The role of soils in provision of genetic, medicinal and biochemical resources

Abstract

Intact, ‘healthy’ soils provide indispensable ecosystem services that largely depend on the biotic activity. Soil health is connected with human health, yet, knowledge of the underlying soil functioning remains incomplete. This review highlights selected services, i.e. (i) soil as a genetic resource and hotspot of biodiversity, forming the basis for providing (ii) biochemical resources and (iii) medicinal services and goods. Soils harbour an unrivalled biodiversity of organisms, especially microorganisms. Some of the abilities of autochthonous microorganisms and their relevant enzymes serve (i) to improve natural soil functions and in particular plant growth, e.g. through beneficial plant growth-promoting, symbiotic and mycorrhizal microorganisms, (ii) to act as biopesticides, (iii) to facilitate biodegradation of pollutants for soil bioremediation and (iv) to yield enzymes or chemicals for industrial use. Soils also exert direct effects on human health. Contact with soil enriches the human microbiome, affords protection against allergies and promotes emotional well-being. Medicinally relevant are soil substrates such as loams, clays and various minerals with curative effects as well as pharmaceutically active organic chemicals like antibiotics that are formed by soil microorganisms. By contrast, irritating minerals, soil dust inhalation and misguided soil ingestion may adversely affect humans.

This article is part of the theme issue ‘The role of soils in delivering Nature’s Contributions to People.

1. Introduction

Soils are—in the best sense of the word—the basis of all terrestrial life. They perform highly relevant and indispensable ecosystem functions, thus providing humans with numerous ecosystem services [1]. These services can be categorized as follows [2–4]:

• Provisioning services: Food web support through products received from soil such as food, fuel, fibre and fresh water.

• Regulating services: Processes in soil that contribute to the status of other environmental compartments, i.e. filtration, storage and transformation of substrates, thus contributing to nutrient and carbon cycling and sequestration, pest and pathogen control and plant growth promotion, water storage and purification, degradation of pollutants, greenhouse gas exchange and climate regulation, erosion control etc.

• Archive and cultural services: Soils are an archive of landscape and human history. People obtain non-material benefits from ecosystems through spiritual enrichment, cognitive development, reflection, recreation and aesthetic experiences.

• Habitat services: Soils are hotspots and preservers of biodiversity and genetic resources as well as providers of living space and ground for all terrestrial organisms, including humans, with all their soil-related activities.

The contribution of soils to ecosystem services and human welfare is more and more recognized and valued, e.g. by initiatives such as the global UN Sustainable Development Goals and UN-FAO Global Soil Partnership [5]. Nonetheless, our understanding is still limited on how soil ecosystems function and how they are interlinked and exchange with other parts of the ecosphere [6]. This especially applies to the vast diversity of habitats, species and genes contained within the soil [7], providing a correspondingly large functional diversity [8,9]. This spectrum of diversity was comparatively described by Sugden et al. [6], who stated that the spatial, chemical and biological heterogeneity within a few cubic centimetres of soil rivals that of a hectare of forest or coral reef.

The level at which soils perform all functions in a well-balanced manner and in concert is termed soil health [10]. The soil health concept recognizes soil as a living system and soil health results from the interaction between all abiotic and biotic processes and properties [11]. Hence, that level of soil functioning is directly linked to the biodiversity of the community of soil organisms [12,13]. Soil health, in turn, is inseparably connected to human health and well-being. The One Health concept proposes a connection between human, animal and environmental health [14]. On one hand, this covers the direct provisioning of goods such as food plants and clean water, which is connected to microbial biodiversity and functioning [15]. On the other hand, it also includes medicinal, emotional and recreational effects on human health and well-being [16,17]. All this requires further research efforts to understand and maintain soil and ecosystem health through sustainable land-use and soil management. Most current research, however, is still focused on the more economic functions such as the production of food, fuel and fibre while more ecosystem-related and non-material functions of soils are poorly investigated [5].

This literature review therefore highlights soil as (i) a genetic resource and hotspot of biodiversity that forms the basis for human health and welfare-related functions, which are (ii) the provision of biochemical resources, through utilizable microbial and enzymatic functions, and (iii) the provision of medicinal services and goods.

2. Genetic resources and biodiversity

The global soils harbour the majority of all living species on Earth [18]. The largest part is as yet unknown (table 1). Anyhow, it is estimated that more than 4.5 million species exist in the global soils and additionally many of the 1.5 million invertebrate species live permanently or during specific life stages in soil [19]. Soils therefore exhibit a substantially larger biodiversity than found aboveground [26,27]. This is on one hand due to the richness of niches and habitats, ranging across scales from the millimetre-size of microaggregates to the kilometre-size of soilscapes, and on the other hand due to the exceptional diversity of species [19,28]. Especially the microbial diversity in soils exceeds that of all other environments [29] and is far greater than the diversity of higher eukaryotic organisms [30]. Estimates from different studies range mostly between 10⁴ and 10⁵ species per gram of soil [20,31]; thus reported numbers of 10⁶ species and higher are probably unrealistic [32–34]. The number of individual microorganisms per gram of soil can be as high as several billion [35,36] (see also table 1). This vast diversity is most often related to the tremendous richness of soil bacterial communities [36,37]. In addition to the prokaryotic bacteria, archaea as well as eukaryotic fungi and protists substantially contribute to soil microbial communities [38,39]. The diversity of archaea and fungi is apparently as high or even higher than the number of operational taxonomic units of the bacteria [20]. The C content (microbial biomass C) of the microbial community in topsoil is typically between 100 and 1000 µg C (g soil)⁻¹, depending on the soil use and properties. Bacteria and often even more so fungi represent the highest share of the soil biota's biomass (table 1) [2,18]. In total, the biomass in the soil can equal or exceed the sum of all living biomass on the soil surface [18]. Microbial biomass C is even higher in the topmost centimetres of the soil, and in litter layers it reaches values of up to 10 000 µg C g⁻¹ [2,40]. Especially for arable soils the very first centimetre of the soil surface is of high functional relevance. It is the biologically most active zone, with increased microbial biomass concentrations [41] tending to aggregate and form biological soil crusts in arid and semi-arid climates and soil layers in temperate climates [42,43]. For example, the highest numbers of microalgae are present at the surface of agricultural soils, with cell numbers of 5 × 10⁸ to 5 × 10¹⁰ cells m⁻² [44]. In subsoil and with increasing soil depth, by contrast, the microbial biomass, species richness, and diversity decline on a logarithmic scale [39].

Table 1.

Mean and high numbers as well as the living biomass of some of the most important soil organisms in soils of Central and Northern Europe (after [19–25], modified).

group	number of individuals per m2		living biomass (g m−2)		global no. of described species	known of expected %
	mean	high	mean	high
virusesa	6 × 106	1.1 × 107	9 × 10−17	1.6 × 10−16	5000	5
microflora
bacteriab	1114	1116	150	103	10 000	1
archaeac	1012	1013			180	?
fungi	1011	1014	100	3.5 × 103	72 000	5
algae	108	1011	20	150	24 000	?
microfauna (0.002–0.2 mm)
flagellates	108	1010			40 000
rhizopods	107	1010	5	150		20
ciliates	106	108
nematodes	106	108	5	50	25 000	6
mesofauna (0.2–2 mm)
rotifers	104	106	0.01	0.3	2000	low
Tardigrada	103	105	0.01	0.5	930
mites (Acari)	7 × 104	4 × 105	0.6	4	45 000	4
Collembola (springtails)	5 × 104	4 × 105	0.5	4	8000	15
Protura, Diplura					1300
macrofauna (2–20 mm)
enchytraeids	3 × 104	3 × 105	5	50	700	10
snails	50	103	1	30
spiders	50	200	0.2	1	38 000
woodlice (Isopoda)	30	200	0.4	1.5	5000
millipedes (Diplopoda)	100	500	4	10	11 000	15
other polypods	130	2 × 103	0.5	3	3200	46
beetles with larvae	100	600	1.5	20
dipteran larvae	100	103	1	15
other insects	150	15 × 103	1	15
megafauna (20–200 mm)
earthworms	100	50	30	200	3500	50
vertebrates	0.01	0.1	0.1	10

^aNumber of viruses in plaque forming units (PFU) per m².

^bIncluding Actinobacteria.

^cEstimated from comparative analysis of data on DNA abundance.

Because only about 1% of the soil microorganisms can be discovered using classical cultivation techniques [45], the identification of the majority of genera and species remained unresolved until the introduction of molecular biological methods to soil biology [45,46]. New knowledge was gained on dominant species, but the task of identifying the huge number of species remains incomplete. Examples of bacteria and archaea, fungi and protists most abundant in soil are listed in table 2.

Table 2.

Examples of phyla of bacteria and archaea, divisions of fungi and taxa of protists (with some examples of especially relevant classes; indented) that were determined with high abundance in soil (listed in alphabetical order); information compiled from [37,46–50].

prokaryote		eukaryote
bacteria	archaea	fungi	protists
Acidobacteria	Crenarchaeota: Thaumarchaeota	Ascomycota: Archaeorhizomycetes Dothideomycetes Eurotiomycetes Leotiomycetes Sordariomycetes	Alveolata: Apicomplexa Ciliophora
Actinobacteria
Bacteroidetes	Euryarchaeota: Thermoplasmata
Chloroflexi			Amoebozoa
Cyanobacteria	Korarchaeota		Archaeplastida: Chloroplastida
Firmicutes	Parvarchaeota
Gemmatimonadetes		Basidiomycota: Agaricomycetes	Opisthokonta
Nitrospirae			Rhizaria: Cercozoa
α-Proteobacteria		Chytridiomycota
β-Proteobacteria		Glomeromycota	Stramenopiles
γ-Proteobacteria		Zygomycota
δ-Proteobacteria
Planctomycetes
Spirochaetes
Verrucomicrobia

The composition and diversity of the community of soil biota are not random [51]. It is formed by the interplay between inanimate soil constituents and the edaphic species. The systems conditions of soil and the environmental boundary conditions shape the edaphic community [52,53] and vice versa the soil organisms work on the soil, for example, by contributing to soil aggregation [54,55]. Hence, there is no particular or ‘typical’ soil microbiome. The relative abundances of major microbial taxa in the soil microbiome can vary considerably depending on the soil type and properties as well as the microhabitat and microhabitat structure [47,56]. Soils are highly heterogeneous, offering a wide variety of microhabitats and microbial hotspots such as the rhizosphere, drillosphere, detritussphere and aggregatosphere [42,57,58]. Soil properties that affect biodiversity are for example the spatial heterogeneous distribution of organic matter [59] and the connectedness of the soil pore system. Low pore connectivity increases the number of microhabitats with different coexisting communities, resulting in higher biodiversity [60]. Consequently, substantial differences exist in the microbial community composition within a few centimetres or even millimetres distance [61]. This leads to high α- and also β-diversity in close proximity [19]. On a local scale, the richness and structural community composition of soil microorganisms and soil faunal species very much depend on plant species and plant functional groups [27,29,30]. This means that agricultural management of soil can also significantly influence the diversity of microbiota [50].

On a global scale, the geographical distribution of soil biota communities is less clear compared with the biogeography of aboveground species and vegetation [62]. Many studies have identified rather specific soil properties such as pH or organic C content (OC) to regulate soils' biodiversity, with the biodiversity increasing with pH and OC [63,64]. Karimi et al. [65] proposed the following sequence of factors influencing soil microbial biodiversity: pH > land management > soil texture > soil nutrients > climate. Other studies, however, suggest the existence of true biogeographic patterns for different types of prokaryotes [66,67]. Moreover, fungal diversity follows biogeographic patterns, with some species being ecologically specialized and geographically restricted [51]. Accordingly, the diversity of fungi and protists was reported to depend mostly on the climate as an ecological driver [68,69]. For example, along a transect from low-lying tropical forest to the High Andes, the richness of all three groups plants, soil bacteria and soil fungi declined with increasing elevation. That study identified temperature as the major driver of community composition, whereas edaphic factors such as pH were of subordinate relevance [70]. To date, however, only little is known about the complex interactions among microorganisms [62]. In regard to the self-organization of soil microbial communities, the soil biome has even been termed a ‘superorganism’ [71]. Accordingly, microorganisms may not occur in an arbitrary or externally regulated community composition and diversity. Instead, soil microbiota are interdependent and interconnected in ecological linkages [72], which may help explain why their biodiversity relates less to environmental conditions.

A clear ecological advantage of the overabundant biodiversity of soil organisms communities is an increased probability of dispersal and decreased risk of local extinction [51]. The two most relevant causes of extinction are the loss of habitat and the displacement by invasive species [73]. Both causes are mitigated by a larger biodiversity. Moreover, the very high soil species richness greatly exceeds the functional diversity, which is termed ‘functional redundancy’ [74]. This complicates finding a direct relationship between the biodiversity and functions of soil microbial communities [75]. Nonetheless, more biodiverse ecosystems exhibit higher stability against external disturbances and are better able to provide ecosystem services and functions [76–79]. Consequently, biodiversity and functional redundancy are necessary to ensure soil ecosystem functioning and services [75]. This is particularly relevant with respect to the ongoing considerable loss of soil biodiversity due to unsustainable human soil use and environmental degradation [77,80,81].

3. Biochemical resources

Soil microbiota are the major drivers of most soil functions, thereby interacting with other species of the edaphon as well as with plants [38,82]. This has prompted high interest and ongoing research to use the abilities of autochthonous microorganisms and their relevant enzymes, (i) to further improve natural soil functions and in particular plant growth, (ii) to act as biological pest control, (iii) to facilitate the biodegradation of pollutants and bioremediation of soil, and (iv) to produce enzymes or chemicals for industrial use.

Supporting or enhancing natural soil functions primarily applies to soil fertility, i.e. the ability of soil to promote plant growth. In this context, plant growth-promoting microorganisms (PGPM) merit particular mention. PGPM can enhance plant growth and strengthen plants against diseases and abiotic stress [83,84]. Effects of PGPM are either direct through synergistic or antagonistic interactions and trophic competition of the microorganism with other members of the microbial community, or indirect through enhanced root growth and exudation [85]. The microbe–plant interaction can be unspecific, when the beneficial PGPM compete with plant pathogens, or specific based on biochemical signalling. Related to the latter, many PGPM produce growth-regulating chemicals such as auxins, cytokinins or gibberellins [86,87]. The outlined effects are either transient or long-term [88]. Some plant growth-promoting rhizobacteria can supply nutrients to crop plants and are termed ‘biofertilizers’ [89]. They assist the plant in exploring for and uptaking nutrients and can thus substantially reduce the requirement for fertilizer, by up to 25% [18]. The application of inoculants such as Azospirillum and phosphate-solubilizing bacteria (Phosphobacteria) has already become a global business, valued at $440 million in 2012 [85]. Relevant PGPM species are especially common among the bacterial genera (with important examples of species in parentheses): Bacillus (Bacillus subtilis, B. cereus), Pseudomonas (Pseudomonas fluorescens, P. putida), Azospirillum, Alcaligenes, Enterobacter, Flavobacterium, Klebsiella and Serratia [38]. Moreover, several soil fungal strains exert positive effects on crop plants, e.g. Aspergillus clavatus, Penicillium commune and Thamnidium elegans [38,90].

The symbioses between microbiota and plant roots are even more effective in promoting plant growth, i.e. the symbiosis with mycorrhizal fungi and rhizobium bacteria [91]. Among the different types of mycorrhizae two dominate in soil: endomycorrhizae and ectomycorrhizae (EM) [39,92]. Endomycorrhizae are mostly arbuscular mycorrhizae (AM) formed by fungi in the order Glomales and are characterized by internal colonization of the root cells [93]. Associations with AM occur in a large number and a variety of plants including many crop plants [94]. EM are less common than AM; they associate with most of the dominant tree species of temperate and boreal as well as of some tropical forests [93]. The EM fungi form a dense mycelial net around and between plant cells [82]. Most mycorrhizae are mutualistic, i.e. in exchange for photosynthates the fungus provides the host plant with soil resources, among which phosphate is most relevant [92]. As a response, plants with mycorrhizae have fewer and shorter fine roots and root hairs [94].

Rhizobium bacteria (belonging to the α-Proteobacteria) fix atmospheric nitrogen (N) in symbiosis with plant roots of legumes [2]. Free-living N-fixing bacteria (diazotrophs), such as Azotobacter, Acetobacter and Azospirillum, as well as many of the photobiont Cyanobacteria also increase bioavailable N forms in soils [95,96]. Additionally, diazotrophs may have plant growth-promoting properties, e.g. release of phytohormones and vitamins along with enhanced nutrient uptake [97]. Furthermore, they can stimulate increased nodulation of legumes by rhizobia [38].

In most soils and in most host plants, the symbiotic or free-living PGPM are already present. Should it become necessary or desired to increase their abundance, this can be attained through inoculation or by improving the soil conditions for the PGPM [94,98]. Microbial infection of legumes with rhizobia is best manipulated by adding the inoculant to the plant seeds prior to sowing [38]. Note that the success of PGPM inoculation and of rhizobial infection in particular depends on a delicate interplay of inoculated strains, soil conditions and plant cultivars [99]. The latter become especially relevant in mixed vegetation [100]. Some rhizobia sub-populations show marked cultivar specificity [101]. This requires further development of more effective inoculation methods in order to achieve efficient results.

Beneficial, pest-suppressing organisms have always been present in the environment and have been unintentionally used by humans [102]. Recent attempts, however, target the identification of particularly effective and specifically acting soil microorganisms that can be patented as a commercial product or biopesticide. Biopesticides are typically applied by augmentation [38]. For this purpose, the population of the pest-suppressing microorganism is massively increased, typically by proliferating the organism in the laboratory for subsequent release in the field. This strategy is similar to chemical pest control [103]. In classical biological control, pest-pathogenic organisms are collected from locations where the pest originated and are subsequently released in an infected area. Finally, the conservation or enhancement of indigenous communities of soil organisms through proper agricultural management is an important measure [38]. This includes the adjustment of soil physical and chemical properties such as soil structure and pore volume as well as nutrient and organic matter status through adapted tillage and fertilization [104,105].

The bacterial and fungal genera that have been frequently used to control plant pathogens include several nonpathogenic fungal strains [38]. These belong to the genera Rhizoctonia, Phialophora, Fusarium and Trichoderma [106]. Patents have been issued for organisms such as the fungi Trichoderma and Pseudomonas, and Bacillus bacteria [102]. Well-known examples are the use of the Bt toxin of Bacillus thuringiensis against insects and of nonpathogenic Agrobacterium strains to control crown gall [106,107]. Examples of successful commercial products are Contans from Conithyrium minitans and Serenade from Bacillus subtilis [102,108]. However, many attempts to develop biopesticides have been unsuccessful. In most cases, this was due to the inability of the introduced organisms to grow and become active in soil [109]. Much research remains to be done to explore the full potential of soil organisms for pest control.

Many approaches have been introduced to use soils and soil reactions for technical purposes. Multifarious microbially driven biochemical reactions take place in soils in concert with chemical reactions occurring at the interfaces of the soil colloids. Soils are three-dimensional entities composed of mineral and organic solids combined with microbial, faunal and plant (root) biomass and structured in soil aggregates [2]. Pores are transport pathways for gas and soil solutions. Moreover, the soil surface and aerial parts of plants can be regarded as upper flux boundaries with the atmosphere, whereas the bottom of a soil profile's unsaturated zone represents the lower flux boundary with the vadose zone and groundwater. In this regard, soils can be considered as porous-bed biogeochemical reactors [7]. This means, there is high potential and interest to develop options for biotechnical uses of soils, soil organisms and soil constituents [110]. By contrast with such attempts, only very few new biochemical reactions or pathways have been discovered since the late 1970s [111,112]. An example of success is the discovery of anaerobic ammonium oxidation (anammox) [113,114]. The number of new discoveries remains scarce, although new methods in molecular microbiology have enabled the discovery of new catabolic genes from all domains of life at a rate recently exceeding 1 million per year [85,110]. Accordingly, the biotechnical applications of soils and soil microbiota are currently largely restricted to bioremediation of environmental pollution and various applications of enzymes in technical processes.

The aim of soil bioremediation measures is to manage microorganisms in order to reduce, transform, eliminate or immobilize contaminants [38,115]. Microorganisms possess manifold biochemical strategies and mechanisms to transform or degrade any type of organic molecule [110]. Today, a range of soil microorganisms is used to remediate pollutants in the environment. In 1974, Pseudomonas putida was the first soil microorganism to be patented for the degradation of a broad range of organic chemicals [116]. Further aerobic bacteria used in bioremediation include species of the genera Pseudomonas, Alcaligenes, Geobacter, Sphingomonas, Rhodococcus and Mycobacterium. Various anaerobic bacteria are used for the reductive degradation of contaminants, especially chlorinated chemicals such as the aromatic polychlorinated biphenyls (PCBs) and the aliphatic chloroethylenes [38]. Such reductive contaminant degradation processes often include iron and manganese oxides as electron acceptors [117,118]. Furthermore, bacterial inoculants can alleviate metal toxicity in polluted soils [85]. Beyond bacteria, fungi are also used in bioremediation. Fungal phyla and subphyla especially used comprise Mucoromycotina, Glomeromycota, Ascomycota, Pezizomycotina, Saccharomycotina, Basidiomycota, Agaricomycotina, Puccioniomycotina and certain others [25]. In particular, the ligninolytic fungi, such as members of the genus Phanerochaete, are able to degrade highly complex and otherwise recalcitrant chemicals such as lignin—and also contaminants such as polycyclic aromatic hydrocarbons (PAHs) [38,119]. Phanerochaete chrysosporium and several other fungi use a peroxidase enzyme system of low specifity but high reactivity [25] to degrade recalcitrant organic contaminants, e.g. DDT, lindane, chlordane and trinitrotoluene, PAHs and various chlorinated phenols [120–122]. Brown rot fungi degrade pharmaceutical antibiotics from the class of fluoroquinolones [123].

Note that single species do not occur in the natural soil environment, but exist and operate as highly interdependent dynamic communities, which are intimately intertwined with the ecosystem's functioning [110,124]. Accordingly, it has frequently been recognized that decontaminating soil through bioremediation is more successful when microbial consortia rather than single degrading species are used or fostered. This enables benefitting from the symbiotic and proto-cooperative synergistic effects among the microbial community [18,85]. For example, the degradation of PCB occurs very effectively in two steps through dechlorination by Phanerochaete fungi and subsequent oxidative degradation by Burkholderia bacteria [125,126].

A further promising approach to use soil microorganisms in soil bioremediation is the employment of biosurfactants or bioemulsifiers [127]. Compounds such as glycolipids (e.g. rhamnolipids), lipopeptides and lipoproteins (e.g. surfactin), and polymeric surfactants (e.g. liposan or sulfated polysaccharide) are produced by different soil bacteria such as Pseudomonas spp., Bacillus spp., Acinetobacter spp. and Sphingomonas paucimobilis [128].

Enzymes are the crucial biocatalysts behind biochemical reactions. Purified exoenzymes can be used for soil remediation, as was described in a ground-breaking publication by Bollag [129]. For that purpose, the preferred exoenzymes are extracellular oxygenases (monoxygenase and dioxygenase) or oxidoreductases classified as either peroxidases or polyphenol oxidases and capable of catalysing the coupling of aromatic compounds [85,129]. Peroxidases require the presence of peroxides (e.g. hydrogen peroxide) for activity and catalyse a variety of reactions, including polymerizing and depolymerizing lignin [130]. Polyphenol oxidases are divided into two subclasses: laccases and tyrosinases. Both enzyme groups require bimolecular oxygen, but no coenzyme, for activity [129]. Enzymes originating from soil microorganisms and also from plants have been successfully tested for use in degrading a broad range of organic contaminants in soil [131–135].

Enzymes are also required in industrial processes. These biocatalysts effectively accelerate reactions, so that biotransformations proceed at several-fold increased reaction rates; they optimize the thermodynamics of a reaction, with enantio- or regioselectivity or specificity toward different chiral groups [136]. The use of and the search for suitable enzymes are relevant contributions to the development of sustainable and green chemistry [137,138]. Similarly, enzymes are used to convert and valorize various agro-industrial residues, e.g. from fruits, grains and lignocellulosic residues [139]. The soil enzymes used for industrial and commercial applications include lipases, amylases, amidases, proteases and alcohol oxidoreductases [138,140–144].

To date, metagenomic transformation techniques have been used to construct metagenomic libraries for functional screening in order to find novel genes coding for enzymes [85,110]. This has led to the discovery of several new genes having better activity and novel sequences. These genes code for enzymes suitable for bioremediation, such as polyphenol oxidase, ester and glycosyl hydrolase, and laccase [145], and for enzymes for industrial and commercial applications, like lipases, esterases, amylases, chitinases, amidases, cellulases and xylanases [110]. Nonetheless, much work remains to be done in order to fully reveal the treasure of enzymes, enzymatic catalysed reactions and chemical products that are still hidden in the soil.

4. Medicinal resources

Soils exert multifaceted effects on human health. This encompasses various aspects, as outlined by Brevik [17]. (i) Soil provides ecosystem services, including healthy food and water, which is termed ‘soil health’. (ii) Soils are an integral part of natural landscapes, thus affecting human well-being indirectly through emotional impact and directly by contact with the multitude of soil minerals and the myriad of biota, especially microbiota. (iii) Several soil substrates such as loams, clays and other minerals have curative effects. (iv) Pharmaceutically active and medically relevant organic chemicals are formed by soil microorganisms. All this results in numerous positive and indispensable effects of soils on human health, many of which are not yet fully investigated and understood. The lack of perception ranges from a neglected holistic consideration of healthy soils for human well-being to specific research for individual medicinal substances. For example, although most natural products that are used as antibiotics or other pharmaceuticals are derived from soil microorganisms, there are many more chemicals and chemical classes to discover [146,147]. Moreover, the research on and the rate of discovery of novel natural products derived from soil has significantly decreased during the past decades [148,149]. This happens while we are facing a need for new pharmaceuticals. For example, fewer and less effective antibiotic drugs are available owing to increasing pathogen resistance, while new developments of antibiotic classes in the pharmaceutical industry are scarce and costly [146,150,151].

On the other hand, soils may also negatively affect human health in various ways, e.g. in the case of pathogens and parasites (see also the article by Samaddar et al. on detrimental organisms in this special issue [152]), when irritating minerals are abundant, or when too much soil dust is inhaled, e.g. by farm workers (see also the following §4a). The most extreme direct soil contact involves deliberate soil ingestion, termed geophagy, which may have positive but also negative consequences for human health. Obviously, unhealthy, degraded and contaminated soils adversely affect human health.

(a) . Soil health and human health nexus

Soil health is related to the ability of soil to provide the aforementioned various ecosystem services. The soil health concept includes the traditional view on soil fertility and the role of soil in water quality, climate change and human health [13]. Human health is inevitably linked to soil health because we depend on it for, among other things, the provision of food and potable water. This provisioning function of soils depends on and can be further improved by intelligent and sustainable agricultural land-use management; it cannot work without the natural soil fertility (with the exception of hydroponic systems), quality and health status [8,153]. The soil health–human health nexus goes even beyond that, e.g. it involves healthy food with high nutritional value that depends on the soil nutrient status, or the provision of a more balanced climate in urban areas [13,154,155]. It also includes the supply of medicinal resources (see §§4b–e). At the same time, unsustainable land-use practices, natural hazards such as flooding and land-slides, and global changes such as climate change and sea-level rise can induce soil degradation and disservices [156,157].

Consequently, the natural conditions and human land use determine whether healthy soils sustain healthy people or not. Related to this, Brevik [17] distinguished positive effects of soils on human health ‘what soils do for us’ and negative effects ‘what soils do to us’.

Soil affects humans not only indirectly through the ecosystem services and especially crop production but soil and soil contact may be directly linked to human health status. There is growing evidence that exposure to soil microorganisms lessens the prevalence of allergic and other atopic diseases [158–160]. The current interpretation is that our immune system needs to be exposed to the complex soil biodiversity in order to develop tolerance and to lower the risk of allergies and other immunity-related disorders [161,162]. Thereby, soil contact should be part of a multitude of interactions with environmental microbiota encompassing possible pathogens, e.g. from food, plants, farm animals, pets etc. [162]. Vice versa, children raised under hyper-hygienic conditions may be more susceptible to atopic diseases when they grow up [163,164].

In this context, the biodiversity hypothesis was formulated stating that contact with natural environments enriches the human microbiome, promotes immune balance and protects from allergy and inflammatory disorders. Humans coexist with two nested layers of biodiversity, microbiota of the outer layer (soil, natural waters, plants and animals) and inner layer (gut, skin, respiratory tract). The inner layer microbiota inhabit our body, which is colonized from the outer layer [161]. Human gut microbiota are assembled over a lifetime, starting at birth, and depend on our diet, infections, the consumption of medical drugs and last but not least the environment [165]. Hence, soils are the major environmental sphere we live on and can both directly and indirectly—through the food harvested from soil—affect our gut microbiome. Both autochthonous and allochthonous members of the very dynamic gut microbiome are affected by the contribution from soil and its microbiome, which is by far more diverse than the human gut microbiome [71]. Importantly, intimate interactions exist between the microbiota and the human metabolism and even the immune system and nervous system [165–167]. Accordingly, we must expect a multifaceted impact of the soil environment on the human microbiome, health status and well-being [165].

Many scientists emphasize that the way humans manage soils and use their ecosystem functions and biodiversity feeds-back on our living environment, food resources and health. There is evidence that the natural microbial diversity of soil regulates the invasion by bacterial pathogens as well as by mobile genetic elements that are hazardous to health [168,169]. The employed soil use systems are even relevant for handling global diseases such as the COVID-19 pandemic [170,171]. For example, disposal practices of wastewater and biosolids as well as medical waste may either render soils a reliable sink for such substrates through immobilization and biodegradation or convert soils into a potential contributor to SARS-CoV-2 transmission [170,172]. However, very little is known about the fate and possible suppression of viruses such as SARS-CoV-2 in soil or the possible chance of proliferation. The overall message is that promoting the ecological complexity and robustness of soil biodiversity through improved management practices represents an underused resource with the ability to improve human health and suppress the transfer of diseases [15].

Furthermore, soil is an intrinsic component of nature and landscapes. There is consensus that, beyond soil-related material goods such as crop plants, humans also need positive contact with nature for health and well-being [173–175]. An increasing number of studies show that recovery from illness and surgery is improved when patients are exposed to intact natural landscapes. Ailments such as cancer and Alzheimer's disease as well as complaints such as lack of concentration, high blood pressure and muscle tension are reduced [176]. This is used in the concept of therapy gardens and landscapes, which for example may have consequences for the location and construction of future hospitals [177–179].

All these considerations require recognizing and researching soils and soil health with a more holistic view that includes disciplines such as medicine, anthropology and sociology, to name a few [17]. It also calls for considering the existing knowledge about the interplay of soils and human culture [180,181]. Such a complex approach targets the WHO's definition of human health as ‘a state of complete physical, mental and social well-being, and not merely the absence of disease or infirmity’ (cited in [182]).

Unhealthy soils with low fertility due to nutrient deficiency, strong acidity or alkalinity, water-logging, poor soil structure and high density, steepness, dryness, heat or frost etc. will perform ecosystem services at only a low level. Such soils can even exert adverse effects on human health, e.g. by providing food with micronutrient deficiency. Moreover, an unhealthy soil status may be linked to soil contamination with organic pollutants or potentially toxic elements (PTE) such as arsenic, cadmium or mercury (As, Cd, Hg), with radionuclides or with excessive salt content, just to name a few [183,184]. Organic contaminants are either of natural origin and produced by, e.g. bacteria, fungi, algae, plants and animals [185], or of anthropogenic origin and in that case often more persistent (e.g. pesticides, pharmaceuticals, contaminants from industry, traffic etc. [119]). Inorganic contaminants either are of geogenic origin or were introduced into soil by human activity [186]. With regard to the regulating services of soil, the natural capacity for filtering, buffering and detoxification of contaminants can be exceeded by the level of contamination. In that case, adverse effects on human health can occur either directly through soil contact or indirectly through contaminated food and water sources.

A prominent example of large-scale exposure of humans to geogenically derived PTEs is the environmental contamination with arsenic (As) in Bangladesh [187]. Geogenic contamination of aquifers occurs in many Asian countries, but the highest contamination level is reported in Bangladesh, affecting millions of people [188]. There, groundwater is widely used as drinking water because of the insufficient quality and management of surface water sources [189]. Additionally, As-contaminated water is used for soil irrigation, resulting in wide-spread contamination of agricultural land and especially paddy soils, exceeding legal threshold values [189]. The human diet is therefore excessively contaminated with As, leading to severe health problems [158,190]. It may be noted that a possible solution to the problem lies in the soil itself, through microbial biomethylation of As to less toxic volatile and non-volatile organic species such as methylarsines and methylarsonic acids [191]. In other examples research points to the linkage between soil contamination with PTEs and the geographical incidence of cancer. McKinley et al. [192] reported a significant relation between soil contents of As and radon (Rn) and the abundance of stomach cancer and skin cancer, respectively, in Northern Ireland.

Direct contact with soil may also induce adverse effects. This refers to inhaled soil dust, which may cause various health problems. Mineral dust particles, when deposited in the lung alveoli, can lead to pulmonary disorders such as irritation of lung tissue, silicosis, cancer and subsequent microbial infections. Moreover, the latter can be directly triggered by biogenic particles [17,163]. Dust formation from soil surfaces occurs on the local scale, e.g. when working on a bare, dry soil surface, and may especially impair farm workers or miners working in quarries excavating soil resources such as sand and loam [193,194]. Dust formation also occurs on a global scale. The latter is particularly relevant when large land surfaces in arid and semi-arid regions are deflated under regular or episodic windy conditions [195,196]. Well-known examples include the dust emissions from large deserts such as the Sahara, Kalahari and Gobi, which may affect the human population in those regions.

A very specific soil-related disease induced by skin contact with soil minerals is podoconiosis [16]. This illness occurs in northwest India, Central America and mainly in tropical highland areas of Africa, whereas it has been eliminated in northern Africa and Europe [197]. Worldwide, around four million people are affected [198]. Podoconiosis is caused by and further progresses when people live and work barefoot on soil, which particularly applies to professional categories such as farmers and mine workers. The disease is induced by skin contact with irritant clays developed from weathering of basaltic rock [16]. The ailment is caused when such clay minerals are absorbed through the foot skin and end up in the lower limb lymph node macrophages. Visible characteristics are oedema with lymph ooze, skin markings and hyperkeratosis with papillomata, which are followed by the prodromal phase, with final painful elephantiasis [198,199]. The best prevention of podoconiosis is wearing footwear and socks, combined with foot hygiene [16,198]. Recently, medical geology mapping was used to identify risk areas [198].

(b) . Loam, clay and other soil minerals in pharmaceuticals and cosmetics

The use of natural minerals of soil origin (pedogenic minerals) for medicinal and cosmetic purposes has a long tradition. Minerals such as clay have been used for therapeutic purposes since prehistoric times and continue to be applied in modern medicine for the treatment of or protection from a wide spectrum of topical and internal diseases ([200,201] and references therein). The earliest written information dates back to Roman times, when ancient authors reported on the pharmacological action of Samian's earth occurring on the islands of Samos and Melos in the Aegean, Greece [200]. A recent study confirmed the antibacterial activity of that mixture of hydrated layered silicates (kaolin and bentonite) with different borates (colemanite, tincalconite) against pathogens, such as Staphylococcus aureus and Pseudomonas aeruginosa [202]. In modern times, the bactericidal character of clays was rediscovered, e.g. by the work of Line Brunet de Courssou [200,203]. She used so-called ‘French Green Clay’ imported from France to effectively treat Buruli ulcer, an infectious disease in tropical regions caused by the bacterium Mycobacterium ulcerans, leading to necrosis of subcutaneous fatty tissues [204]. The French green clays consist primarily of reduced Fe-smectite and mixed-layered illite–smectite [205].

Within the wide range of pharmaceutical and cosmetic applications, the different pedogenic minerals are administered either (i) orally as pills, powders, suspensions and emulsions, or (ii) topically as creams, powders, ointments, emulsions, bathes, solutions, compresses or poultices, depending on the intended purpose [16,200,206]. In severe cases, minerals used as antianaemics (melanterite) and homoeostatics (halite and sylvite) are administered parenterally in a dissolved form [16]. Examples for relevant minerals as well as major therapeutic and cosmetic uses and effects are outlined in table 3.

Table 3.

Minerals used as active ingredients in pharmaceutical preparations and cosmetic products with physical and physico-chemical properties, chemical features and pharmaceutical or cosmetic effects (from [16,206–209], rearranged and complemented).

activity	mineral	chemical formula (only given on first mention) or dominant minerals	physical and physico-chemical properties and chemical features	pharmaceutical/cosmetic effect
pharmaceutical products
oral administration
antacids	calcite	CaCO3	reaction with acids (HCl); release of non-toxic ions	minerals react with (excessive) stomach acid neutralizing H+, or have high sorptive capacity to adsorb H+
	magnesite	MgCO3
	periclase	MgO
	brucite	Mg(OH)2
	gibbsite	Al(OH)3
	hydrotalcite	Mg6Al2(CO3)(OH)16 · 4H2O
	palygorskite	(Mg,Al,Fe3+)5(Si,Al)8O20 (OH)2(OH2) · 4.4H2O	surface adsorption of H+ and decomposition in gastric acid; release of non-toxic ions
	sepiolite	Mg8Si12O30(OH)4(OH2)4 · 8H2O
	smectites	montmorillonite, saporite, hectorite
	loess	mix. of silicates and calcite	reaction with acids (HCl)
gastrointestinal protectors	gibbsite		high sorption capacity and large specific surface area	stabilization of the mucus of gastric and intestinal mucous membranes, and/or immobilization of gases, toxins, bacteria and viruses
	palygorskite
	sepiolite
	smectites
	kaolinite	Al2Si2O5(OH)4
antidiarrhoeals	gibbsite		high sorption capacity and large specific surface area	elimination of (a) symptoms through immobilization of liquid in the small intestine especially by swelling minerals, and (b) causes by adsorption of toxins and/or release of beneficial ions, e.g. Ca2+ and Al3+, forming insoluble salts in the intestine
	palygorskite
	sepiolite
	smectites
	kaolinite
	gibbsite		decomposition in gastric acid; release of Ca2+ or Al3+ ions
	calcite
osmotic oral laxatives	mirabilite	Na2SO · 4.10H2O	high solubility in water and HCl; release of Na+ or Mg2+ ions and non-toxic anions when ingested	Na+ and Mg2+ ions stimulate colon–rectum defaecation: interfere with osmotic regulation of the intestines, resulting water transport into intestines increases volume, thus stimulating intestinal muscle activity
	epsomite	MgSO · 4.7H2O
	periclase
	brucite
	magnesite
	loess	mix. of silicates and calcite	ion exchange upon acid neutralization
direct emetics	chalcanthite	CuSO · 4.5H2O	highly soluble Cu2+ and Zn2+ minerals	vomiting induced through irritation of the gastric mucosa and neuronal stimulation after absorption by and distribution within the blood plasma, e.g. of released Cu2+ and Zn2+
	goslarite	ZnSO · 4.7H2O
	zincosite	ZnSO4
mineral supplements	calcite		highly soluble in water and HCl; release of essential ions	supply of deficient essential elements, such as P, Ca, Mg, Na, K and Fe, in case of physical weakness, convalescence or asthenia
	magnesite
	hydroxy-apatite	Ca5(PO4)3(OH)
	epsomite
	periclase
	brucite
	halite	NaCl
	sylvite	KCl
	melanterite	FeSO · 4.7H2O
oral and parenteral administration
homoeo­statics	halite		high water solubility; release of Na+ or K+ ions and non-toxic anions when ingested	solutions of saline minerals to compensate for losses of electrolytes such as Na+ and K+ ions through dehydration
	sylvite
antianemics	melanterite		highly soluble Fe2+ minerals	anaemia (deficiency of red blood cells and haemoglobin) treated with minerals releasing Fe ions (reduced Fe2+(= ferrous) ions preferred to Fe3+(= ferric) ions)
topical administration
antiseptics and disinfectants	sulfur	S	high astringent capacity	destruction or inhibition of microbial growth in living tissues (antiseptics) or on inanimate surfaces (disinfectants) is achieved through use of minerals containing sulfur, sulfate or borate
	borax	Na2B4O7 · 10H2O
	chalcanthite
	zincite	ZnO
	goslarite
	zincosite
	alum	KAl(SO4)2 · 12H2O
dermatological protectors	kaolinite		high sorption capacity; non-fibrous shape	skin protection through high sorbing applications taking up liquid excretions, dissolved or suspended substances such as grease, toxins, microbiota and viruses, creating a surface with increased evaporation
	talc	Mg3Si4O10(OH)2
	smectites
	zincite
	hydrozincite	Zn5(CO3)2(OH)6
	smithsonite	ZnCO3
	rutile	TiO2
anti-inflam­matories and local anaes­thetics	kaolinite		high absorption and heat retention capacities	inflammation reduced and muscular or rheumatic pain alleviated through tempe­rature-regulating clays (cold or heat)
keratolytic reducers	sulfur		reaction between sulfur and cysteine in keratinocytes	reduction of the thickness or peeling of the superficial layer of the skin (cornea) especially by sulfur- and sulfide-containing minerals; treatment of skin diseases such as seborrheoic dermatitis, psoriasis, chronic eczemas or acne
	greenockite	CdS
decongestive eye drops	halite		Na+ mineral; high water solubility	saline, isotonic solutions to cure eye dryness and stinging caused by ocular irritation through aerosols, particles and light
cosmetic products, solar protectors	rutile		high refraction index, high light-scattering properties	use for topical application; minerals prevent or delay skin damage by solar ultraviolet radiation; natural minerals such as rutile replaced by synthetic analogues or synthetic TiO2
	zincite
toothpastes	nitre	KNO3	non-toxic K+ minerals; high water solubility	minerals with suitable hardness and particle size used as abrasives or for pain relief through release of K+ ions acting on nerves inside the dentine
	calcite		non-toxic; hardness is inferior to that of enamel
cosmetic creams, powders and emulsions	palygorskite		opacity and high sorption capacity	opaque, adhering minerals with high sorption capacity preferably used as admixtures in creams and make-up products, to give opacity and cover blemishes, remove or adjust shine, take up liquids, grease and toxins, and form a protective film; excipients in pharmaceuticals and cosmetics to improve characteristics such as smell, taste, colour or mechanical properties such as viscosity, facilitating the preparation and formulation of products
	sepiolite
	kaolinite
	smectites
	talc
	muscovite	KAl2(Si3Al)O10(OH)2	micaceous habit and high reflectance
bathroom salts	halite		high water solubility; release of Na+, K+ or Mg2+ ions	highly soluble, especially saline minerals used for this purpose
	sylvite
	epsomite
	mirabilite
deodorants	alum		high astringent capacity	alum has possible negative effects owing to high Al content and the risk of corrosive effects on the skin

The therapeutic activity of minerals depends on their physical and physico-chemical properties as well as their chemical composition [201,206,210]. The physical size and shape of clay minerals is primarily relevant to support the physico-chemical and chemical action such that smaller mineral particles have a higher specific and reactive surface area. A second feature is a potentially direct physical impact [201]. For example, clay minerals shaped like fibrous needles might penetrate and damage bacterial cell membranes, thus distorting membrane transport or even leading to leakage [201]. One frequent observation is that bacteria are encased by clay particles, blocking their interaction with their environment as well as with other organisms [211,212].

The physico-chemical and chemical action of minerals is directly related to their therapeutic activity [201,206,207]. Briefly, minerals (e.g. carbonates, carbonate-containing loam and clays with high sorption capacity) that react with acids can serve as antacids. They are also effective as antidiarrhoeals, osmotic oral laxatives and mineral supplements because nutritive cations can be released upon the neutralization reaction. Minerals with a high sorption capacity are also effective gastrointestinal and dermatological protectors, anti-inflammatories and local anaesthetics. Furthermore, they are suitable to produce creams, powders and emulsions. For the latter preparations, minerals that are highly opaque or have a high reflectance are often used, whereas minerals with a high refraction index are preferred as solar protectors. Water-soluble minerals (e.g. salts) are typically used as homeostatics, antianaemics and decongestive eye drops and are contained in toothpastes and bathroom salts. Further toothpaste ingredients include minerals with appropriate hardness for use as abrasives. Minerals with high astringency act as antiseptics and disinfectants (in deodorants, for example), while minerals reacting with cysteine are suitable keratolytic reducers. One typical prerequisite is that minerals used in pharmaceuticals and cosmetics be free of any natural content of or contamination with toxic chemicals. One exemption is minerals used as emetics. Here, the action of (toxic) Cu²⁺ and Zn²⁺ ions is used to induce vomiting, which at the same time eliminates these toxicants from the body.

Highly relevant for medicinal purposes is the fact that some types of clay exhibit bacteriostatic and bactericidal activity [200]. Chemical effects of clays on bacteria appear to dominate the antibacterial mechanisms [213,214]. Relevant mechanisms causing the antibacterial activity of different minerals and more specifically of clays have been summarized in the excellent review by Williams [201]. These mechanisms encompass the sorptive properties of minerals leading to the release of mineral-bound cytotoxic metals on the one hand [215,216]. In the case of Al release this may imply Al binding to phospholipids resulting in osmotic imbalance and cell lysis [217,218]. On the other hand, nutrients can sorb to the minerals so that nutrient availability for bacteria becomes insufficient [219]. A second general mechanism is the formation of peroxides and radicals. Hydroxyl radicals are directly formed by Fenton reactions from minerals containing reduced, ferrous iron (Fe²⁺) [220]. Beyond Fe²⁺, other transition metals (e.g. Mn, Cu and Zn) can also contribute to bacteriostatic and bactericidal properties [217]. Hydroxyl radicals degrade intracellular proteins and DNA [221], a mechanism that has also been reported for antibacterial clays [203,217]. Lipid peroxidation and oxidative stress lead to increased membrane permeability [222]. Furthermore, some kaolin minerals have photocatalytic properties [223,224] and may induce photodegradative damage to bacteria. Finally, an altered pH and oxidation state of the microenvironment can hamper bacteria [225,226] and further result in the combined action of Al and Fe on membranes and on intracellular proteins [203,227]. All these mechanisms are rather unspecific so that antibacterial clays are only applied topically for wound healing and to fight skin diseases [201].

From the several thousand known minerals, only about thirty are used in the pharmaceutical and cosmetic industries [206]. Traditionally, rather pure minerals from mining deposits or mixed mineral substrates (loam) from soil were used. Today, most of the minerals are synthetic analogues, but some pedogenic minerals with their natural inhomogeneity are still in use—a notable exception in pharmacy [207]. This is because the synthesis of more complex minerals is difficult and expensive, while natural minerals are abundant and inexpensive [206,228]. Importantly, for some applications, it is the specific status and mixture of different minerals, found in certain natural soil deposits, that causes the pharmaceutical effect [201]. Different individual minerals used for pharmaceutical and cosmetic purposes are listed in table 3.

The minerals in use can be assigned to the following classes: chlorides, carbonates, oxides and hydroxides, borates, nitrates, phosphates, sulfates and sulfides, elements and phyllosilicates (clay minerals) [16,206]. Among the clay minerals, the smectites especially are used in the pharmaceutical and cosmetic industries because they exhibit the highest swelling and cation exchange capacity. Among non-silicate minerals, the water-soluble chlorides and sulfates of Na⁺, K⁺, Mg²⁺ and Fe²⁺ are mostly used as active ingredients in laxatives, homeostatics, antianaemics and mineral supplements [206]. Smectitic clays, especially montmorillonite, are the most commonly used antibacterial minerals owing to their nanometric particle size, high specific surface area, high sorption capacity and high catalytic activity [2,200]. Bactericidal properties are exhibited by minerals such as illite and smectite that bear Fe²⁺ and other transition metals, such as Co²⁺, Ni²⁺ (cobalt, nickel), Al³⁺, Cu²⁺ and Zn²⁺ in their structures, and clays bearing one or more ferrous iron-rich associated phase, such as pyrite and marcasite (FeS₂), magnetite (Fe^IIFe₂^IIIO₄), pyrrhotite (Fe_1−xS) and goethite (α-FeOOH) [200]. Ferrous iron in solution drives the bacterial elimination and a steady production of reactive oxygen species (ROS) [229]. Morrison et al. [226] provided a comprehensive study and overview of which mineralogical and chemical compositions of clays—based on their chemical buffering capacity and oxidation state—yield antibacterial activity.

(c) . Mud therapy and further medicinal substances from soil

Bathing in mud has been known since ancient Roman times for its positive effect on osteoarthritis. Cleopatra used mud from the Dead Sea (today in Israel) to enhance her beauty [16]. The healing ability of mud, peat and clay has been repeatedly scientifically reaffirmed and continues to be used in fangotherapy [230]. Fangotherapy is the use of mud for healing purposes [230]. The use of peat and clay is also often termed as ‘fango’, but fango means mud in Italian, so that peat and clay are not fango treatments in the strict sense. Nonetheless, the common feature of all these three materials is that they hold heat, making them useful as a thermal application for chronic diseases [231]. Mud therapy is suitable to treat diseases such as neurological, rheumatological, cardiovascular, gynaecological, inflammatory and menstrual cycle disorders, or skin diseases [232,233].

Each of these materials—mud, clay and peat—has special properties. Clays are mainly derived from sedimentary rock (representing soil from previous geological eras) and are the most stimulating of the fango substances. Clays such as kaolinite, illite and smectite with their high adsorbing properties also remove skin impurities and stimulate blood circulation [16].

Mud also largely consists of minerals such as clay minerals but additionally contains 2–4% organic substances, which contribute to the overall therapeutic use of mud by adding anti-inflammatory or analgesic properties [232,234]. Sulfur-containing muds, especially, have anti-inflammatory effects, promote blood circulation, strengthen the immune system and induce other effects [232]. Sulfur and its species and minerals, respectively, are supposedly the most relevant constituents in the different kinds of therapeutic mud. Sulfur-rich mineral and mud baths are helpful against osteoarthritis, rheumatoid arthritis and other inflammatory conditions [232]. Mud with its mostly acidic humic substances, vitamins, amino acids and plant hormones helps against arthritis [235] and other musculoskeletal disorders and injuries [16]. Therapeutic mud has to ‘mature’ or ‘ripen’ in mineral water over a period of up to 12 months before use. That process leads to some conversion of the mud composition and appearance by redox reactions. Those reactions most likely affect the pedogenic oxides and sulfur compounds contained in the mud [16].

By contrast, peat is mainly organic and derived from the accumulation and partial humification of plant material under water-saturated conditions and over thousands of years. Several studies showed that peat has a number of positive medicinal effects, e.g. it is anti-inflammatory, analgesic, a circulatory stimulant, antiviral and endocrine balancing [232]. A distinction is made between high-moor (bog) peat with high acidity (pH 3–4) and low nutrient content and low-moor (fen) peat with typically higher pH (pH 6–8) and higher nutrient content [236]. Thereby, low-moor peat also consisting of mosses and other plants is reported to exhibit anti-inflammatory, antiviral and antiseptic properties. It is used in fangotherapy against arthritis, muscle pain, joint pain and inflammation [232]. High-moor peat reportedly has ‘immune-boosting’, endocrine balancing, relaxing and revitalizing action. Applications with high-moor peat are also meant for revitalization and aesthetics [232].

Mud, but also clay and peat, are typically applied as mud packs or mud baths. Mud packs for local application can be prepared by placing and enwrapping layers of smooth mud paste in cloth before placing it on specific body parts. Alternatively, it is directly applied on the skin, e.g. as a face mask. Mud baths are prepared in special bathing tubs in which people immerse the whole body (except the head) for up to 1 h [232].

Mud, clay and peat of different provenance often have different compositions and thus may have different therapeutic properties. Black mud from ‘dark cotton soil’ in India, which is Vertisol soil, with an abundance of swellable clay minerals [237], is rich in mineral components and holds water for a long time. Mud from the Dead Sea is especially rich in salt and minerals, natural tar and further organic constituents [232]. Mud from the North Sea is primarily used to treat dermatological and musculoskeletal disorders [238]. In any case, mud, clay and peat are prepared before use by drying, sieving and powderizing in order to remove coarse impurities such as plant residues and rock fragments. Chemical contamination must be avoided [16].

(d) . Antibiotics from soil microorganisms

Antibiotics are defined as a large group of organic chemicals produced by microorganisms that belong to several, chemically heterogeneous classes and are deleterious to the growth or metabolic activities of other microorganisms [239,240]. After Alexander Fleming discovered in 1929 that secondary metabolites from fungi can be used as antibiotics to treat infectious diseases in humans and mammals [241], it quickly became clear from the research of S. A. Waksman and others that soils and other natural substrates harbour large numbers of organisms capable of producing antibiotic substances [242]. In fact, soils are a habitat for numerous autochthonous microorganisms that form antibiotics in situ [239,243,244]. Soil microorganisms that are able to produce antibiotics are fungi or bacteria belonging to the phyla Actinobacteria, Proteobacteria (e.g. Pseudomonas, myxobacteria), Firmicutes (Bacillus), Bacterioidetes and Cyanobacteria [51,245,246]. The vast majority of secondary metabolites are produced by Actinobacteria and fungi, and among these about 70% of all metabolites ascribed to Actinobacteria are produced by species of one genus, i.e. Streptomyces [29,51]. Antibiotics-producing fungi mostly belong to the genera Penicillium, Aspergillus, Trichoderma and Fusarium [151,246].

Well-known soil-derived antibiotics are streptomycin, cycloheximide, tetracycline and pyrrolnitrin, which are synthesized by representatives of the genera Streptomyces, Bacillus and Pseudomonas [239,245,246]. Antibiotics formed in situ in the soil, especially rhizosphere soil, as well as in roots and seeds, are for example 2,4-diacetylphloroglucinol (2,4-DAPG), herbicolin A, pyrrolnitrin, pyoluteorin, phenazine-1-carboxylic acid (PCA), surfactin, iturin, tensin and viscosinamide. These antibiotics are present in quantities ranging between 0.02 and 5.0 µg (g soil)⁻¹, with even higher concentrations of up to 180 µg (g soil)⁻¹ soil for iturin and surfactin [29,247–249].

Although the production of medicinal products and of antibiotics in particular increasingly involves chemically synthesized substances, until today the majority of the antibiotics used are derived from natural chemotypes or are even natural drugs [150]. Among 162 antibiotics marketed in the years 1982–2019, 7% were natural products and 48% were derived from natural products [250]. Some examples of antibiotics originating from the soil are listed in table 4. However, even more compounds remain to be discovered. It was estimated that several thousand antibiotic substances exist in soil and that only a small proportion of less than 5% has been characterized [257,258]. Approximately 800 compounds have been reported from Bacillus species, and a similar number from pseudomonads, while more than 7000 different secondary metabolites, including numerous antibiotics, were found in Streptomyces isolates [29,51,259,260]. By contrast, efforts to explore soils for structurally novel antibiotics with new modes of action have significantly decreased over the past two decades [29], because it is a time-consuming and costly task. This reflects the fact that most antibiotics are not always present in the soil but are formed only when required in certain niches or microhabitats of soil, thus varying in time and space [261]. Furthermore, antibiotics may exert quite different functions. On the one hand, antibiotics directly suppress competitors and thus provide a survival advantage to the producing microorganism in the highly resource-limited soil environment [240,262]. On the other hand, at low concentration, they may rather have a signalling function, e.g. at subinhibitory concentrations they can induce changes in transcription, virulence, motility and biofilm formation of microorganisms [29,263]. Antibiotics may also have roles in more complex interactions, including virulence on host plants or the shaping of multitrophic interactions [29,264,265]. Consequently, our understanding of antibiotics' functioning is mostly based on clinical research using in vitro assays under controlled laboratory conditions; this, however, may not resemble the functions realized in the natural environment [29,266]. Based on the multifarious antibiotics contained in soil, we may conclude that most are unsuitable for medicinal purposes owing to their unspecificity towards a target microorganism, toxicity, weak activity, insufficient pharmacokinetic properties, etc. [150].

Table 4.

Examples of marketed antibiotics originating from microbial natural products (from [51,150,251–256]).

original metabolite	commercial productsa/chemical group*	producing organisms
penicillins	Penicillin G V, Ampicillin, Methicillin, Amoxicillin, Carbenicillin	Penicillium spp., Aspergillus spp.
cephalosporins	Mefoxin, Ceclor, Claforan, Rocephin, Ceftin	Acremonium spp., Emericellopsis spp., Amycolatopsis lactamdurans, Streptomyces clavuligerus
daptomycin	Cubicin	Streptomyces roseosporus
erythromycin	Erythrocin, Zithromax, Biaxin, Ketek	Saccharopolyspora erythraea
fosfomycin	Monuril	Streptomyces fradiae
fusidic acid	Fusidin, Fucidine	Fusidium griseum
gentamycin	G-Myticin, Garamycin
munumbicins		Streptomyces strain NRRL 30562
mupirocin (pseudomonic acid)	Bactroban	Pseudomonas fluorescens
streptogramins	Synercid	Streptomyces pristinaespiralis
streptomycin	Estreptomicina, Devomycin	Streptomyces griseus
terragine		environmental DNA expressed in Streptomyces lividans
thienamycin	Primaxin, Invanz	Streptomyces cattleya
turbomycin A and B	*triaryl cations	clones P57G4, P89C8, P214D2 from metagenomic library of soil microbial DNA
vancomycin	Vancocin	Streptomyces orientalis
violacein, deoxyviolacein	*long-chain N-acyl amino acid antibiotic, bis-indole pigment	Chromobacterium violaceum

^aSome selected trade names.

Modern methods, however, enable a more efficient screening of soils to discover new promising medicinal products. Such techniques include replacing conventional nutrient-rich isolation media with oligotrophic isolation media, constructing simulated natural environments, and cell encapsulation in gel microdroplets [267–269]. More importantly, techniques such as combinatorial chemistry, DNA-based methods (metagenomics) and high-throughput screening are increasingly replacing the classical activity-based functional screening [270,271]. To access the natural products produced by non-cultivable microorganisms, soil DNA is directly cloned into plasmid, cosmid or BAC (bacterial artificial chromosome) vectors. A library of soil-extracted DNA is constructed and screened for the production of biologically active small molecules. If successful, analysis of the cloned soil DNA may indicate novel genes that encode useful enzymes and antibiotics [30,272]. The screening of soil metagenomic libraries can either be based on sequence similarity or focus on enzyme activity and functional gene products, which requires cloning genes of interest in a host such as Escherichia coli [30].

Such modern approaches have yielded novel developments. Therapeutic and pharmacologically important novel antibiotics are deoxyviolacein, violacein and turbomycin A and B. All are broad-spectrum antibiotics acting against both Gram-negative and Gram-positive bacteria [110,251,273]. Tigecylcine, a glycilcycline, is a derivative of tetracycline, which is a long-known natural antibiotic [274]. Further compounds that are under development also belong to well-known antibiotic classes such as glycopeptides and rifamycins [51,150]. New antibiotic classes were detected with the streptogramins dalfopristin and quinupristin (Synercid1), and the lipopeptide daptomycin (Cubicin1) [149,250,275]. Other new developments are: diaminopyrimidine AR-100 (iclaprim), inhibiting dihydrofolate reductase; the glycolipodepsipeptide ramoplanin, inhibiting peptidoglycan transglycosylation [10]; and the peptide deformylase inhibitor LBM-415 [149,150,276–278]. Finally, the antibiotic compounds palmitoylputrescine and terragine have been identified using the new methodological approaches [29,279–281]. At the same time, the culture-based approaches also continue to yield novel antibiotics such as platensimycin and dentigerumycin [282,283].

(e) . Further medicinal substances from soil

In addition to antibiotics, numerous other organic medicinal products can be obtained from metabolites and especially the secondary metabolism of soil microorganisms. These are primary metabolites such as amino acids, vitamins and nucleotides, and secondary metabolites that can (potentially) be used as hypocholesterolemics, anti-cancer drugs, immunosuppressants, stimulators of gastrointestinal motility, enzyme inhibitors, products acting against insects, antiparasitics, ruminant growth stimulants and herbicides [153,284]. To screen the vast number of soil microorganisms and secondary metabolites for these medicinal substances, the introduction of DNA-based approaches helped to boost the progress and state of knowledge. Genome sequencing revealed that Streptomyces species encode about 10 times as many secondary metabolites as predicted from known secondary metabolomes [285]. Similar to the antibiotics these mostly originate from Actinobacteria and especially from the genus Streptomyces, fungi, cyanobacteria and myxobacteria [150,286,287]. A number of the medical compounds developed from that approach were approved for use as pharmaceuticals; many further compounds are under investigation [284,288,289]. Other secondary metabolites were identified as unsuitable, typically because of excessive toxicity against the treated organism [16]. Some compounds and their medicinal uses are briefly outlined in the following; for a more thorough compilation, see Nieder [16]. A brief overview of soil organism-derived compounds from different drug classes is given in table 5.

• Antineoplastic drugs, chemotherapeutics: most of the compounds (60%) exerting anti-cancer activity were first isolated from soil and soil microorganisms [153]. The first of these microbial metabolites used in cancer therapy was actinomycin D, which is related to the antibiotic chemical actinomycin A. It specifically targets and downregulates the expression of stem cells, thus leading to the inability of breast cancer cells to initiate tumour progression, or to cell death in several tumour cell lines [290,291]. Other approved compounds belong to the chemical classes of anthracyclines (e.g. doxorubicin, epirubicin and bleomycin), mitosanes (mitomycin C), anthracenones (e.g. mithramycin and streptopzotocin), enediynes, as well as taxol and epothilones [288,289]. The compounds from the various chemical classes typically act on DNA by interfering with the (pathological) reproduction of DNA and synthesis of RNA. They can be used to treat various types of cancer [284,286,292].

• Enzyme inhibitors: enzyme inhibitors are secondary metabolites especially extracted from Streptomyces. The effect mechanism is the formation of an inactive enzyme–inhibitor complex [293]. Common targets of the various inhibitors are enzymes such as amylases, glucosidases, lipases and proteases. Amylase inhibitors are used to treat carbohydrate-related diseases such as diabetes, obesity and hyperlipaemia. Other enzyme inhibitors are suitable to control arthritis, pancreatitis, cancer and AIDS, Alzheimer's disease etc. Examples of products originating from soil microbiota are paim from Streptomyces corchorushii, lipstatin from Streptomyces toxytricini, and antipain from Streptomyces yokosukaensis [294–296]. Statins are mentioned below (hypocholesterolemic drugs).

• Immunosuppressants: these medicinal products are used to suppress the immune reaction after transplantation of organs such as heart, liver and kidney. Many of them have similarities with or are additionally used as antibiotics. Examples are cyclosporin A, produced by the fungus Tolypocladium nivenum. It acts by binding to a specific protein of immunocompetent lymphocytes such as T lymphocytes, thus reducing the functioning of T cells. Further compounds that are relevant for medicinal use are rapamycin from Streptomyces hygroscopicus and tacrolimus from Streptomyces tsukubaensis. The latter is a macrolide compound that inhibits cell-mediated and humoral immune responses [16,284,288,297].

• Hypocholesterolaemic drugs: statins, a class of hypolipidaemic drugs, inhibit the enzyme HMG-CoA reductase, thus lowering the intracorporal cholesterol level. This subsequently reduces the risk of atherosclerosis and cardiovascular as well as peripheral vascular diseases. Statins such as compactin and mevastatin have been isolated from soil microorganisms of the genera Penicillium, Aspergillus and Streptomyces, and also from genera such as Doratomyces, Pleurotus, Trichoderma and others [298,299].

• Probiotic preparations: a further, yet very different usage of soil microorganisms for medicinal purposes is the preparation of food supplements comprising homeostatic soil organisms. Such preparations include several probiotic bacteria, especially Lactobacilli, i.e. Lactobacillus acidophilus, L. bulgaricus, L. delbreukii, L. caseii, L. plantarum, L. brevis, L. lactis, as well as Bacillus licheniformus, Bacillus subtilis, Bifidobacterium bifidum, and the yeast Saccharomyces [16]. All these microorganisms contribute to a healthy status of the intestinal microflora by producing low-molecular-mass organic compounds such as lactic acid and acetic acid as well as hydrogen peroxide. In this manner, they increase the acidity of the intestine and inhibit the exponential reproduction of harmful microorganisms [300]. The commensal flora in the soil is highly relevant for the establishment of healthy bacteria within the digestive tract, addressing the problems presented by Crohn's disease and the leaky gut syndrome [16,300].

Table 5.

Examples of marketed pharmaceuticals from different drug classes derived from microbial natural products (from [51]).

drug class	compound	commercial producta	producing organism
immunosuppressant	cyclosporin A	Sandimmune	Tolypocladium spp., other Hypocreales
	tacrolimus (FK506)	Prograf	Streptomyces tsukubaensis
	rapamycin (sirolimus)	Rapamune	Streptomyces hygroscopicus
	mycophenolic acid	Cellcept (mycophenolate mofetil)	Penicillium spp.; Verticicladiella abientina; Septoria nodorum
anti-tumour	bleomycin		Streptomyces verticillus
	doxorubicin	Adriamycin, Doxil	Streptomyces peucetius
	daunorubicin	Daunoxome	Streptomyces peucetius and other Streptomyces spp.
lipase inhibitor	lipstatin	Xenical (Orlistat)	Streptomyces toxytricini
cholesterol lowering	lovastatin	Mevacor, Zocor (Simvastatin)	Aspergillus terreus, Monascus ruber, other fungi
	mevastatin	Pravachol (Pravastatin)	Penicillium spp.
anti-migraine	ergotamine	Ergostat, Cafergot	Claviceps spp.

^aSome selected trade names.

(f) . Geopaghy

Small amounts of soil may be involuntarily ingested by people when eating food with adhering soil (especially root crops), when working or when playing sports on dusty or sticky soil [301]. A typical habit of children under the age of 18–20 months in their oral phase is to mouth all kinds of things in order to explore their environment [302,303]. Estimates by the United States Environmental Protection Agency (US EPA) indicate that such children ingest 200 mg soil day⁻¹ or less, but in extreme cases, the value can reach up to 25–60 g soil day⁻¹ [301]. Note, however, that this occurs unintentionally without the purpose to consume soil regularly.

By contrast, geophagy (or geophagia) is the deliberate ingestion of soil [17]. Most primate species and a number of other animals such as several bird species are geophagic [16,163,304]. Archaeological research has shown that humans, starting from the early hominids, also have a long tradition of geophagy as part of their dietary habits [163,305]. Geophagy has been reported on all continents around the globe in all socio-economic, ethnic and religious groups and cultures [306]. It is not restricted to communities of low social status [307]. The practice of geophagy still occurs in many parts of Africa, America, Asia (including India and China), Australia and Europe [308–310]. It has, however, become lost in industrialized countries and urbanized environments [17]. Present-day geophagy comprises the collection, preparation and dietary consumption of specific soils. To this end, especially stone-free, fine-textured, clayey soils from river banks, freshwater seeps and springs are used [163]. Preparation of soil may include mixing with food such as fat and grain flours, portioning, and drying or baking, e.g. to sell as soil cookies (figure 1) [309]. In several areas of the world, e.g. in sub-Saharan Africa, geophagy is especially wide-spread among young children and pregnant and lactating women [305,307].

Figure 1.

Motivations, beneficial and adverse effects related to geophagic soil eating.

Geophagic habits are linked with diverse cultural, medicinal, physiological and nutritional factors [311]. Note, however, that there is actually no clear clinical evidence for the beneficial effect of geophagy [163]. Hence, in various cases, it is suspected that geophagy is done more due to traditional habits or based on anecdotal knowledge rather than health-related evidence [163]. Positive health effects of geophagy are counteracted by adverse effects (figure 1).

Clays and pedogenic oxide minerals such as goethite and haematite may exert beneficial effects by releasing adsorbed nutrient cations such as Ca²⁺, Mg²⁺, K⁺ and also trace elements such as Fe, Mn and Cu [2,302,312]. This is relevant in regions with wide-spread soils of low nutrient status [313]. A proper nutrient supply through the diet is especially relevant for the fetus and nursed infants, explaining the preference for geophagy among pregnant women [307]. Additionally, ion exchange reactions of clays and pedogenic oxides as well as the dissolution of carbonates help neutralize excessive acid in the stomach. Soil can also be used as a laxative (see also information on the pharmaceutical use of loam, clay and other soil minerals in §4c). Several authors also assume that ingested soil may help to detoxify adverse chemicals contained in poisonous plants or contaminated food; detoxification would involve the adsorption of toxic chemicals onto the soil colloids [16,302,314]. Geophagy may have several positive effects during pregnancy. In their review, Sing & Sing [163] reported that anti-nausea properties of some colloidal clays may reduce symptoms of morning sickness in the first period of pregnancy, while the above-mentioned supply with nutrients, especially Ca, is relevant at later stages of pregnancy. Finally, the soil may be eaten as a last resort replacement of other food in the case of starvation [305,309].

Contrasting the outlined beneficial effects of eating soil, adverse effects form the other side of the coin. Although the dissolution of mineral nutrients by ion exchange or proteolysis of minerals will be substantially enhanced in the stomach's liquids with pH 2, this may not release sufficient amounts of all nutrients. Moreover, nutrients may again become biologically unavailable prior to uptake, when they reach the intestine with its alkaline pH [315]. The intracorporal nutrient status can even be reduced, when soil minerals and humic substances with a high sorption capacity and/or with a low content of exchangeable nutrient ions are ingested [316]. Humus-rich soil can effectively chelate Fe, which ultimately causes a deficiency of Fe, leading to anaemia. In vitro soil ingestion simulations showed that soil can reduce the digestive absorption of previously bioavailable nutrients, in particular of trace elements such as Fe, Cu and Zn [317]. Correspondingly, health problems related to a deficiency of trace elements are frequently observed among geophagic populations [16]. On the other hand, consumption of soil with very high content of exchangeable K can lead to a surplus of K in the body, causing hyperkalaemia [163]. Frequent or excessive soil eating can result in excessive tooth wear and chronic intestinal blockage [312]. Ongoing constipation through the accumulation of soil in the digestive tract also reduces the digestive absorption of food ingredients and may provoke abdominal pain, dysphagia, and ultimately obstruction and perforation of the colon [318,319]. Problems from geophagy may be aggravated when the consumed soil contains relevant amounts of toxic compounds from geogenic or anthropogenic origin, such as PTEs (e.g. Cd, Hg, As) or toxic chemicals (e.g. pesticides, industrial contaminants) [16,17,119,301]. Finally, soils can be a significant source of pathogenic microorganisms and parasitic faunal species (e.g. Clostridium botulinum, geohelminthic nematodes) that potentially cause acute or chronic diseases [320] (see also the article by Samaddar et al. on detrimental organisms in this special issue [152]). Determining the content of available elements and the mineral composition of consumed soil may help to better understand the motivation behind geophagic practice and also to assess the possible consequences for human health [203,316,321].

Data accessibility

This article has no additional data.

Competing interests

I declare I have no competing interests.

Funding

I received no funding for this study.