function and behavior in neurodevelopmental conditions. While more research is needed to replicate these findings in larger and more diverse populations, synbiotics could become part of an integrated therapeutic approach for ASD—one that addresses not only the brain but the gut as a therapeutic gateway.

Protein glycosylation is when sugar molecules are strongly linked to amino acids. This mechanism affects key biological processes such as cell signaling, cell adhesion, and endocytosis. With over 200 enzymes involved, the variants based on composition and structure are numerous. Errors in the process can impact protein functions. However, there is a lack of highly selective enrichment strategies and high-throughput quantitative approaches for precise glycosylation tracking. 

To meet this need, the researchers developed a new strategy called “Deep quantitative glycoprofiling” (DQGlyco) to investigate the glycosylation dynamics in human cells treated with a fucosylation inhibitor and in the brains of mice colonised with defined gut microbiomes. Indeed, while the gut microbiome’s composition impacts behaviour and brain physiology, the molecular mechanisms remain unclear.

The new glycoproteomics workflow increased the detection of unique N-glycopeptides by 60% in a standard mixture.  DQGlyco enabled high-throughput sample preparation and enrichment of hundreds of samples per day, with enrichment selectivity exceeding 90% for all samples.

Deep glycoproteome analysis in mouse brain

Applying the strategy to a more complex system, like a mouse brain, a deeper glycoproteome analysis was achieved. 

N-glycosylation:

• DQGlyco enabled the identification of 177,198 unique N-glycopeptides and 8,245 N-glycosites on 3,741 N-glycoproteins, a 25-fold improvement compared to current N-glycoproteomics studies. 
• The majority of identified glycoforms were on plasma membrane or extracellular proteins. 
• 332 new glycoproteins were identified, highlighting the sensitivity of the method
• N-glycans identification was in line with different enrichment strategies, suggesting a low enrichment bias toward specific glycopeptides

O-glycosylation:

• the method identified 32,287 O-glycopeptides on 3,450 O-glycoproteins in mouse brain samples, demonstrating an extensive characterisation of intact O-glycosylation in mammalian tissue
• Over 494 unique O-glycan compositions were identified, showing structural diversity 
• Intracellular proteins were predominantly modified by N-acetylglucosamine (GlcNAc), while N-glycans were predominantly modified by GlcNAc, suggesting distinct regulatory mechanisms for N- and O-glycosylation.

Glycosylation heterogeneity

Focusing on glycosylation heterogeneity, different sites on the same protein showed a substantial variation in microheterogeneity, more than in the whole glycoproteome.

• The diversity is site-specific, with an average of 17.4 glycoforms per site. 
• No correlation between the number of glycosites per protein or glycoforms per site and the abundance of the respective protein. 
• Nearly half of the sites modified by only one glycoform were found to be modified by high mannose, implying that these sites are subjected to a low number of processing events. 
• The distribution of N-glycosylation classes varied between human cell lines and mouse brain, suggesting differences in the regulation of glycosylation processes. 
• O-glycosylation and phosphorylation often co-occur on the same protein regions, resulting in posttranslational modification crosstalk.
• Around 25% of O-glycosylated peptides were previously reported to be phosphorylated, independent of glycan mass and composition.
• The model discriminated between sites of low and high microheterogeneity, like bends and turns
• Extracellular glycosites showed a larger extent of glycan microheterogeneity than their cytoplasmic counterparts on the same proteins, suggesting subcellular differences

Glycoform distributions in cells and tissue

The complexity of the glycosylation pathways makes it quite impossible to predict the composition of mature glycans, and glycoforms of any composition or structure could potentially be surface-exposed in cells. 

In this study, researchers identified 3,990 glycopeptides on 826 sites and 513 proteins in intact living human HEK293 cells showing significant changes in abundance based on the enzyme. Not only that. 

• High-mannose glycoforms were generally less surface exposed, while most fucosylated or sialylated glycoforms were often at the surface 
• Sites with at least two high-mannose surface-exposed glycoforms were generally less accessible

Was this heterogeneity reflected at the tissue level? It looks like it. Indeed, the overall mouse brain, liver and kidney showed distinct glycoproteomes while maintaining high consistency within the same tissue. In particular:

• The liver glycoproteome showed the highest variability across mice
• Glycosylation sites with high tissue specificity were significantly enriched in protein domains crucial for cell adhesion, cell signalling, and immunity

Focusing on the brain, quantitative glycoproteomics was performed to determine the biophysical properties of over 30,000 glycoforms. From this:

• High-mannose glycoforms were more soluble than processed glycans, cadherin-13 protein in particular, maybe because of the interactions with the extracellular matrix.
• Different glycoforms at the same site vary in solubility, indicating that glycosylation microheterogeneity impacts protein states 
• Most glycosylations tend to influence protein solubility in the same direction

Gut microbiome modulates the mouse brain glycoproteome

The gut microbiome composition can impact brain development and function via the gut-brain axis by nervous or chemical signalling. Glycosylation, a crucial component of neuronal functions, is enriched in mitochondrial proteins and could be linked to the axis.

Therefore, researchers assessed the impact of different gut microbiome compositions on the brain proteome and glycocoproteome, finding significant changes in protein abundance and glycoform levels in three groups of six adult germ-free mice. Additionally, the thermal proteome profiling allowed the understanding of the impact of gut colonisation on the brain proteome of adult mice. Many proteins involved in axon guidance and neuronal migration showed changes in glycosylation and thermal stability after microbiome colonisation when compared to germ-free models. 

The glycosylation changes seem to be site-specific. Indeed, glycoforms at the same site, independently of glycan composition, tended to change in abundance in the same direction, suggesting a regulation of the overall level of glycosylation of specific glycosites.

In conclusion

This study highlights a significant link between site glycosylation microheterogeneity and protein states in mouse tissues and human cell lines.

Through an innovative strategy, DQGlyco, it was possible to achieve quantitative and comprehensive analyses of protein glycoforms across a large number and variety of samples. The discovery of tissue-specific glycosites opens paths for exploring the roles of glycosylation in modulating protein activity across diverse tissues. The study also supports the impact of the gut microbiome on brain glycosylation and the potential of site-specific modulations in glycosylation. 

The findings, published in Cell, suggest that N-acyl lipids are important, overlooked molecules shaped by diet and gut microbes.

“We anticipate that this resource will spur the development of additional ways to find N-acyl lipids and will help uncover additional biological and health associations,” the researchers say. 

N-acyl lipids are made from a fatty acid and an amine, and they’re known to play important roles in the body, including controlling appetite and regulating insulin. N-acyl lipids made from short-chain fatty acids are typically produced by gut microbes, but many likely remain undiscovered because current tools can’t always recognize them.

To better detect and understand N-acyl lipids, Helena Mannochio-Russo at the University of California, San Diego, and her colleagues created a special search tool to scan public databases of chemical information from more than 2,700 studies.

Uncovering N-acyl lipids

The researchers identified hundreds of N-acyl lipids, many of which had not been recognized before. These molecules were found in humans, rodents, food, plants and microbes. 

The gut microbiota appears to both produce and influence the levels of many of these N-acyl lipids. The team also found that diet and antibiotics can change N-acyl lipid levels. With this data, the researchers created a N-acyl lipid database.

To see how gut microbes and these lipids might relate to disease, the team analyzed stool samples from people with and without HIV. Certain N-acyl lipids, especially those linked to short-chain fatty acids, were higher in people with the condition, and their levels were associated with immune markers and HIV viral load. 

Treatment targets

N-acyl lipids made from molecules such as cadaverine and putrescine were higher in people with HIV-associated neurocognitive disorders, the researchers also found. By growing gut bacteria in lab dishes, the team confirmed that some microbes can produce these lipids, including cadaverine-based ones. 

Some of these lipids could also change how immune cells develop and function. For example, certain lipids helped promote immune cells that help keep the immune system balanced and reduced the formation of inflammatory immune cells. 

These results suggest that the levels of some N-acyl lipids could be used as biomarkers or treatment targets. The new database and search tools now allow scientists to reanalyze past studies and uncover other insights about N-acyl lipids and their role in the body, the authors say.

This complex neuroimmune-endocrine network, mediated through vagal afferents, microbial metabolites, and barrier integrity pathways, demonstrates increasingly recognized correlations with neurodegenerative disorders and disease pathogenesis.

Drawing on current evidence, MicrobiomePost’s instant book synthesizes the principal mechanisms of microbial-neural signaling:

• microbial production of neuroactive compounds (GABA, serotonin, SCFAs) directly modulates central nervous system activity;
• intestinal barrier dysfunction permits translocation of proinflammatory mediators that may initiate neuroinflammatory cascades;
• butyrate emerges as a key regulator of both epithelial tight junction stability and microglial activation states.

Download the instant book

The findings, published in Cell Reports Medicine, suggest that modifying the microbiota could influence multiple sclerosis progression and provide new therapeutic targets.

Previous studies have shown that the gut microbiota is altered in people with multiple sclerosis, with some microbes linked to disease worsening and others associated with protection. However, it’s unclear how the microbiota and its metabolites are linked to long-term changes in disease severity and the transition to progressive multiple sclerosis — a stage of the disease where disability worsens over time.

To measure microbial composition and metabolic changes associated with disease severity, Luke Schwerdtfeger at Brigham and Women’s Hospital in Boston analyzed blood and stool samples from people with multiple sclerosis.

Microbial imbalance

The study participants were part of the Comprehensive Longitudinal Investigation of Multiple Sclerosis at the Brigham and Women’s Hospital (CLIMB study), which tracks people with multiple sclerosis over time, collecting clinical data, MRI scans and biological samples.

Certain gut bacteria, such as Alistipes and Bacteroides, are linked to worsening disability, while others, such as Streptococcus thermophilus and Eubacterium hallii, are associated with stability or improvement, the researchers found. 

Multiple sclerosis treatments appeared to influence gut bacteria composition, increasing beneficial microbes while reducing harmful ones. Some microbes, including Ruminococcus and Lachnoclostridium, were linked to better cognitive scores, while others were associated with worsening cognitive abilities.

Metabolic byproducts

People who transitioned to progressive multiple sclerosis had specific changes in metabolites, especially in lipids and bile acids. Certain metabolites were linked to worsening disability, while others were associated with stability. 

The researchers found that metabolic pathways related to vitamin B6, fatty acids and drug metabolism were more active in people transitioning to progressive multiple sclerosis. The team also identified gut microbes, including Akkermansia and Lachnospiraceae, that produce metabolites linked to disease progression.

The findings suggest that changes in gut bacteria and their byproducts play a role in worsening symptoms, offering potential targets for future treatments. However, the authors say, larger and more detailed studies are needed to better understand how gut microbes influence multiple sclerosis.