Gut microbes produce compounds that prime immune cells to destroy harmful viruses in the brain and nervous system

0
102

Gut microbes produce compounds that prime immune cells to destroy harmful viruses in the brain and nervous system, according to a mouse study published today in eLife.

The findings suggest that having healthy and diverse microbiota is essential for quickly clearing viruses in the nervous system to prevent paralysis and other risks associated with diseases such as multiple sclerosis.

A condition that causes progressive damage to nerve cells, multiple sclerosis has become more common over the past several decades.

Viral infections in the brain or spinal cord are thought to trigger this disease.

Some scientists believe that changes in the way we eat, increased sanitation or growing antibiotic use may be causing detrimental changes in the helpful bacteria that live within the human body, potentially increasing the risk of multiple sclerosis and other related diseases.

“We wanted to investigate whether gut microbes could alter the immune response to a virus in the central nervous system and whether this affects the amount of damage the virus causes,” says one of the lead authors David Garrett Brown, a graduate research assistant in the Department of Pathology at University of Utah Health, Salt Lake City, US.

To do this, Garrett Brown and co-lead author Ray Soto looked at the effect of Mouse Hepatitis Virus, a virus that infects cells in the mouse nervous system and causes multiple-sclerosis type symptoms, on two groups of mice: some with normal gut microbes and some that were bacteria-free.

They found that bacteria-free mice had a weak immune response, were unable to eliminate the virus and developed worsening paralysis, while those with normal gut bacteria were better able to fight off the virus.

Mice treated with antibiotics before the onset of disease were unable to defend themselves.

They also had fewer immune cells called microglia, which help flag viruses for destruction by other immune cells.

Next, the team identified compounds produced by gut bacteria that might help the microglia.

When they administered these helpful compounds to the bacteria-free mice, they saw that the animals were protected from neurologic damage caused by the virus.

“We’ve shown that gut microbes protect infected mice from paralysis by turning on a specific pathway in central nervous system cells,” explains June Round, Associate Professor in the Department of Pathology at University of Utah Health, and a co-senior author alongside Professor Thomas Lane, from the same department.

“This suggests that signals from microbes are essential to quickly clear viruses in the nervous system and prevent damage from multiple sclerosis-like diseases.

Our results emphasise the importance of maintaining a diverse community of bacteria in the gut, and that interventions to restore this community after taking antibiotics may be necessary.”


The microbiota consists of a multispecies microbial community living within a particular niche in a mutual synergy with the host organism.

Besides bacteria, the microbiota includes fungi, archaea, and protozoans (12), to which viruses are added, which seem to be even more numerous than microbial cells (3).

The gastrointestinal tract (GIT), with its epithelial barrier with a total area of 400 m2, is a complex, open, and integrated ecosystem with the highest exposure to the external environment.

The GIT contains at least 1014 microorganisms belonging to >2,000 species and 12 different phyla, the associated microbiome containing 150- to 500-fold more genes than the human DNA (147).

The GIT microbiota exhibits a huge diversity, being individually shaped by numerous and incompletely elucidated factors, such as host genetics, gender, age, immune system, antropometric parameters, health/disease condition, geographic and socio-economical factors (urban or rural, sanitary conditions), treatments, diet, etc. (89).

Recent metagenomic data demonstrated that the majority of component species is not present in the same time and in the same person, but, however, few species are abundant in healthy individuals, while other species are less represented (47).

In addition to the distribution along the digestive tract segments, the GIT microbiota of the three distinct transversal microhabitats, i.e., floating cells in the intestinal lumen, cells adherent to the mucus layer and respectively to the surface of the epithelial cells, is also different (3).

gastrointestinal tract (GIT), with its epithelial barrier with a total area of 400 m2, is a complex, open, and integrated ecosystem with the highest exposure to the external environment.

The GIT contains at least 1014 microorganisms belonging to >2,000 species and 12 different phyla, the associated microbiome containing 150- to 500-fold more genes than the human DNA (147).

The GIT microbiota exhibits a huge diversity, being individually shaped by numerous and incompletely elucidated factors, such as host genetics, gender, age, immune system, antropometric parameters, health/disease condition, geographic and socio-economical factors (urban or rural, sanitary conditions), treatments, diet, etc. (89).

Recent metagenomic data demonstrated that the majority of component species is not present in the same time and in the same person, but, however, few species are abundant in healthy individuals, while other species are less represented (47).

In addition to the distribution along the digestive tract segments, the GIT microbiota of the three distinct transversal microhabitats, i.e., floating cells in the intestinal lumen, cells adherent to the mucus layer and respectively to the surface of the epithelial cells, is also different (3).

Recent findings suggest that the microbial colonization of the GIT starts before birth, as revealed by the placental microbiome profile, being composed of members of Firmicutes, Proteobacteria, Tenericutes, Bacteroidetes, and Fusobacteria groups, which were found to share some similarities with the human oral microbiome (10).

Also, the meconium of full term infants is not sterile, harboring 30 genera normally found in the amniotic fluid, vagina, and the oral cavity (8911).

We can assume that the bacteria reach these sites mainly from the vaginal tract, although selective translocation is also possible.

Archaea were also detected in the vaginal microbiota of pregnant women, accounting for a mother-to-child transmission (12).

Vaginally born infants have a microbiota containing species derived from the vaginal microbiota of their mothers. Conversely, in the case of cesarean section delivered babies, the microbiota is similar to the skin microbiota and is rich in Propionibacterium spp. and Staphylococcus spp. (13).

It is generally accepted that the pregnancy period and the first 1,000 days after birth are the most critical timeframes for interventions and any modulation made at this point has the potential to improve child growth and development (14).

Delivery mode seems to influence immunological maturation through microbiota development. Cesarean section delivered children were found to have a higher number of antibody-secreting cells (11).

Furthermore, the human milk is involved in the GIT microbiota and immune system development. In addition to its nutritional components, this natural functional food contains numerous bioactive substances and immunological components that control the maturation of the newborn intestine and the composition of the microbial community.

Numerous studies revealed that breast-feeding has a protective role in infants, conferred by a complex mixture of molecules, including lysozyme, sIgA, alpha-lactalbumin, lactoferrin, but also free oligosaccharides, complex lipids, and other glycoconjugates (14).

The proteolytic processing of glycoprotein k-casein, with the release of glycomacropeptides, prevents colonization of the gut by pathogens, through competition with the receptors of the gut epithelial cells in breast-fed infants.

Lactoferricin is a potent antimicrobial agent, explaining the decreased infant death rate caused by gastrointestinal and respiratory infections in breast-fed infants (1415).

Moreover, breast milk contains ~109 bacterial cells/L (16) and prebiotic oligosaccharides (fructans) which stimulate the multiplication of Bifidobacterium spp. and Lactobacillus spp., while follow-on milk powder stimulates proliferation of enterococci and enterobacteria (1718).

As the infant grows, solid foods are introduced, therefore the microbiota diversity increases, and the microbiota community evolves toward the adult-like state.

Although some dominant enterotypes represented by Bacteroides, Prevotella, and Ruminococcus genera are recognized, however, the final composition of the adult microbiota is unique and the factors guiding this feature are still a matter of debate (19).

The very active microbial community has been shown to mutually interact with the host and to exert a lot of beneficial roles, explaining its tolerance by the host organism.

The GIT microbiota is involved in energy harvest and storage, and, due to its particular metabolic pathways and enzymes, it extends the potential of the host metabolism. This property is believed to exhibit a potent evolutionary pressure toward the establishment of bacteria as human symbionts (11).

The GIT microbiota influences the normal gut development, due to its ability to influence epithelial cell proliferation and apoptosis of host cells.

Although the intimate interactions between microbiota and host cells are widely unknown, a major mechanism seems to involve short-chain fatty acids (SCFA), resulted from the fermentation of indigestible polysaccharides (fibers), such as butyrate, acetate, and propionate with an important anti-inflammatory role. SCFAs also support intestinal homeostasis in the normal colon, by aiding intestinal repair through the promotion of cellular proliferation and differentiation.

However, SCFAs seem to inhibit the cancerous cells proliferation.

Among the different SCFAs, butyrate has a paramount role in intestinal homeostasis due to its role as a primary energy source for colonocytes (2021).

In addition, the GIT microbiota stimulates the nonspecific and specific immune system components development, just after birth and during the entire life and it acts as an antiinfectious barrier by inhibiting the pathogens’ adherence and subsequent cellular substratum colonization and by the production of bacteriocins and of other toxic metabolites.

Moreover, the microbiota is predominantly composed of anaerobes which prevent the process of translocation of aerobic/facultatively anaerobic bacteria and the consecutive systemic infections in immunodeficient individuals.

Importantly, some GIT microbiota representatives (Escherichia coli and Bacteroides fragilis) are involved in the synthesis of vitamins, such as B1, B2, B5, B6, B12, K, folic acid, and biotin. Also, the GIT microbiota has the ability to degrade xenobiotics, sterols and to perform biliary acids deconjugation (B. fragilis and Fusobacterium spp.) (19).

All these aforementioned effects are occurring when the microbiota community is characterized by an interspecies balance, known as eubiosis.

Any perturbation of eubiosis, known as dysbiosis, could become a pivotal driver for various infectious and non-infectious diseases, each of them with specific microbiota signatures that can further trigger pathophysiologies in different organs (11).

Our aim was to review these physiological roles, focusing on one side the GIT microbiota contribution to the immune system development and education, and on the other side, to what is happening when eubiosis is replaced by the dysbiosis status; in this case the immunostasy is altered, the host becomes more susceptible to infections, both exogenous and endogenous; immunotolerance is affected and the immune system will react against the self-components (autoimmunity), or vary in intensity, being either over (allergic reactions and chronic inflammation) or less/inappropriately (immunodeficiency and cancer) activated.


More information: D Garrett Brown et al, The microbiota protects from viral-induced neurologic damage through microglia-intrinsic TLR signaling, eLife (2019). DOI: 10.7554/eLife.47117

Journal information: eLife
Provided by eLife

LEAVE A REPLY

Please enter your comment!
Please enter your name here

Questo sito usa Akismet per ridurre lo spam. Scopri come i tuoi dati vengono elaborati.