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Keymaster and gatekeeper microbiota: how food and cells lead us to disease directly form the gut

An international research team has established a link between gut microbiota and chronic inflammatory diseases such as arthritis. The team from Université Laval has discovered that a protein naturally present in the gut acts on the microbiota and causes the formation of molecules that exacerbate the symptoms of these diseases. The details of this finding are published now in the Journal of Clinical Investigation Insight. The protein in question, phospholipase A2-IIA, was discovered several years ago in the fluid that surrounds the joints of people with arthritis. The protein was subsequently detected elsewhere in the body, notably in the gut where it is produced in abundance. It took a long time before scientists realized that it exhibits antibacterial activity. The protein interacts little with the membrane of human cells, but it has high affinity for bacterial membrane sas well. S as it does on animal cells, it splits membrane lipids and releases free fatty acids.

To study the effect of this protein on gut microbiota, researchers used a line of transgenic mice. These mice have the human gene that codes for phospholipase A2-IIA. As they age, they spontaneously develop manifestations of chronic systemic inflammation. Experiments on these mice revealed that phospholipase alters the profile of bacterial lipids that end up in the gut. By releasing fatty acids from the bacterial membranes, the protein produces proinflammatory lipids that exacerbate chronic inflammation and increase the severity of arthritis symptoms in these mice In another article published simultaneously in the same journal, japanese researchers of the University of Tokyo demonstrated that the action of phospholipase on the gut microbiota of mice also affects psoriasis, another inflammatory disease, as well as skin cancer. These breakthroughs could have therapeutic implications, according to the scientists.

The work of both teams suggests that blocking the bacterial proinflammatory lipids produced in the gut by this protein could reduce symptoms in people with systemic inflammatory diseases. In the light of what has been said, this means that local inhibition of phospholipase with natural molecules or drugs may alleviate the inflammatory process that exacerbates certain diseases that recognize microbiota as a potential trigger, like rheumatoid artrhritis or multiple sclerosis. Either free unsaturated fatty acids and lyso-lpids may be reshaping microbiota and let it directly participate in the autoimmune response. In the meantime, they could trigger immune cells. Not all bacteria have a cellular membrane as first barrier. Gram-positive bacteria have peptidoglycan in the outer layer and this could make them resistant to phospholipase A2-IIA. Gram-negative bacteria, on the contrary, have a thick lipid and carbohydrate layer called lipopolysaccharide (LPS).

The enzyme might release from LPS fatty acids having the methyl-side “signature” typical for bacteria, priming immune cells for a dysregulated response. Eventual Gram-negative depauperisation in the gut, at least for most sensitive bacterial strains, is also an unbalancing factor for the local microbiota. Scientists know, indeed, that all autoimmune diseases are preceded by an important microbiota subversion; there might be known and unknown factors that cowork for the final onset of the disease. Diet is without doubt a concurrent factor: our daily diet leaves a genetic “signature” on the gut microbiota and its very shaping by food is among the known factors. Thus what we eat may determine our health and future predisposition for sickness. Its the final conclusion of Washington University School of Medicine. They found that eating more meat, having less of certain bacteria in the gut, and more of certain immune cells in the blood, all may converge toward multiple sclerosis (MS).

The team investigated the gut microbiome, immune systems, diet and blood metabolites in 49 volunteers, 24 healthy controls and 25 patients with MS and, to look for correlations that might be subtle but important. Food quality was central for the study and the strongest systemic linkage the researchers found involved eating red meat. Their analysis linked higher meat consumption to a decrease in people’s gut composition, especially in the population of Bacteroides thetaiotaomicron strain. B. thetaiotaomicron is associated with digesting fibers from vegetables, which have a notorious beneficial effects on the gut, derived by the production of short-chain fatty acids (SCFAs). These metabolites have been shown to righteously help immune system to avoid deregulation toward autoimmunity. Higher meat consumption, which was observed in the MS patients, was also linked to an increase in T-helper 17 lymphocytes in the immune system, and an increase in S-adenosyl-L-methionine (SAM) in their blood.

This metabolite is known to regulate processes like protein and DNA methylation. These post-translational changes are the main driver for cellular maturation and differentiation. DNA methylation, in particular, is central for gene expression or silencing. It is speculative that SAM increase in MS patients’ blood has something to do in promoting a wrong gene expression in immune cells. The relationship between meat eating and disability and the other factors was not deterministic in this research; some healthy people eat a lot of meat yet they won’t develop MS. But the pattern of all the factors was suggestive that, in MS, something goes wrong with people’s gut bacteria that dissociates them from the immune system, leading to heightened T-helper 17 lymphocytes and autoimmune attacks against myelin. And there is a undeniable association with meat eating. It would be interesting to discover what is the causal (molecular) factor(s) linking eating red meat and the higher vulnerability for multiple sclerosis.

  • Edited by Dr. Gianfrancesco Cormaci, PhD, specialist in Clinical Biochemistry.

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Scientific references

Doré E et al. JCI Insight. 2022 Jan 25; 7(2):e152638.

Miki Y et al. JCI Insight. 2022 Jan 25; 7(2):e152611.

Shah S, Locca A et al. EBioMed 2021; 71:103577.

Daberkow DP et al. Curr Protoc. 2021; 1(12):e314.

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Dott. Gianfrancesco Cormaci

Medico Chirurgo, Specialista; PhD. a CoFood s.r.l.
- Laurea in Medicina e Chirurgia nel 1998 (MD Degree in 1998) - Specialista in Biochimica Clinica nel 2002 (Clinical Biochemistry residency in 2002) - Dottorato in Neurobiologia nel 2006 (Neurobiology PhD in 2006) - Ha soggiornato negli Stati Uniti, Baltimora (MD) come ricercatore alle dipendenze del National Institute on Drug Abuse (NIDA/NIH) e poi alla Johns Hopkins University, dal 2004 al 2008. - Dal 2009 si occupa di Medicina personalizzata. - Guardia medica presso strutture private dal 2010 - Detentore di due brevetti sulla preparazione di prodotti gluten-free a partire da regolare farina di frumento enzimaticamente neutralizzata (owner of patents concerning the production of bakery gluten-free products, starting from regular wheat flour). - Responsabile del reparto Ricerca e Sviluppo per la società CoFood s.r.l. (Leader of the R&D for the partnership CoFood s.r.l.) - Autore di articoli su informazione medica e salute sul sito www.medicomunicare.it (Medical/health information on website) - Autore di corsi ECM FAD pubblicizzati sul sito www.salutesicilia.it
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