Microbes Saving Lives and Reducing Suffering

Abstract

Given the overexploitation of the resources of planet Earth, due in large part to the ever-increasing human population (https://www.un.org/sustainabledevelopment/sustainable-consumption-production/), which has already compromised vital planetary processes (https://reports.weforum.org/docs/WEF_Business_on_the_Edge_2024.pdf), the limitations of which are encapsulated in planetary boundaries (Richardson et al. 2023; Gupta et al. 2024; https://www.pik-potsdam.de/en/news/latest-news/earth-exceed-safe-limits-first-planetary-health-check-issues-red-alert) and climate tipping points (Wunderling et al. 2023; Wunderling, von der Heydt, and Aksenov 2024), it would not be unexpected that a visitor from Mars might well be confused, or at least bemused, by our efforts to save lives and reduce morbidity. The Martian might be similarly bemused when it learned that although warfare is a constant feature of biosphere ecology, including human behaviour, with military personnel of opposing armies doing their best to kill one another, military physicians will try their best to save the lives of injured prisoners of the opposing side. But warfare and other activities of individuals and groups aimed at harming others notwithstanding, saving lives and preventing/reducing human suffering is an ingrained moral-ethical-humanitarian imperative (https://www.ohchr.org/sites/default/files/Documents/Publications/Factsheet31.pdf). While we cannot prevent death, we try hard to prevent avoidable, premature death and disease. But trying hard is not the same as succeeding (Kruk et al. 2018). This is reflected in the United Nations Sustainable Development Goal (SDG) 3 Ensure healthy lives and promote well-being for all at all ages which identifies major deficits in global healthcare and provides a roadmap to correct these deficits (https://sdgs.un.org/2030agenda).

The pursuit of saving lives and ameliorating human suffering is arguably the highest calling of humankind. Though generally considered to be the domain of clinicians—the healers—it clearly includes the endeavours of other health professionals, emergency responders, carers, parents–family–friends, the pharmaceutical industry, international organisations and a variety of non-governmental organisations. More indirectly it includes inter alia those of engineers, educators, the body politic and financial services. Microbial technologies, exemplified by vaccines and microbially inspired and produced pharmaceuticals and diagnostics, play a central role in the prevention, amelioration and curing of disease, saving millions of lives and reducing billions of cases of suffering every year (https://immunizationdata.who.int). Moreover, life-saving microbial technologies play out not only in the healthcare sector but also in wastewater and drinking water monitoring and treatment (Fowler and Smets 2017), food provision, bioremediation, etc. As a consequence, they rank very high among human endeavours to prevent and counter disease. Microbial technologies are thus central to the aims of SDG 3. Moreover, given that new life-threatening problems, such as diverse impacts of global warming (Lenton et al. 2023), have arisen and appropriate microbial technologies either exist or can be developed to contribute to their mitigation, the scope and scale of life-saving/−prolonging/−improving microbial solutions will continue to grow (Verstraete et al. 2022).

Despite this, microbes, if at all discussed in strategy documents, are usually mentioned only in the context of problems they pose (causing disease, food deterioration, materials corrosion, etc.), rarely as solutions they can provide for problems, and consequently are massively underexploited. Reasons for this include germophobia (the prevalent view of microbes as being dangerous germs, to be feared and therefore killed), their invisibility (out of sight, out of mind, which means they are not on the radar screens of most decision-makers) and the fact that their vital importance to the well-being of humanity, food plants and animals, climate, the biosphere is a relatively recent realisation that has not yet permeated the body of general knowledge. While this is slowly changing, time is not on our side in confronting pressing issues and crises which demand immediate implementation of effective solutions. We need to accelerate appreciation of the power of microbes to address problems and the deployment of relevant microbial technologies (Timmis, de Lorenzo, et al. 2017; Timmis, de Vos, et al. 2017).

In exhorting leaders and policy decision-makers to exploit microbial technologies to mitigate and solve major problems and global crises, we ask them to step outside of their comfort zones, enter the (for them) new information world of the microbiologist, see the bigger picture and engage in systems thinking. However, in order to be effective in this endeavour, we, the scientists and microbiologists, must also appreciate the wider context, be systems thinkers and communicate the bigger picture. But most of us only feel authoritative in discussing our own narrow field of activity, because our scientific training inhibits us from expressing opinions about issues the rigour of which we are not able to verify. This key element of scientific training, which guides our personal academic activities, can in fact promote ‘silo’ rather than systems thinking, and a reluctance to step outside of the comfort zones of our own specialities. The constant and justified exhortation to engage in inter- and trans-disciplinary research in which some of the most significant discoveries are to be made is only modestly successful, partly because of this and partly because of the difficulty of finding willing and capable assessors of grant applications for such projects and subsequent manuscript submissions, which as a consequence often result in unwarranted rejection, disappointment and discouragement to engage further in such research. Therefore, if microbiologists want society to take full advantage of the power and potential of currently unfamiliar microbial technologies, and for leaders and policy-makers to step outside their comfort zones and take the risk (for them) of implementing new solutions they only incompletely understand, we must ourselves step outside of our comfort zones and take the risk of engaging in conversations of broader issues.

The burden of disease is usually expressed in terms of disability-adjusted life years (DALYs): one DALY represents the loss of the equivalent of 1 year of full health. ‘DALYs for a disease or health condition are the sum of years of life lost (YLLs) due to premature mortality and years of healthy life lost due to disability (YLDs) due to prevalent cases of the disease or health condition in a population’. (https://www.who.int/data/gho/indicator-metadata-registry/imr-details/158#:~:text=DALYs%20for%20a%20disease%20or,%2C%20Sex%2C%20Cause%2C%20Risk%20factors). According to the World Health Organisation (WHO) report for 2020–21 (https://www.who.int/news-room/fact-sheets/detail/the-top-10-causes-of-death), cardiovascular, respiratory and infectious diseases were leading causes of death globally, with significant differences between low/medium income countries (LMICs) and high-income countries (HICs) (see also https://ourworldindata.org/burden-of-disease; https://www.healthdata.org/research-analysis/library/global-burden-disease-2021-findings-gbd-2021-study). Cancer and dementia are also important in HICs.

Microbes are centrally involved in initiation and progression of disease in some of these classes. However, and crucially, microbes and their activities can be harnessed to reduce disease so, for our discourse, the lens of predisposing parameters/risk factors of disease is of greatest interest because this reveals intervention options for detection-monitoring, prevention and treatment (Ezzati et al. 2002). Often, risk factors fall into the classes of too much (e.g., exposure to air pollution, untreated drinking water sources and unhealthy food) or too little (e.g., food, micronutrients and exercise). According to Ezzati et al. (2002), ‘In the poorest regions of the world, childhood and maternal underweight, unsafe sex, unsafe water, sanitation, and hygiene, indoor smoke from solid fuels, and various micronutrient deficiencies were major contributors to loss of healthy life. In both developing and developed regions, alcohol, tobacco, high blood pressure, and high cholesterol were major causes of disease burden’. It is also important to keep in mind that preventable human suffering also has many other causes, including poverty, abuse, warfare, migrations, trafficking, accidents, lack of education and, especially, global warming, some of which can be addressed with microbial technologies. In this discourse, we review these diverse health risk factors in the context of microbial causes, solutions and mitigation strategies with the aim of providing an integrated health-environment-humanitarian ecosystem perspective to promote a more systems approach to reducing human suffering.

The human microbiome consists primarily of microbial populations—microbiota—on the different body surfaces: skin, oral cavity, gastrointestinal (GI) tract, respiratory tract, ocular surface and genital tract. Some internal tissues/organs may also be colonised temporarily (e.g., blood following a cut or graze, after brushing the teeth; see also Tan, Ko, et al. 2023; Michán-Doña, Vázquez-Borrego, and Michán 2024) or longer term (e.g., tumour colonisation: Nejman et al. 2020). Each body site is characterised by unique physiological conditions that select microbiota of different compositions with different activities and interactions with host tissues—functionalities—and health consequences (McCallum and Tropini 2024). Most of these interactions are either positive or essential: they are the basis of the goods and services the microbiome contributes to the human-microbiome partnership.

In humans, aggression is expressed in different forms—physical and psychological—at different levels, in different circumstances, including abuse of the vulnerable, discrimination, demonisation of groups and nations, conflicts and warfare. It is often expressed in the context of political polarisation, in and out grouping and ‘othering’ (https://ethicsunwrapped.utexas.edu/glossary/in-group-out-group; Hitlin, Kwon, and Firat 2021), which are often exploited by individuals to gain and maintain personal power, influence and wealth. Comprehensive data on harm and suffering visited by humans on humans are lacking because of extremely low reporting. Data on warfare-violence lethality indicate that the number of premature deaths per 100,000 range between 50 and 500 (https://ourworldindata.org/grapher/global-death-rate-in-violent-political-conflicts-over-the-long-run; https://ourworldindata.org/war-and-peace; https://ourworldindata.org/grapher/deaths-in-armed-conflicts; https://www.dw.com/en/global-conflicts-death-toll-at-highest-in-21st-century/a-66047287; Rutar 2024). However, these numbers are those easily measured and just the tip of the iceberg because, as is the case for current conflicts in 2024, a large number of people not killed directly during the conflict experience all manner of injuries and deprivation, including the stress-anxiety of experiencing traumatic events (Alburez-Gutierrez et al. 2024), displacement and forced migration, poor access to food, hygiene, healthcare and medicines, education, etc., and human suffering, including grieving for lost family–friends and fragmentation of social groupings, that can translate into massive human suffering, initiation of new and exacerbation of existing health conditions including stress-anxiety-neuropsychiatric disorders, and poorer quality of life, all of which can result in premature death. The long-term effects on the young are not known but are significant. These, coupled with long-term interruptions in education, have life-changing consequences, analogous in some ways to those of ‘long Covid’. The global health impact of violence and aggression has not been quantified but it can be assumed that it is huge.

While warfare is all about killing and maiming personnel of the ‘other side’, prevention of loss of life and suffering, and healing of personnel of the ‘own side’ are also central elements of warfare. This latter includes vaccination of personnel against infections anticipated in theatres of war, and measures to reduce infections resulting from conditions of poor hygiene that are typically experienced, but also treating physical and mental injuries of affected military and civilian personnel (see also https://www.nato.int/cps/en/natohq/official_texts_224669.htm). Available microbial technologies relevant to treatment of physical injuries include antibiotics, microbially produced biocompatible wound dressings, and microbially derived promoters of wound healing (Rivero-Buceta et al. 2020; Canchy et al. 2023; Yin et al. 2024).

Since it is known that anxiety-stress are influenced by the gut microbiota, there may be opportunities for microbiota interventions that lessen the effects of, and accelerate recovery from, trauma-induced mental problems. Posttraumatic stress disorder (PTSD) in both combatants and civilians, especially the young, is a common outcome of war, developing in 15% of people exposed to trauma (https://www.who.int/news-room/fact-sheets/detail/post-traumatic-stress-disorder#:~:text=An%20estimated%203.9%25%20of%20the%20world%20population%20has%20experienced%20PTSD,conflict%20or%20war%20(3). However, almost 4% of the global population experience PTSD during their lifetimes, with rates particularly high following sexual violence. A recent study found that adolescents with PTSD had a distinct gut microbiome profile and lower microbial diversity compared to resilient individuals. Lower microbiome diversity was associated with more posttraumatic symptoms in early childhood, increased emotional and behavioural problems in adolescence, and poor maternal care-giving. The study also revealed less mother–child microbial synchrony in youth with PTSD, suggesting that reduced microbial concordance between mother and child may indicate susceptibility to posttraumatic illness. Importantly, when germ-free mice were transplanted with microbiomes from individuals with PTSD, they displayed increased anxiety behaviour, suggesting that the trauma-associated microbiome profile contributes to the anxiety component of PTSD. This important study highlights the potential role of the microbiome as a biological marker for PTSD risk and resilience, and suggests new avenues for microbiome-related diagnosis and treatment following trauma (Yirmiya et al. 2024).

Another relevant aspect of microbes in the context of warfare is the potential use of pathogens as weapons (Casadevall and Pirofski 2004; Oliveira et al. 2020; Gani Mir et al. 2022). While most countries have long abandoned microbial weapon research because of the lack of predictability and the logistics of handling and delivery, the relatively low cost of microbial weapons keep them as options for less technically advanced groups, especially terrorist groups. The anthrax attack of 2001 is one such example (Bush and Perez 2012). The COVID-19 pandemic was a timely reminder that the issue of biological warfare needs to remain in focus (Gostin and Nuzzo 2021). Microbial warfare research and development in most countries focuses on developing barriers—defensive strategies—which include early detection systems (Gani Mir et al. 2022) and response strategies that include new vaccines (Croucher 2024), phages, antibiotics, as well as handling strategies for delivery media: air, water, food, fomites.

The production and use of munitions is associated with environmental pollution which is harmful to health. Mapping and remediation of contaminated sites is thus essential and microbial biosensors for pollutant detection and bioremediation processes involving microbes and microbe–plant partnerships that degrade the pollutants is a promising option (Lewis, Newcombe, and Crawford 2004; van Dillewijn et al. 2007; Kalsi et al. 2020).

Violence and aggression may be characteristic of wars but are also generally prevalent in society and impact health (e.g., see Wang, Fu, et al. 2022). A report by the Organisation for Economic Cooperation and Development (OECD; https://www.oecd-ilibrary.org/docserver/health_glance-2017-8-en.pdf?expires=1726900577&id=id&accname=guest&checksum=5451ACDC424800864A175A53EF79BF20) identifies diet, smoking and alcohol consumption as playing important roles in global deaths, with violence, accidents and self-harm being important in ‘external’ causes of death. Alcohol consumption is sometimes linked to violence and abuse, which in turn are linked to physical and mental injuries. Alcohol consumption and substance abuse may also be linked to risk-taking, like dangerous driving, unsafe sex, etc., associated with higher probabilities of injury and suffering. Thus, violence and aggression are influenced by a range of factors that are networked and partly reinforcing and downward spiralling. Since these are in part behavioural in nature, their roots often lie in mental make-up/state, tendency to risk-taking, aggressivity, upbringing and other influences, some of which have been associated with the human microbiome.

One fascinating study has shown that the microbiome is implicated in aggressive behaviour in fruit flies (Grinberg et al. 2022) and a recent study from the same group demonstrated the microbiome also played a role in aggressive behaviour in a mouse model (Uzan-Yulzari et al. 2024). In both cases, germ-free or antibiotic-treated animals were more aggressive than their wildtype control. Surprisingly in both models, recolonization with bacteria (mono-colonisation in flies or faecal microbiota transplantation (FMT) in mice) caused aggression levels to return to normal. Changes in aggression levels were accompanied with changes in pheromone and metabolite levels and also changes in gene expression levels. The researchers also conducted an FMT experiment in mice with faecal material from 1 month-old human babies who had received antibiotics during the neonatal period, or not, and demonstrated again that antibiotic treatment in the infants increased aggression in the transplanted mice. Given that aggressive behaviour is responsible for a considerable amount of human suffering at all levels of society, from personal relationships, to road rage, to wars, the possibility of modulating it through targeted microbiota interventions should be considered. It is also worth noting that the gut microbiota is also implicated in substance abuse, so there may be opportunities for microbiota interventions to ameliorate its practice and effects (Kazemian and Pakpour 2024) (Table 1).

While everyday life experience varies enormously among individuals and communities, in general most of it is occupied by work or education and sleep, with the rest usually filled with household chores, meals and leisure-hobbies-sport (lifestyle), including and especially electronic and social media activities. In many settings, each of these three daily activities roughly take up about 8 h or an equal third of the day. While everyday life can be stimulating, fulfilling and enjoyable for many, it can be a battleground for others and, for some, home or work-school may represent confined spaces harbouring chronic stressors. This can create new or exacerbate existing neuropsychiatric disorders which can in turn worsen quality of life and work or education, and sleep experiences, which can then lead to a downward spiral. Some younger members of society who may be particularly concerned about global problems, like climate change, species extinctions-biodiversity loss and environmental degradation, and influenced by social media may be especially susceptible to development of such disorders. The U.K. National Health Service motto of Every mind matters (https://www.nhs.uk/every-mind-matters/mental-health-issues/) is an inspirational principle that should guide mental health policy and strategy everywhere.

The development of a new or improved technology to combat disease will often result from the targeted or untargeted discovery of a new or better biological product, activity or process. The microbial world, with its 3.8 billion year evolutionary history during which it biochemically and ecophysiologically explored a vast range of environments/substrates/energy sources, its huge phylogenetic diversity (one estimate suggests that there are one trillion species of microbes: Locey and Lennon 2016) and range of habitats colonised that are too hostile for most visible organisms, possesses an exceptional spectrum of activities and creates a vast range of chemicals and materials that greatly exceeds those of larger organisms. Prospecting the microbial world for new chemicals traditionally required their cultivation. Since only a tiny fraction could thus far be cultivated, there is a huge reservoir of functions remaining to be discovered. However, with genomics and metagenomics revealing potential functions of interest without cultivation, and recombinant DNA techniques permitting expression of such functions in culturable microbes (the cell factories; see below), the exploration, discovery and mining of new microbial products and functions is proceeding at an accelerating pace (Rodríguez et al. 2024; Van Goethem et al. 2024; Wang, Xiang, et al. 2024; Wang, Li, et al. 2024).

Key to the discovery of useful new products is the existence or development of selection systems and screens that access and identify what is sought. A simple screen deployed in early antibiotic discovery involved the ability of products secreted by potential producer organisms to inhibit test microbes. Microbes can now be engineered in a variety of ways to respond to a vast range of external signals that that identify sought products. Screens that target specific metabolic reactions/processes are particularly useful, especially combined with genomics/metagenomics to identify relevant protein:protein and protein:ligand interactions. This approach has been enormously simplified by the availability of the artificial intelligence-based AlphaFold protein structure prediction software (https://deepmind.google/technologies/alphafold/) and the ability to model the interacting interfaces (https://blog.google/technology/ai/google-deepmind-isomorphic-alphafold-3-ai-model/#life-molecules). Predicting interacting surface structures enables the identification of potential sites of action for the design of agonists and antagonists—drug candidates—that promote or prevent such interactions (see Timmis 2018; Abramson et al. 2024).

There are many microbial technologies that save lives but one of the most powerful and pervasive is the cell factory technology (Timmis and Hallsworth 2024). This is because it is highly versatile, can be deployed for so many applications, and is in constant evolution through the development of new genetic tools and the application of metabolic design and synthetic biology tools and strategies. A few examples are listed here for illustration.

Established microbial technologies, such as diagnostics, prophylaxes, drug production, wastewater treatment, agrobiologicals, processes to produce foods, food derivatives and supplements, etc., are powerful, applicable in many settings to solve diverse types of problem, and sustainable-environmentally friendly. They prevent many millions of premature mortalities and unnecessary morbidities and suffering. Newer applications show great promise. However, evaluating applications in microbiome science, because of the extreme variation in human microbiomes, and the difficulty of establishing evidence for efficacy, are challenging (see also Zmora et al. 2018; Suez et al. 2018). Compounding the complexity of microbiota design and intervention is the complexity of causes of and risk factors influencing many problematic disorders, particularly those in which the environment plays a role (e.g., chronic intoxication by environmental pollutants), and especially neuropsychiatric conditions. Nevertheless, microbiota analysis in diagnostics, and microbiota intervention prophylaxis and therapies undoubtedly have significant potential. Some approaches are likely to be extremely successful, whereas others will be unsuccessful or only partially successful, applicable to a smaller proportion of medical conditions. Unfortunately, because there is considerable commercial interest in some developing technologies, some research progress is occasionally accompanied by handwaving and hype, which raises unwarranted expectations in the public that may not be fulfilled and that may ultimately lead to unhelpful scepticism. Cornerstones of scientific research are rigour and caution in interpretation and prediction: hype has no place and must be discouraged. What we have attempted to do in this discourse is to display the range of current microbial technologies that are applicable to current and future global challenges, and to give a flavour of the even greater diversity of applications in the pipeline. This does not mean that all pipeline possibilities will ultimately realise their current apparent potential.

Global warming and associated climate change and extreme weather events are certainly a major, if not the greatest challenge, having pervasive negative impacts on health, ranging from direct effects of heat exposure, to loss of agricultural land resulting in reduced food production, ecosystem perturbations and losses, loss of living space causing human displacements to more crowded settlements, and so forth. When humanity goes extinct, and going extinct will be very much a health issue, global warming will be the most likely cause. Efforts to confront the multitude of health challenges of global warming obviously have to focus on reducing GHG emissions, increasing carbon capture and mitigating continued damage from the present climate threats.

The other major challenge is the increasing human population, which is also intertwined with global warming and is associated with a number of health issues, including those due to malnutrition resulting from insufficient availability of food. This means that food productivity needs to increase but, as we have indicated above, agrochemical-based increases in food production creates further health problems and is unsustainable. Humans will increasingly live more densely in urban settings, especially megacities, and will suffer from overcrowding, increasing susceptibility to infection and other diseases, increasing exposure to pollution, reducing microbiome diversity, etc., all of which will reduce their resilience to stress and disease (https://www.weforum.org/publications/global-risks-report-2024/digest/).

The aim of this discourse is not to be comprehensive and explore all possible microbial technologies that can help raise barriers to factors that promote human suffering. Rather it is to emphasise the exceptional range of challenges facing humanity and the applications and intervention opportunities available that can make a material difference in disease prevention, and to map them on the spectrum of processes that negatively impact human health, of the varied aspects of sustainability, ecosystem and planetary health, societal inequality, and of human activities and endeavours. It is imperative that current, and especially future, efforts are based on a much broader view of what negatively impacts health and how it can be countered. There is an urgent need to integrate comprehensively the diverse contributions to morbidity and mortality and the pivotal role of microbial technologies in healthcare strategies.

Microbial technologies are available to address many of the issues articulated in this discourse and indeed others. However, and crucially, it is essential to recognise that advances in medicine per se are important but will not significantly address the more fundamental challenges facing humanity (see also https://www.goinvo.com/vision/determinants-of-health/). Of course, although microbial technologies are key enablers of improved health for all, they can only achieve their potential in a conducive political, legislative and societal framework that inter alia seeks to protect the environment and biodiversity, and to conserve planetary health and resources (e.g., see Timmis and Ramos 2021; Gupta et al. 2024). To be perfectly explicit: microbial technologies save lives and reduce human suffering; increasing their deployment will save more lives; not increasing their deployment—either though ignorance or design—is condemning humans to unnecessary suffering with the personal responsibility that such decisions embody.

G.C. received honoraria from Janssen, Probi, Boehringer Ingelheim and Apsen as an invited speaker, and research funding from Pharmavite, Reckitt, Tate and Lyle, Nestle, Fonterra and is or has been a paid consultant for Heel Pharmaceuticals, Bayer Healthcare, Yakult and Zentiva. The other authors declare no conflicts of interest.