1. Prebiotics, Probiotics, Paraprobiotics, Postbiotics and Synbiotics

The term “probiotic” was adopted in 2001 at an International Meeting of Experts under the auspices of the World Health Organization (WHO) and the Food and Agriculture Organization (FAO) and was subsequently revised in 2014. Definition of “probiotics” includes all micro-organisms that are beneficial to the health of the host when used in the appropriate dose ^[1], with capacity of survival in the gut without the danger of transferring elements of pathogenicity, antibiotic resistance, and toxicity.

Presently, probiotics are the subject of comprehensive research to design innovative products, effective marketing, regulation, and rigorous control, and to support consumer interest and safety in prescribing the product by healthcare practitioners. Most probiotic strains represented by the species of lactic acid bacteria, bifidobacteria and yeasts, present on the consumer market are considered to be safe for use in food and as supplements. 

The differences between “paraprobiotics” and “postbiotics” are that paraprobiotics are considered lifeless or inoperative probiotic cells, while “postbiotics” are tonic metabolites of probiotics, both with common origins that are widely studied in functional biotics. Postbiotics have multiple benefits over conventional probiotics, through the molecular structure, which is already known, are used in purified compounds, have a specific activity, and intervene more easily on microbe-associated molecular pattern (MAMP), i.e., on MAMP-PRR to promote the downstream path. Another difference is that they are easy to make industrially through easy processes of production, packaging, transport, storage, administration etc. ^[2].

2. Probiotics in the Management of Various Pathologies

2.1. Probiotics in Digestive Tract Pathology

Antibiotics can cause a microbial imbalance in the gut resulting in antibiotic-associated diarrhea (AAD). Probiotics can prevent AAD by rebalancing the intestinal microflora, repairing the intestinal barrier, etc. Probiotics are increasingly used to prevent and treat diarrheal disease more in children than in adults.

2.2. Probiotics in Pulmonary Viral Infections

The pulmonary microbiota plays a particularly important role in preserving the homeostasis of the respiratory system, to promote and preserve a state of immune tolerance, to prevent an unwanted inflammatory reaction after inhalation of harmless environmental agents. This activity is supported by an indestructible and permanent link between the microbiota and the immune cells in the lungs, which through specialized sensors detect invasive micro-organisms ^[3].

Changes in the lung microbiome through which dysbiosis can occur, will influence the host’s immunity and defense; understanding these complex interactions between the host and the pathogen elucidates the pathogenesis of chronic lung disease ^[4]. Probiotics can be a valuable alternative for preventing and ameliorating respiratory tract infections with viral agents, which cause so many diseases in children and adults.

2.3. Probiotics and COVID-19

Balancing the intestinal microbiota during and after viral infections can be achieved with the help of probiotics that adhere and line the intestinal mucosa, constituting a strong barrier against pathogens and at the same time, activate the immune system. When an infection occurs in the lungs, the alarm signals are transmitted from the lung to the intestine on the lung-gut axis and from there, the information is transmitted further to the central nervous system (brain) on the gut–brain axis, to stop the inflammatory processes. These data are processed in the cerebral cortex and sent back on the brain–lung–intestine axis, so that the defense processes are implemented; in this way, the microbiota, through its bacterial complexity, mobilizes itself to defend the lung.

Probiotics and their mechanisms of action in the prevention and treatment of respiratory diseases, could bring great benefits in the COVID-19 pandemic. In an experiment conducted by Harata et al. on BALB/c mice infected with influenza virus IFV A/PR/8/34 (H1N1), who were administered intranasally the probiotic LGG, it was found that LGG reduced the respiratory symptoms, increased survival rate compared to the control group and improved the immune responses by increasing the activation of natural killer (NK) lung cells ^[5].

3. Photobiomodulation Applied on the Gut–Lung–Brain Axis

Scientific basis for the use of light in clinical medical applications originated at the beginning of the last century in Niels Ryberg Finsen’s first successful experiments ^[6] on smallpox in red light (1893) and further in 1895, on the treatment of Lupus vulgaris (also known as tuberculosis luposa ^[7]), i.e., painful cutaneous tuberculosis skin lesions with nodular appearance.

Presently, lots of therapeutic techniques that employ low-level laser or LED light limited to a specified set of wavelengths from red to near-infrared, and for some special applications even ultraviolet (UVB), proved to be safe, with no known side effects, used to relieve pain or to heal wounds, ulcers, and to treat many different diseases and disorders under the term of photobiomodulation or PBM, as it stimulates and enhances cell function.

Circadian clocks have proven to be particularly important for human physiology adapted to the light-dark cycle of 24 h, so that a person’s sleep habits, eating patterns and diet can desynchronize the body’s clocks and can contribute to the onset of non-communicable diseases ^[8][9]. External optical signals captured by optical photoreceptors are processed and activate the expression of circadian genes in the central nervous system, influencing molecular clocks and having major implications for some diseases ^[10]. The spectral quality of the sun modulates our neurotransmitters, and our health suffers because contemporary life often lacks strong daily circadian stimuli ^[11].

There is a permanent feedback between probiotics, microbiota, immune system, neuroendocrine, and nerve cells, the intestine–brain axis being significant.

Reasonable dietary fiber consumption and probiotics improve the balance of the intestinal microbiota by stimulating the production of short-chain fatty acids, important for the body’s energy and inflammatory reactions and response, regulating hunger, nutritional status, and body weight, insulin response and energy storage in the liver and muscles ^[12].

The pioneering of laser medicine (low-level laser applications that is, current photobiomodulation or PBM), is due to the doctor Endre Mester (1903–1984) who immediately after the discovery of the first operational laser, began in 1967 his applications on cutaneous neoplasms; and thus, he discovered the positive biological effects, which were then used successfully in the alternative treatment of various medical conditions ^[13].

Depending on the dose of radiation (light) applied, the cellular response will be different, so that low doses of energy will have beneficial, positive, stimulating effects; and, exactly the opposite, for high doses, which will be inhibitory; so, this is the biphasic dose response.

PBM can modulate oxidative stress (in certain cells with low ROS levels, it increases ROS synthesis; and in other cases, it reduces the oxidative stress), reduces the reactive nitrogen species, the prostaglandins levels, and it regulates the NF-kB pathway, it decreases the inflammatory markers in activated inflammatory cells, leading to an overall reduction in inflammation, effects particularly important for respiratory dysfunctions, musculoskeletal system disorders, brain and intestinal tract ^[14].

4. Photobiomodulation and COVID-19

Coupled complex PBM and probiotic interventions can adjust the microbiome, improve the activity of the immune system, and save the lives of people with immune imbalances, as in the model suggested in Figure 1.

Figure 1. Probiotics, photobiomodulation, and the microbiome in COVID-19.

Figure 1 shows a model of the abscopal effect of PBM on the human microbiome and the relationship between probiotics, the immune system, and diseases affecting the host.

Probiotics may have the ability to modulate exacerbated immune responses, such as the COVID-19 cytokine storm. Targeting the SARS-CoV-2 cytokine storm using PBM and probiotics could be a useful treatment choice.

In the case of COVID-19, PBM could influence the balance between anti-inflammatory and pro-inflammatory cytokines, leading to the resolution of the infectious disease.

Table 1 shows the effects of PBM in the action on probiotics ^[15], followed by a series of experimental animal studies ^{[16][17][18][19][20]}, in vitro and/or in vivo cellular models ^{[21][22][23][24]}, including the latest clinical trials in patients with COVID-19 ^[25][26], which demonstrates the perspective applications of PBM for the targeting and modulation of the microbiome ^{[16][27][19][20]}, with also the enrichment of the functional genes ^[19], the immune system ^[28][27][17], the auxiliary control of chronic degenerative diseases and viral infections ^{[22][24][25][26]}, as a challenge for future research in the 21st century (see also Figure 1).

Table 1. Effects of photobiomodulation on microbiome and disease management.