Author: Dario

Metabolism as a common origin of diseases

The complex chronic diseases – like Alzheimer, depression, multiple sclerosis, type 1 diabetes, inflammatory bowel diseases And tumors – they share a multifactorial origin linked to the interaction between genetics, environment And microbiome. For years, research has focused on genomics, proteomics And microbiomics, but these disciplines alone cannot explain the evolution of the disease or predict its course. The global increase in these conditions, despite enormous scientific investments, requires a change of perspective based on the role of metabolism as a triggering factor, rather than as a simple consequence of pathological processes.

The decisive contribution of metabolomics

There metabolomics represents the missing key element to truly understanding these diseases. metabolomics study the metabolites, molecules that reflect the interaction between diet, microbiome And genetics, offering a direct image of the state of health. In particular, the Western-style diet (WSD), theobesity and metabolic disorders profoundly alter the balance of metabolites produced by the intestine, favoring underlying inflammatory conditions that can “prepare the ground” for the development of chronic diseases. metabolomics It therefore allows us to identify new biomarkers, to understand the disease progression and to identify therapeutic targets earlier and more effective.

From diet to microbiome: an integrated disease model

Innovative models connect the nutrients introduced with the diet, the effects on microbiome, the production of microbial metabolites and the changes observed in the metabolic profiles of patients. This approach confirms the critical role of microbiome as a regulator of inflammation and as a possible therapeutic target. The results suggest that only by integrating the metabolic perspective will it be possible to advance the precision medicine, improve prevention and identify new strategies against complex chronic diseases, overcoming the limitations of approaches based exclusively on genetics.

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Tryptophan metabolism and inflammatory pathways

The tryptophan It is an essential amino acid with very limited reserves, easily subject to deficiency and metabolic deviation. Only a small part generates serotonin, while approximately 95% is directed towards the path of kynurenine, activated by enzymes IDO And TDO. When the immune system produces inflammatory cytokines, IDO increases its activity and accelerates the transformation of tryptophan, reducing its availability for serotonin synthesis and generating potentially harmful metabolites. Among these, a particularly critical role is played byacid quinoline, capable of activating the NMDA receptors and generate oxidative stress.

Quinolinic acid and neurodegeneration

The increase of thequinolinic acid It is detected in different conditions: depression, Parkinson, Alzheimer, ALS and cognitive disorders associated with HIV. In depressed patients, levels in the cerebrospinal fluid are higher and correlate with the severity of symptoms. In Parkinson’s disease, it contributes to the death of dopaminergic neurons; in Alzheimer’s disease, it is associated with inflammation, plaques And neurofibrillary tangles; in ALS it causes motor neuron damage and mitochondrial dysfunction. In HIV-positive patients, levels can increase up to twenty-fold, causing severe cognitive impairment. Its neurotoxicity results from excessive activation of NMDA receptors, the production of free radicals and from the alteration of the neuronal cytoskeleton.

Therapeutic perspectives

The evidence shows that the tryptophan dysregulation and excessive production of quinolinic acid contribute to inflammation, oxidative stress and loss of protective metabolites such as acid picolinic and acid kynurenic. For this reason, research aims to modulate the kynurenine pathway, reducing the flow towards toxic metabolites and promoting neuroprotective ones. IDO/TDO inhibitors and antioxidants such as glutathione, curcumin or epigallocatechin, and nutritional approaches that ensure adequate tryptophan levels and support antioxidant defenses. These strategies may help prevent brain degeneration, but long-term clinical studies are needed.

For further information: 

Friedman M. Analysis, Nutrition, and Health Benefits of Tryptophan. Int J Tryptophan Res. 2018 Sep 26;11:1178646918802282. doi: 10.1177/1178646918802282.

Hestad K, et al. The Role of Tryptophan Dysmetabolism and Quinolinic Acid in Depressive and Neurodegenerative Diseases. Biomolecules. 2022 Jul 18;12(7):998. doi: 10.3390/biom12070998.

OMahony SM, et al. Serotonin, tryptophan metabolism and the brain-gut-microbiome axis. Behav Brain Res. 2015 Jan 15;277:32-48. doi: 10.1016/j.bbr.2014.07.027.

Origins and production of butyric acid

The neurodegenerative diseases, like Alzheimer And Parkinson, also appear to be influenced by the intestine. The microbiota, that is, the set of microorganisms that populate our intestine, plays a fundamental role in communication with the brain through the microbiota-gut-brain axis. When this ecosystem is altered (dysbiosis), the production of metabolites beneficial to the body’s well-being also changes, promoting inflammation and contributing to the development of neurological disorders.

Role of butyric acid in the microbiome, cell signaling, and the immune system

In the colon, butyric acid supports the intestinal cell function, regulates the cellular differentiation, modulates inflammation and helps prevent microbiome imbalances. It acts as signaling molecule, activating receptors such as HCA2 And PPAR, fundamental for the fat metabolism and for processes that can influence the growth of tumor cells. It also plays a key role in regulation of immunity, promoting the action of the regulatory T lymphocytes and helps control chronic inflammation. Clinical studies show positive effects in diseases such as colitis, diabetes, and inflammatory bowel disorders.

Effects on the brain, metabolism, cardiovascular system and cancer

Research shows a link between butyric acid and brain health: can affect anxiety, stress and pathologies such as Alzheimer, Parkinson, autism And depression, thanks to its action on mitochondria, epigenetics And microbiome homeostasis. He is also involved in the energy metabolism, improving insulin sensitivity And weight control. In animal studies it reduces atherosclerotic lesions and may help regulate blood pressure. Our understanding of the underlying molecular mechanisms is likely to increase as the omics technologies, in particular the metabolomics. Since butyric acid is a byproduct of fiber fermentation, this may explain why the high-fiber diets They help protect against colorectal cancer, obesity, stroke, type 2 diabetes, and other diseases.

For further information: 

Borycka-Kiciak K, et al. Butyric acid – a well-known molecule revisited. Prz Gastroenterol. 2017;12(2):83-89. doi: 10.5114/pg.2017.68342.

Bourassa MW, et al. Butyrate, neuroepigenetics and the gut microbiome: Can a high fiber diet improve brain health? Neurosci Lett. 2016 Jun 20;625:56-63. doi: 10.1016/j.neulet.2016.02.009.

Morrison DJ, Preston T. Formation of short chain fatty acids by the gut microbiota and their impact on human metabolism. Gut Microbes. 2016 May 3;7(3):189-200. doi: 10.1080/19490976.2015.1134082.

Ríos-Covián D, et al. Intestinal Short Chain Fatty Acids and their Link with Diet and Human Health. Front Microbiol. 2016 Feb 17;7:185. doi: 10.3389/fmicb.2016.00185.

Silva YP, et al. The Role of Short-Chain Fatty Acids From Gut Microbiota in Gut-Brain Communication. Front Endocrinol (Lausanne). 2020 Jan 31;11:25. doi: 10.3389/fendo.2020.00025.

The role of the microbiota: a delicate balance

The neurodegenerative diseases, like Alzheimer And Parkinson, also appear to be influenced by the intestine. The microbiota, that is, the set of microorganisms that populate our intestine, plays a fundamental role in communication with the brain through the microbiota-gut-brain axis. When this ecosystem is altered (dysbiosis), the production of metabolites beneficial to the body’s well-being also changes, promoting inflammation and contributing to the development of neurological disorders.

Barriers Weakening: A Journey from the Gut to the Brain

There dysbiosis It can damage the intestinal barrier, making it more permeable and allowing toxic substances to enter the blood. Similarly, the blood-brain barrier can also weaken. This double weakening facilitates the passage of inflammatory molecules and microorganisms to the brain, activating immune cells and promoting immune-mediated processes. neuroinflammation, a key element in the progression of neurodegenerative diseases. Three pathways are involved: nervous, endocrine and immune, which together form a continuous communication system between the intestine and the brain.

New therapeutic perspectives: the microbiota as a target

Recent research suggests that modifying the microbiota could help slow or mitigate neurodegenerative diseases. Stool samples from individuals with Parkinson’s disease reveal that levels of short-chain fatty acids, namely acetate, butyrate and propionate, show a marked decrease.

Approaches such as probiotics, prebiotics, postbiotics, fecal microbiota transplantation, and dietary modifications are showing promising results. In particular, the butyrate It is considered a postbiotic with a broad therapeutic profile, contributing to the maintenance of the integrity of the intestinal epithelium and the blood-brain barrier, intestinal motility and transit, anti-inflammatory effects, and neuronal function. Furthermore, can reverse cognitive decline, thus improving neurodegenerative processes. 

Despite the ongoing challenges, these therapies represent a new frontier in the understanding and management of neurodegenerative diseases.

For further information: 

Nie T, You L, Tang F, Duan Y, Nepovimova E, Kuca K, Wu Q, Wei W. Microbiota-Gut-Brain Axis in Age-Related Neurodegenerative Diseases. Curr Neuropharmacol. 2025;23(5):524-546.