Pathogens and Humanity – what next?

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For centuries humans have experienced a shortening of their life’s potential due to infection and trauma – in most cases the end being brutal and fast. In the Western world through various changes to public health, medicine and diplomacy, these risks have significantly reduced – and until recently, were viewed with complacency.

Rather, the wealthier and developing countries have extended lifespan and morbidity time frames, by leading lifestyles that kill us less dramatically, but erode capability and function through the development of non-communicable diseases (NCD). This has created a modern risk profile where NCD burden meets infection that care, and medical expertise has struggled to compress to a more familiar profile.

Bacteria as enemies

Interestingly, the risk of medicine induced disease complications through the inappropriate use of antibiotics in the food chain and medicine, is the next progressive inducer of accelerated death. Antibiotic-resistant infections directly killed 1.2million people globally in 2019 and are estimated to have been involved in a further 4 million, about 500,000 more than the loss related to Covid in 2021. In the UK a conservative estimate indicates about 5,000 deaths a year are attributable. Resistance to two types of antibiotics, fluoroquinolones and beta-lactam considered the ‘first line of defence’ against severe infections accounted for 70 per cent of the global death toll.[1]

The authors estimated disease burden for 23 pathogens and 88 pathogen–drug combinations in 204 countries and territories in 2019 on the basis of two counterfactual scenarios: one in which all drug-resistant infections were replaced by drug-susceptible infections, and one in which all drug-resistant infections were replaced by no infection. Using this method, the study directly addresses the difference between burden associated with resistance, and burden attributable to resistance.

Bacteria it seems are not retreating from being a global challenge, albeit virus’s have been front and centre for the last 2 years, infectious disease is a significant problem for which medicine has a limited and diminishing range of answers. Bacterial antimicrobial resistance (AMR)—which occurs when changes in bacteria cause the drugs used to treat infections to become less effective, has emerged as one of the leading public health threats of the 21st century.

Bacteria as friends

The hoped for move towards Sars-Cov-2 endemicity has to do with reaching a dynamic equilibrium where on average one person infects one other person. This could include seasonality or other fluctuations. However, endemicity does not imply mild disease, and mild disease does not imply endemicity. The relatively stable presence of an endemic disease is a world away from the unpredictable spikes and surges of the current pandemic, in which the global exposure yet to be contained leaves some high levels of uncertainty.

For the avoidance of doubt, Omicron is not globally endemic right now in much the way as the moon is not made of cheese.

Yet whilst Covid is a viral related series of symptoms, there is a clear relationship between bacteria and the ability to resist, manage or thrive in the face of Sars-Cov-2 infection. Dysbiosis appears to be a significant contributory factor in the severity of Covid infection and others, as the resident bacteria regulate our immune system and response to infections and behavioural events, that contribute to NCD development.
The gut microbiota play a vital role in protecting the body from pathogens and in regulating immune responses to infections, and that seems to be the case for Covid. Trillions of bacteria, fungi, viruses and other single-celled organisms reside in the gastrointestinal tract in a dynamic, commensal ecosystem. And each of us harbours our own unique community. When our gut microbiota are in a diverse but healthy and balanced state, they support the proper functioning of our immune system. When the balance is perturbed—‘dysbiosis’—our defences are compromised, and we are more susceptible to infections, inflammation and disease generation.

In one study of 100 patients hospitalised with Covid, researchers determined that microbiome diversity was reduced compared to pre-pandemic patients, regardless of medication history.[2] The species missing are involved in managing excessive immune responses, indicating that Sars-Cov-2 has some direct effect of microbiome survival. This dysbiosis can in turn contribute to a change in the barrier, becoming hyperpermeable, reducing SCFA production and allowing lipopolysaccharides to transfer to the blood stream. This can evolve the gut lung axis into a transfer of molecules of activation, resolving or prolonging the symptoms.[3]

Probiotics

Currently there are at least 10 international trials exploring the therapeutic role of probiotics in treating people with Covid. A recent pre-review study with 182 participants suggests that the well-known probiotic ‘LGG’ is well-tolerated and is associated with prolonged time to development of COVID-19 infection, reduced incidence of symptoms, and changes to gut microbiome structure when used as post-exposure prophylaxis within 7 days after exposure.[4] Meaning LGG probiotic may protect against the development of symptoms when used as post-exposure prophylaxis within 7 days after COVID-19 exposure, sustaining immune modulation and reducing risk of hyperpermeability.

Further work from Addenbrookes Hospital has demonstrated how lactic acid bacteria and chicory inulin combine to reduce symptom severity and also enhance recovery post infection.[5]

SARS-CoV-2, the coronavirus that causes Covid-19, will continue to change and produce new variants. The primary point of entry is of course via the mucosal tissues. The mucosal surfaces such as in the lungs and gut play an essential role in the modulation of the immune responses, by combating pathogenic microorganisms and avoiding excessive inflammation or tissue damage.

This fine tuning of the local immunity is also dependent on the equilibrium of the local microbiota supported by exogenous bacteria and compromised by antibiotics, while a breakdown in the mucosal tolerance together with a dysbiotic condition may favour the establishment and progression of infections, such as that caused by SARS-CoV-2 virus as well as NCDs.

Prevention and management

The regular consumption of a probiotic such as LGG increasingly seems a safe and supportive action, especially where exposure to infection or risk from serious consequences of infection are raised. It also implies that eubiosis, induced by probiotics in the face of antibiotic induced dysbiosis may have immune related benefits for NCD management as well as infectious events.[6]

Vitamin D continues to benefit from research with the Royal Society in the UK stating ‘We urge UK and other governments to recommend vitamin D supplementation at 800–1000 IU/day for all, making it clear that this is to help optimise immune health and not solely for bone and muscle health’. However, experience shows that its easier to persuade a population to pursue a passive immune intervention, than it is to encourage a daily active intervention.

The role of Vitamin K a synergistic nutrient with Vitamin D is also finally receiving the recognition of the role it plays along with D and A in the management of immune responses, especially with Covid.[7] Some years ago a review piece discussed the importance of vitamins D,A,K and E in the generation and management of tolerance in mucosal tissues, it seems that slowly science is catching up – how long before people and governments understand that food and its constituents are essential for a healthy and capable immune response to infections and NCDs?
Membrane lipid replacement represents a plausible strategy for enhancing immune capability and assisting in the recovery from fatigue and other symptoms people experience after infection. A recent (Dec 21) review paper in the journal Membranes teases out the mechanisms and application for this approach to care.[8]

References
[1] Laxminarayan R Duse A Wattal C et al. Antibiotic resistance—the need for global solutions. Lancet Infect Dis. 2013; 13: 1057-1098
[2] Yeoh YK, Zuo T, Lui GC, Zhang F, Liu Q, Li AY, Chung AC, Cheung CP, Tso EY, Fung KS, Chan V, Ling L, Joynt G, Hui DS, Chow KM, Ng SSS, Li TC, Ng RW, Yip TC, Wong GL, Chan FK, Wong CK, Chan PK, Ng SC. Gut microbiota composition reflects disease severity and dysfunctional immune responses in patients with COVID-19. Gut. 2021 Apr;70(4):698-706.
[3] de Oliveira GLV, Oliveira CNS, Pinzan CF, de Salis LVV and Cardoso CRB (2021) Microbiota Modulation of the Gut-Lung Axis in COVID-19. Front. Immunol. 12:635471
[4] Paul E. Wischmeyer, Helen Tang, Yi Ren, Lauren Bohannon, Zeni E. Ramirez, Tessa M. Andermann, Julia A. Messina, Julia A. Sung, David Jensen, Sin-Ho Jung, Alexandra Artica, Anne Britt, Amy Bush, Ernaya Johnson, Meagan V. Lew, Hilary M. Miller, Claudia E. Pamanes, Alessandro Racioppi, Aaron T. Zhao, Neeraj K. Surana, Anthony D. Sung. Daily Lactobacillus Probiotic versus Placebo in COVID-19-Exposed Household Contacts (PROTECT-EHC): A Randomized Clinical Trial medRxiv 2022.01.04.21268275;
[5] Thomas R, Aldous J, Forsyth R, Chater A, Williams M (2021) The Influence of a blend of Probiotic Lactobacillus and Prebiotic Inulin on the Duration and Severity of Symptoms among Individuals with Covid-19. Infect Dis Diag Treat 5: 182.
[6] Patangia, D. V., Anthony Ryan, C., Dempsey, E., Paul Ross, R., & Stanton, C. (2022). Impact of antibiotics on the human microbiome and consequences for host health. MicrobiologyOpen, 11, e1260
[7] Visser MPJ, Dofferhoff ASM, van den Ouweland JMW, van Daal H, Kramers C, Schurgers LJ, Janssen R and Walk J (2022) Effects of Vitamin D and K on Interleukin-6 in COVID-19. Front. Nutr. 8:761191.
[8] Nicolson, G.L.; Ferreira de Mattos, G.; Ash, M.; Settineri, R.; Escribá, P.V. Fundamentals of Membrane Lipid Replacement: A Natural Medicine Approach to Repairing Cellular Membranes and Reducing Fatigue, Pain, and Other Symptoms While Restoring Function in Chronic Illnesses and Aging. Membranes 2021,

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