Introduction
In this paper, we will analyse the Anthropocene as the context in which human actions are continuously leading to global change that is resulting in mass-extinction and biodiversity loss. The anthropogenic planetary context is defining humans' experiences of health and well-being, their relationships with the environment, risks to and experiences of ill-health and diseases [Reference Whitmee, Haines, Beyrer, Boltz, Capon, de Souza Dias, Ezeh, Frumkin, Gong, Head and Horton1]. Biodiversity loss has a direct impact on human health [Reference Marselle, Stadler, Korn, Irvine and Bonn2]. One of the pathways of impact is related to the microbiota. Biodiversity loss is directly impacting the microbiota diversity of humans, soil and other species, which are interrelated [Reference Trevelline, Fontaine, Hartup and Kohl3]. Decreased diversity of the human gut microbiota during the development phase and during later life course can have several impacts on health outcomes [Reference Haahtela4,Reference Lindley, Cook, Dennis and Gilchrist5]. One of the pathways of interaction between the human gut microbiota and health outcomes is through epigenetics. This can be exemplified through the current obesity epidemic. A framework capturing the complex interaction between the anthropogenic activities and their impact on health through the reduction of biodiversity and epigenetic changes has been constructed (Fig. 1).
In this paper, the existing scientific evidence will be reviewed and analysed within this proposed framework, using obesity as an example. This paper addresses the growing interest in microbiota in relation to health that seems to be (partly) mediated via epigenetics. The paper gives an overview over existing data, providing advice for future research and public health directions on this topic.
Anthropocene
The Anthropocene is the new geological epoch where anthropogenic activities, such as the burning of fossil fuels (technology and infrastructure) and land use change (agriculture and urbanisation), are shaping and have led to a dysbiosis in planetary processes [Reference Crutzen, Crutzen and Brauch6, Reference Gillings and Paulsen7]. Anthropogenic activities led to a global change, including increased use of pesticides, use of plastics (a derivate of oil) and other contaminants that are polluting oceans, air and soil, leading to changes at the planetary scale [Reference Rockström, Steffen, Noone, Persson, Chapin, Lambin, Lenton, Scheffer, Folke, Schellnhuber, Joachim, Nykvist, De Wit, Hughes, Van der Leeuw, Rodhe, Sörlin, Snyder, Costanza, Svedin, Falkenmark, Karlberg, Corell, Fabry, Hansen, Walker, Liverman, Richardson, Crutzen and Foley8].
Planetary changes include climate change and biodiversity loss [Reference Rockström, Steffen, Noone, Persson, Chapin, Lambin, Lenton, Scheffer, Folke, Schellnhuber, Joachim, Nykvist, De Wit, Hughes, Van der Leeuw, Rodhe, Sörlin, Snyder, Costanza, Svedin, Falkenmark, Karlberg, Corell, Fabry, Hansen, Walker, Liverman, Richardson, Crutzen and Foley8]. Climate change has a direct impact on biodiversity, which, in turn, is impacting climate change through its central role in ecosystem health, regulating local and regional climate [Reference Cardinale, Duffy, Gonzalez, Hooper, Perrings, Venail, Narwani, Mace, Tilman, Wardle, Kinzig, Daily, Loreau and Grace9–Reference Seddon, Mace, Naeem, Tobias, Pigot, Cavanagh, Mouillot, Vause and Walpole13]. Deteriorated local, regional and planetary ecosystems play a central role in influencing population health, putting people at higher risk for a range of infectious and non-communicable diseases, such as obesity, which have gained more momentum in research since the WHO Ecosystem Millennium Assessment in 2005 [14], the WHO/CBD State of Knowledge Review on Biodiversity and Human Health [15] and particularly since Whitmee et al. [Reference Whitmee, Haines, Beyrer, Boltz, Capon, de Souza Dias, Ezeh, Frumkin, Gong, Head and Horton1] defining work on Planetary Health.
Biodiversity and genetic (intraspecies) and species loss are direct consequences of the global change in characterising the Anthropocene [Reference Seddon, Mace, Naeem, Tobias, Pigot, Cavanagh, Mouillot, Vause and Walpole13, Reference Johnson, Balmford, Brook, Buettel, Galetti, Guangchun and Wilmshurst16]. It is impacting food security, microbial ecology and functionality, and, above all, human health [15]. Microbial ecology and functionality play a central role in the human microbiota gut, through interaction with environmental microbial diversity in soil and food over a life-span [Reference Gillings and Paulsen7, Reference Bell, Gessner, Griffiths, McLaren, Morin, van der Heijden, van der Putten, Naeem, Bunker, Hector, Loreau and Perrings17–Reference Lozupone, Stombaugh, Gordon, Jansson and Knight22]. Humans have evolved within the planetary system and are dependent upon its functioning local, regional and planetary ecosystems. Human gut microbiota and immune system have co-evolved due to exposure to various microbes in the surrounding environment [Reference Davenport, Sanders, Song, Amato, Clark and Knight23], such as helminths; or, as Rook [Reference Rook and Brunet24] defines them, as ‘immunoregulatory old friends’ which have been lost through global changes, biodiversity loss in the soil environment [Reference Rook25–Reference Rook and Knight27].
The impact of global change and biodiversity loss in the context of the Anthropocene on the human gut microbiota has not been directly analysed yet. While the Anthropocene can be defined as a dysbiosis of the planetary system, a dysbiosis of the human gut microbiota could be seen as a resemblance of this on an ecosystem level, indicating a systemic dysbiosis on the micro and macro levels of the planetary system.
The human gut microbiota
The terms microbiota and microbiome are often used interchangeably. In this paper, the term microbiota is used to refer to all microorganisms that reside within the human body, and the term microbiome to their genomes and genetic information [Reference Robertson, Manges, Finlay and Prendergast28]. The average ratio of bacteria cells to human cells has been estimated to be 1:1 [Reference Baothman, Zamzami, Taher, Abubaker and Abu-Farha29–Reference Whiteside, Razvi, Dave, Reid and Burton31]. Most of the bacteria are located in the large intestine and on the human skin, with Bacteroidetes and Firmicutes, as main phyla accounting for >90% of the total gut microbiota [Reference Baothman, Zamzami, Taher, Abubaker and Abu-Farha29].
The human microbiota gut is formed of phyla, bacterial species and strains, yeasts and other microbes [Reference Ley, Peterson and Gordon32]. It is important for maintaining human health, playing a role in proper digestion, synthesis of vitamins, production of neurotransmitters, absorption of minerals, regulating the immune system and inflammatory response while preserving the integrity of the gut epithelial barrier [Reference Brandtzaeg33–Reference Soderborg, Clark, Mulligan, Janssen, Babcock, Ir, Lemas, Johnson, Weir and Lenz37].
The development of the human gut microbiota composition in the first 2 years of life defines the immune system among other functions, central for child development and growth [Reference Robertson, Manges, Finlay and Prendergast28]. Several studies have found an association with lower diversity in the gut and chronic inflammation, thereby influencing obesity and other non communicable diseases (NCDs), such as allergies, diabetes, cancer and some psychiatric disorders [Reference Johnson, Balmford, Brook, Buettel, Galetti, Guangchun and Wilmshurst16, Reference Rook and Brunet24–Reference Rook and Knight27, Reference Bloomfield, Rook, Scott, Shanahan, Stanwell-Smith and Turner38–Reference Cornejo-Pareja, Muñoz-Garach, Clemente-Postigo and Tinahones47].
The effects of the Anthropocene on the human gut microbiota
A recent review of geographical differences in gut microbiota with diet showed that people eating an omnivorous diet had a higher diversity of bacteria compared to vegetarians [Reference Senghor, Sokhna, Ruimy and Lagier48]. Moreover, gut microbiota composition differs widely according to a geographical area and between different ethnic groups within the same area, with the highest diversity of bacteria species encountered in the African population [Reference Senghor, Sokhna, Ruimy and Lagier48]. A comparative study of gut microbiota among Colombians, Europeans and Asians found that in Colombians, there is a tendency in Firmicutes diminishing with increasing body mass index (BMI), whereas no association was observed for Bacteroidetes [Reference Escobar, Klotz, Valdes and Agudelo49]. Escobar et al. [Reference Escobar, Klotz, Valdes and Agudelo49] pointed out that geography contributed to determining bacteria composition more than BMI or gender.
Research by McDade et al. [Reference McDade, Tallman, Madimenos, Liebert, Cepon, Sugiyama and Snodgrass50] in a rural Ecuadorian Amazonian context found no existing chronic background inflammation among residents. Blackwell et al. [Reference Blackwell, Trumble, Maldonado Suarez, Stieglitz, Beheim, Snodgrass, Kaplan and Gurven51] reported similar results among Bolivian Amazonian foraging horticulturalists with higher inflammatory indicators in younger age which are depleted in later years of life. Further research has shown that babies that have been exposed to unharmful infections (old friends) in early childhood have a stronger immune system and low chronic inflammation in later life [Reference McDade, Georgiev and Kuzawa52, Reference McDade, Ryan, Jones, MacIsaac, Morin, Meyer, Borja, Miller, Kobor and Kuzawa53]. Similar results have been reported from other Ecuadorian Amazonian and Peruvian Amazonian contexts [Reference Tallman54, Reference Urlacher, Ellison, Sugiyama, Pontzer, Eick, Liebert, Cepon-Robins, Gildner and Snodgrass55]. Chronic background inflammation is directly related to metabolic disorders, of which obesity is one.
Recent studies on the diverse human gut microbial functionality have looked at the impact of ‘westernisation’ and industrialisation; how ‘cultural change’ have impacted human gut microbiota by looking at hunter-gather groups, people living in rural and urban contexts [Reference Clemente, Pehrsson, Blaser, Sandhu, Gao, Wang, Magris, Hidalgo, Contreras and Noya-Alarcón56, Reference Yatsunenko, Rey, Manary, Trehan, Dominguez-Bello, Contreras, Magris, Hidalgo, Baldassano and Anokhin57]. Clemente et al. [Reference Clemente, Pehrsson, Blaser, Sandhu, Gao, Wang, Magris, Hidalgo, Contreras and Noya-Alarcón56] analysed faeces, skin and oral samples among rural Yanomami people in the Venezuelan Amazon region. They demonstrated an even more diverse composition and with the lowest variability of human microbiota than those of ‘semitransculturated’ Guahibo Amerindians and Malawians. The microbiome was similar across Yanomami people than across other study participants. Clemente et al. [Reference Clemente, Pehrsson, Blaser, Sandhu, Gao, Wang, Magris, Hidalgo, Contreras and Noya-Alarcón56] concluded that the way of living, having been isolated in the Amazon in contrast to a ‘semi-westernised’ lifestyle had an essential impact on the microbiota composition. Yatsunenko et al. [Reference Yatsunenko, Rey, Manary, Trehan, Dominguez-Bello, Contreras, Magris, Hidalgo, Baldassano and Anokhin57] conducted a cohort study among Venezuelan Amazonian, rural Malawian and urban US people on the impact of microbiota between age and geography. They found a difference in ‘bacterial assemblage and functional gene repertoires’ (p. 222) between the first two more rural Venezuelan and Malawian and the urban US populations with similarities across age [Reference Yatsunenko, Rey, Manary, Trehan, Dominguez-Bello, Contreras, Magris, Hidalgo, Baldassano and Anokhin57]. They concluded that a difference in the diet has contributed to the distinct adult microbiota. Diet then is associated with lifestyle and social structure [Reference Yatsunenko, Rey, Manary, Trehan, Dominguez-Bello, Contreras, Magris, Hidalgo, Baldassano and Anokhin57]. In another study on seasonality and food consumption and impact on human gut microbiota among Hadza hunter-gatherers in Tanzania, Smits et al. [Reference Smits, Leach, Sonnenburg, Gonzalez, Lichtman, Reid, Knight, Manjurano, Changalucha and Elias58] have demonstrated that seasonality and availability of food and food quality plays a role in the human gut microbiota among people with a very biodiverse and a highly functional human gut microbiota. Smits et al. [Reference Smits, Leach, Sonnenburg, Gonzalez, Lichtman, Reid, Knight, Manjurano, Changalucha and Elias58] presented that while Firmicutes composition was the same during different seasons, Bacteroidetes operational taxonomic units changed. In comparison with 18 different populations from 16 distinct countries, they conclude that those from more agricultural and rural hunter-gatherer areas where higher in Prevotellaceae than those from urbanised and industrialised contexts. Commonalities were also found with the existence of Spirochaetaceae and Succinivibrionaceae among agricultural and rural areas, and the seasonal disappearance of Bacteroidetes taxa was shown similar to those generally encountered among people living in industrialised contexts [Reference Smits, Leach, Sonnenburg, Gonzalez, Lichtman, Reid, Knight, Manjurano, Changalucha and Elias58]. They concluded that there is a substantial ‘cultural’ difference between human gut microbiota [Reference Smits, Leach, Sonnenburg, Gonzalez, Lichtman, Reid, Knight, Manjurano, Changalucha and Elias58]. This evidence suggests that the analysis of the association between gut microbiota and obesity must be geographical location dependent, and the comparison between distant geographical locations would be invaluable in unveiling underlying mechanisms.
Epigenetics and epigenetic pathways
Epigenetics is the study of heritable changes which affect gene functioning without modifying the DNA sequence [Reference Bird59, Reference Lock, Burke, Dupré, Landecker, Livingston, Martin, Meloni, Pálsson, Rapp and Weiss60]. Epigenetic patterns are shaped dynamically throughout the life-course, and vary from cell types, in contrast to the genetic sequence. The ways epigenetic changes regulate DNA expression and cell maintenance are mainly attributed to the covalent modification of DNA by methylation [Reference Gluckman and Hanson61].
Epigenetic mechanisms have been associated with the microbiota in their modulation of weight, metabolism, appetite control, insulin signalling and inflammation through metabolite production [Reference Dhurandhar and Keith62–Reference Youngson and Morris67]. These mechanisms are gaining progressively more attention as potentially explaining the growing prevalence of obesity worldwide [Reference Harakeh, Khan, Kumosani, Barbour, Almasaudi, Bahijri, Alfadul, Ajabnoor and Azhar34, Reference Chang and Neu68].
There is evidence to show that epigenetics plays a vital role in transmitting obesity and type-2 diabetes risk to the offspring [Reference Baskaran and Kandemir69]. Current research has also shown that obese people tend to have different epigenetic patterns compared to non-obese, reinforcing the relative importance of epigenetics in the study of obesity [Reference Dalgaard, Landgraf, Heyne, Lempradl, Longinotto, Gossens, Ruf, Orthofer, Strogantsev and Selvaraj70–Reference Prescott and Logan73].
The role of the gut microbiota in human health using obesity as an example
The development of the early human gut microbiota and immune system and future influences through food intake are essential when approaching obesity. The modulation of host energy balance (intake and type of food, food behaviour, intestinal absorption, energy recovery from the diet and the anabolic/catabolic balance) and others have concluded that obesity can be viewed as a condition of persistent low-grade inflammation and inflammatory disease [Reference Cox, West and Cripps74–Reference Wensveen, Valentić, Šestan, Turk Wensveen and Polić78].
The obesity epidemic has become a primary global public health concern as the prevalence of obesity has been growing fast and steady since the 1970s, but at different rates across nations [Reference Offer, Pechey and Ulijaszek39]. According to the most comprehensive analysis, by 2025, the global obesity prevalence will reach 18% in men and 21% in women, while severe obesity will reach 6% in men and 9% in women [79]. Within the global burden of obesity, global childhood obesity has risen dramatically over the last few decades: children are increasingly becoming heavier worldwide [Reference Baker, Olsen and Sørensen80] and obese children are at higher risk of becoming obese and overweight adults [Reference Chang and Neu68].
Obesity is defined by an excessive accumulation of fat mass within the body [81]. According to the thrifty genotype hypothesis [Reference Neel82], the current human predisposition to fat accumulation is the result of an evolutionary selection of people with specific genetic combinations which have made them more resistant to the hunger/feast diet. This same genetic predisposition, in a modern obesogenic environment with constant access to food alongside urbanisation and sedentary lifestyles, has generated a higher prevalence of obesity and overweight [Reference Popkin and Gordon-Larsen83]. There is also a link between mitochondrial abnormalities and metabolic disorders, such as obesity, diabetes and insulin resistance, suggesting that excessive energy stores have adverse effects on lipid and glucose metabolism, as it may decrease insulin sensitivity within muscle, liver and adipose tissue and thereby disrupting the balance between energy storage and expenditure [Reference Bournat and Brown84–Reference Sivitz and Yorek86]. Obesity has increased alongside the establishment of modern developed states, social welfare systems and economic structures [Reference Offer, Pechey and Ulijaszek39, Reference Ulijaszek87–Reference Ulijaszek, McLennan, Graff and Singer89]. Current projections estimate a shifting burden of obesity towards the poorer and lower-income nations, as many of them are dramatically changing their diets towards high energy-dense foods often lacking essential nutrients [Reference Popkin and Gordon-Larsen83].
Some genetic determinants play a role in the development of obesity; monogenic forms of severe early onset obesity in children have been described, such as Biedl syndrome or Prader–Willi syndrome [Reference Zhang, Li, Gan, Zhou, Xu and Li90]. The primary mechanism which has been suggested to explain – at least partially – these associations is an epigenetic modification of DNA expression [Reference Gluckman and Hanson91]. The ways epigenetic changes regulate DNA expression and cell maintenance are mainly attributed to the covalent modification of DNA by methylation [Reference Gluckman and Hanson91]. Current research has also shown that obese people tend to have different epigenetic patterns compared to non-obese, reinforcing the relative importance of epigenetics in the study of obesity [Reference Dalgaard, Landgraf, Heyne, Lempradl, Longinotto, Gossens, Ruf, Orthofer, Strogantsev and Selvaraj70–Reference Prescott and Logan73, Reference Warin, Moore, Davies and Ulijaszek92].
In humans, the microbiota composition is usually different in lean and obese people with obese having showed a reduction in Bacteroidetes accompanied by a rise in Firmicutes [Reference Harakeh, Khan, Kumosani, Barbour, Almasaudi, Bahijri, Alfadul, Ajabnoor and Azhar34, Reference Soderborg, Borengasser, Barbour and Friedman36, Reference Dhurandhar and Keith62, Reference Kumar, Lund, Laiho, Lundelin, Ley, Isolauri and Salminen63, Reference Nielsen, Haase, Jaksch, Nalla, Søstrup, Nalla, Larsen, Rasmussen, Dalgaard and Gaarn66, Reference Chang and Neu68, Reference Goni, Cuervo, Milagro and Martínez93, Reference Remely, Aumueller, Merold, Dworzak, Hippe, Zanner, Pointner, Brath and Haslberger94]. Evidence shows that some bacteria, particular in the Firmicutes phyla, are better at harvesting energy from the food than other phyla and bacterial species thereby contributing to weight gain [Reference Harakeh, Khan, Kumosani, Barbour, Almasaudi, Bahijri, Alfadul, Ajabnoor and Azhar34, Reference Paul, Barnes, Demark-Wahnefried, Morrow, Salvador, Skibola and Tollefsbol65, Reference Chang and Neu68, Reference Goni, Cuervo, Milagro and Martínez93]. Remely et al. [Reference Remely, Aumueller, Merold, Dworzak, Hippe, Zanner, Pointner, Brath and Haslberger94] also found a significantly higher ratio of Firmicutes and Bacteroidetes in type-2 diabetics compared to lean controls and obese. Others have shown no difference between the two phyla in obese and lean controls [Reference Baothman, Zamzami, Taher, Abubaker and Abu-Farha29, Reference Harakeh, Khan, Kumosani, Barbour, Almasaudi, Bahijri, Alfadul, Ajabnoor and Azhar34, Reference Goni, Cuervo, Milagro and Martínez93], hence illustrating how a rise in phyla may indicate different results in different people or might be a consequence of status rather than a cause. Also, in the phyla of Firmicutes, there are both so-called beneficial bacteria and Gram negatives; hence, more research is needed to see what types of bacteria, strains and species within the phyla that are in particular linked to excess body weight or linked to changes in how bacteria extract energy from the diet.
A lack of diversity in the microbiota has been associated with dysbiosis in the gut and low-grade chronic inflammation that promotes metabolic disorders, such as obesity and type-2 diabetes in both humans and animals [Reference Harakeh, Khan, Kumosani, Barbour, Almasaudi, Bahijri, Alfadul, Ajabnoor and Azhar34, Reference Luo, Leach, Barres, Hesson, Grimm and Simar64, Reference Remely, Aumueller, Merold, Dworzak, Hippe, Zanner, Pointner, Brath and Haslberger94–Reference Larsen, Vogensen, Van Den Berg, Nielsen, Andreasen, Pedersen, Al-Soud, Sørensen, Hansen and Jakobsen96]. Importantly, the ecosystem of the microbiota continues to change throughout a life course and is likely to be affected by epigenetics [Reference Cureau, AlJahdali, Vo and Carbonero97]. Following, the microbiota is becoming increasingly more recognised as an influencer in epigenetic modifications that takes place throughout a life course [Reference Chang and Neu68]. With this, more research needs to be done in order to fully comprehend the relationship between epigenetics and obesity, in terms of what is the first modulator.
Epigenetic mechanisms have been associated with the microbiota in their modulation of weight, metabolism, appetite control, insulin signalling and inflammation through metabolite production [Reference Dhurandhar and Keith62–Reference Youngson and Morris67]. These mechanisms are gaining progressively more attention as potentially explaining the growing prevalence of obesity worldwide [Reference Harakeh, Khan, Kumosani, Barbour, Almasaudi, Bahijri, Alfadul, Ajabnoor and Azhar34, Reference Chang and Neu68].
The combination of potential genetic/epigenetic, social and environmental risk factors for obesity, has prompted research to focus on the variation of individual risk within obesogenic environments; e.g. epigenetic processes that take place in early life, energy-rich environments such as infant over-nutrition, and maternal obesity, which can significantly increase the risk of obesity later in life [Reference Gluckman and Hanson91]. This has contributed to a shift towards epigenetic mechanisms, and to how genes are regulated and expressed throughout a life course [Reference Palou and Bonet98]. Nevertheless, epigenetic changes and obesity outcomes should be considered into a broader approach accounting for the complexity of the issue, new developments of understanding of the gut microbiota concerning biodiversity in surrounding environments and the importance of the gut microbiota in the context of the Anthropocene [Reference Rook25, Reference Rook and Knight27, Reference Prescott and Logan73, Reference von Hertzen, Beutler, Bienenstock, Blaser, Cani, Eriksson, Farkkila, Haahtela, Hanski, Jenmalm, Kere, Knip, Kontula, Koskenvuo, Ling, Mandrup-Poulsen, von Mutius, Makela, Paunio, Pershagen, Renz, Rook, Saarela, Vaarala, Veldhoen and de Vos99].
Early life factors
Some research has emphasised the importance of preserving the microbial ecology of the gastrointestinal tract during early development, i.e. pre-natal, in pregnant women and foetuses after birth. The microbiota development is expected to begin at birth when babies pass through the vaginal canal where they are exposed to the mother's bacteria and also through breastfeeding [Reference Chang and Neu68]. New research has also indicated that the colonisation of microbes may begin even before birth, as some live bacteria get transferred across the placenta hence indicating the importance of nurturing the gut during pre-natal and during pregnancy [Reference Aagaard, Ma, Antony, Ganu, Petrosino and Versalovic100].
It is estimated that humans establish their full microbiota within the first 2–3 years of life [Reference Robertson, Manges, Finlay and Prendergast28, Reference Soderborg, Borengasser, Barbour and Friedman36, Reference Nielsen, Haase, Jaksch, Nalla, Søstrup, Nalla, Larsen, Rasmussen, Dalgaard and Gaarn66]. Increasing importance has been given to ‘windows of opportunity’ for preventing obesity and other metabolic disorders in early life. This might include proper nutrition during pregnancy and breastfeeding and avoiding antibiotics and caesarean section (C-section) whenever possible [Reference Robertson, Manges, Finlay and Prendergast28, Reference Gilbert, Blaser, Caporaso, Jansson, Lynch and Knight101–Reference Nauta, Ben Amor, Knol, Garssen and Van der Beek103]. Caesarean delivery has been associated with increased body mass in childhood and adolescence [Reference Blustein, Attina, Liu, Ryan, Cox, Blaser and Trasande104] and with an increased risk of both overweight and obesity in preschool children [Reference Rutayisire, Wu, Huang, Tao, Chen and Tao105]. Exposure to antibiotics before 6 months of age or during infancy has been associated with increased body mass in healthy children [Reference Saari, Virta, Sankilampi, Dunkel and Saxen106]; and evidence suggests that antibiotics may permanently dysregulate foetal metabolic patterns as they can alter epigenetic pathways or maternal microbiota [Reference Saari, Virta, Sankilampi, Dunkel and Saxen106, Reference Azad, Moossavi, Owora and Sepehri107]. The offspring of malnourished parents (either over- or under-nourished) have an increased risk of developing both diabetes 1 and 2 and obesity as a result of the changes in the gut microbiota and epigenetic markers [Reference Nielsen, Haase, Jaksch, Nalla, Søstrup, Nalla, Larsen, Rasmussen, Dalgaard and Gaarn66, Reference Canani, Di Costanzo, Leone, Bedogni, Brambilla, Cianfarani, Nobili, Pietrobelli and Agostoni108].
Exposure to antibiotics in utero or very early life and risk of obesity
Prenatal exposure to antibiotics was found to be associated with childhood obesity [Reference Mor, Antonsen, Kahlert, Holsteen, Jørgensen, Holm-Pedersen, Sørensen, Pedersen and Ehrenstein109, Reference Mueller, Whyatt, Hoepner, Oberfield, Dominguez-Bello, Widen, Hassoun, Perera and Rundle110]. The association between antibiotic use and obesity was stronger in babies born with a higher birth weight (>3500 g), while the association with overweight was stronger among babies born smaller (≤3500 g) [Reference Mor, Antonsen, Kahlert, Holsteen, Jørgensen, Holm-Pedersen, Sørensen, Pedersen and Ehrenstein109]. The association was maintained during all pregnancy period, without meaningful differences [Reference Mueller, Whyatt, Hoepner, Oberfield, Dominguez-Bello, Widen, Hassoun, Perera and Rundle110].
Early infancy exposure to antibiotics was consistently found to be associated with an increased risk of obesity later in life [Reference Saari, Virta, Sankilampi, Dunkel and Saxen106, Reference Ajslev, Andersen, Gamborg, Sørensen and Jess111, Reference Bailey, Forrest, Zhang, Richards, Livshits and DeRusso112]. Cumulative exposure to broad-spectrum antibiotics in early life was found to be associated with an increased risk of obesity [Reference Bailey, Forrest, Zhang, Richards, Livshits and DeRusso112]. The effect was maintained in exposure at both very early ages (0–5 months) and later (5–11 months). Interestingly, narrow-spectrum antibiotics were not associated with an increased risk of obesity in any of the age groups considered, suggesting that they could not reach or alter the gut microbiota [Reference Bailey, Forrest, Zhang, Richards, Livshits and DeRusso112]. Consistently, macrolides, a type of broad-spectrum antibiotics were found to be more strongly associated with obesity compared to other molecules [Reference Saari, Virta, Sankilampi, Dunkel and Saxen106]. The association between antibiotic use within the first 24 months and obesity was found to be stronger in boys than girls, and with similar cumulative effects [Reference Saari, Virta, Sankilampi, Dunkel and Saxen106].
Antibiotics were found to modify the association between maternal and child body weight. In an analysis of the Danish National Birth Cohort, a strong association between maternal the BMI and child BMI at age 7 was found [Reference Ajslev, Andersen, Gamborg, Sørensen and Jess111]. This could be explained through a different mechanism including genetic/epigenetic factors, social and behavioural, or through the transmission of gut microbiota at the time of delivery. Antibiotic use before age 6 months interacts with this association, increasing the risk of obesity in children born by normal weight mother, but decreasing it in children born by overweight one [Reference Ajslev, Andersen, Gamborg, Sørensen and Jess111]. These results suggest that gut microbiota transmission might have a predominant role in explaining mother–child concordance for body weight.
Caesarean section and risk of obesity
Delivery by C-section reduces the ability of the new born to come into contact with the vaginal and faecal microbiota of the mother during birth. Therefore, they miss this physiological source of bacterial colonisation.
Delivery via C-section was consistently associated with an increased risk of obesity later in life [Reference Blustein, Attina, Liu, Ryan, Cox, Blaser and Trasande104, Reference Rutayisire, Wu, Huang, Tao, Chen and Tao105, Reference Mueller, Whyatt, Hoepner, Oberfield, Dominguez-Bello, Widen, Hassoun, Perera and Rundle110, Reference Keag, Norman and Stock113]. In meta-analysis, children born by C-section were more likely to be obese by the time they reach 5 years [Reference Keag, Norman and Stock113]. In one of the studies, by age 11, caesarean-delivered children had almost doubled risk of being overweight or obese. This association was stronger and longer lasting among children born from overweight/obese mothers than from normal-weight mothers [Reference Blustein, Attina, Liu, Ryan, Cox, Blaser and Trasande104]. This partially contradicts the interaction maternal-child weight with antibiotic use [Reference Ajslev, Andersen, Gamborg, Sørensen and Jess111]. Risk estimate was similar for delivery by planned or emergency C-section [Reference Mueller, Whyatt, Hoepner, Oberfield, Dominguez-Bello, Widen, Hassoun, Perera and Rundle110]. To what extent C-section has also linked to alterations in the microbiota needs further examination.
Mode of infant feeding and impact on gut microbiota and obesity
Breastfeeding contributes to the protection against obesity in children [Reference Yan, Liu, Zhu, Huang and Wang114]. Breastfeeding at 1 month of age and for more than 6 months was associated with the maximum inverse associations, in one study [Reference Wang, Collins, Ratliff, Xie and Wang115]. Gut microbiota and its dysbiosis in very early ages were shown to play a vital role in this association, as infant exclusively breastfed or formula fed had radically different microbes profiles, with partially breastfed infants having an intermediate profile [Reference Forbes, Azad, Vehling, Tun, Konya, Guttman, Field, Lefebvre, Sears and Becker116]. Interestingly, among partially breastfed infants, formula supplementation was associated with a profile similar to that of non-breastfed infants, whereas the introduction of complementary foods without formula was associated with a profile more similar to that of exclusively breastfed infants [Reference Forbes, Azad, Vehling, Tun, Konya, Guttman, Field, Lefebvre, Sears and Becker116].
Factors associated with obesity later in life
Through the life course, many factors have shown to have an impact on the microbiota, such as diet, nutrition, antibiotics, disease, genetics and exposure to medications [Reference Baothman, Zamzami, Taher, Abubaker and Abu-Farha29]. Growing evidence also supports the association between human microbiota and obesity and several studies have demonstrated how the ‘indigenous’ gut microbiota plays a crucial role as an epigenetic regulator via epigenetic modifications that impact gene expression at different life stages [Reference Chang and Neu68].
There have been studies suggesting that an increase of members of the Firmicutes phylum leads to elevated short-chain fatty acids (SCFAs), such as butyrate, and increased energy extraction from the diet in addition to promoting the maintenance of the intestinal epithelium [Reference Chang and Neu68]. The SCFAs have been found to influence the epigenetic regulations of genes in obese subjects and how an epigenetic mechanism in the gut microbiota may be altered due to nutrition [Reference Canani, Di Costanzo, Leone, Bedogni, Brambilla, Cianfarani, Nobili, Pietrobelli and Agostoni108].
SCFAs are also believed to engage the epigenetic regulation of inflammatory reactions via a free fatty acid receptor (FFAR) and other short-chain fatty acid receptors [Reference Remely, Aumueller, Merold, Dworzak, Hippe, Zanner, Pointner, Brath and Haslberger94]. They have also been linked to different levels of the satiety hormone, which could lead to an increase in food intake [Reference Soderborg, Borengasser, Barbour and Friedman36]. Besides, these may shape epigenetic mechanisms, and for example, butyrate is known as a potent histone deacetylate inhibitor thereby playing a role in metabolic processes [Reference Chang and Neu68]. There is also an association between the microbiota and T-cell differentiation linking gut dysbiosis to changes affecting the Th17/Treg balance under inflammatory digestive conditions and are also relevant in the early stages of obesity and insulin resistance [Reference Luo, Leach, Barres, Hesson, Grimm and Simar64].
Another way of modifying the gut microbiota is through diet. As our gut microbiota is very dynamic, it can easily be profoundly affected by external exposures, such as diet, lifestyle, epigenetics, genetics age, nutrition, medication and other environmental factors influencing the diversity of the gut microbiota [Reference Gupta, Paul and Dutta117, Reference Ley, Turnbaugh, Klein and Gordon118]. In mice, switching from low fat, plant-based diet rich in fibre, to a ‘Western diet’ high in fat and sugar altered the bacteria composition within a single day [Reference Turnbaugh, Hamady, Yatsunenko, Cantarel, Duncan, Ley, Sogin, Jones, Roe and Affourtit45]. In humans, ‘Western’ high-fat diets have resulted in a reduction in Bacteroidetes and an increase in Firmicutes and foods high in fibre have shown to increase the phylum of Bacteroidetes and to a more diverse microbiota [Reference Harakeh, Khan, Kumosani, Barbour, Almasaudi, Bahijri, Alfadul, Ajabnoor and Azhar34]. Others have shown that gut dysbiosis can be altered by a diet rich in non-digestible but fermentable carbohydrates, which were found to promote significant weight loss [Reference Zhang, Li, Gan, Zhou, Xu and Li90].
Several studies have stated that epigenetic processes in relation to the gut microbiota play a crucial position in the development of obesity and other metabolic disorders, as bacteria can cause changes in the DNA methylation patterns of host cells by providing epigenetically active metabolites and substances, and these metabolites are essential for DNA methylation so vital for humans [Reference Harakeh, Khan, Kumosani, Barbour, Almasaudi, Bahijri, Alfadul, Ajabnoor and Azhar34, Reference Kasubuchi, Hasegawa, Hiramatsu, Ichimura and Kimura35, Reference Kumar, Lund, Laiho, Lundelin, Ley, Isolauri and Salminen63–Reference Nielsen, Haase, Jaksch, Nalla, Søstrup, Nalla, Larsen, Rasmussen, Dalgaard and Gaarn66, Reference Chang and Neu68, Reference Goni, Cuervo, Milagro and Martínez93, Reference Remely, Aumueller, Merold, Dworzak, Hippe, Zanner, Pointner, Brath and Haslberger94].
Effects of diet and/or probiotic supplementation on the alteration in body composition and microbiota
The role of gut microbiota in diet-related obesity and some genetic forms of obesity has been investigated in a clinical trial including children with Prader–Willi syndrome and diet-related obesity [Reference Zhang, Li, Gan, Zhou, Xu and Li90]. A diet rich in non-digestible carbohydrates induced significant weight loss and concomitant structural changes of the gut microbiota in both groups, together with the alleviation of inflammation. This change was also accompanied by a relative increase of functional genome groups for acetate production from carbohydrates fermentation in the gut. These findings suggest a role of gut dysbiosis in obesity which is independent of the aetiology of the condition [Reference Zhang, Li, Gan, Zhou, Xu and Li90].
However, not all probiotics impact dysbiosis in the same way. Supplementation with galactooligosaccharides among overweight and obese men and women selectively increased the abundance of Bifidobacterium species in faeces by five-fold (p = 0.009) [Reference Canfora, van der Beek, Hermes, Goossens, Jocken, Holst, van Eijk, Venema, Smidt and Zoetendal119]. However, this did not contribute to significant changes in insulin sensitivity, as no significant alterations in peripheral and adipose tissue, insulin sensitivity, body composition, energy and substrate metabolism were found [Reference Canfora, van der Beek, Hermes, Goossens, Jocken, Holst, van Eijk, Venema, Smidt and Zoetendal119].
A complex double-blind, randomised cross-over clinical trial was conducted to examine the exposure to probiotics on psychological state, eating behaviour and body composition among women [Reference De Lorenzo, Costacurta, Merra, Gualtieri, Cioccoloni, Marchetti, Varvaras, Docimo and Di Renzo120]. Study subjects were classified as (1) metabolically obese/normal-weight [Reference Seo and Rhee121]; (2) metabolically healthy/obese [Reference O'Connell, Lynch, Cawood, Kwasnik, Nolan, Geoghegan, McCormick, O'Farrelly and O'Shea122]; (3) metabolically unhealthy/obese or ‘at risk’ obese [Reference De Lorenzo, Costacurta, Merra, Gualtieri, Cioccoloni, Marchetti, Varvaras, Docimo and Di Renzo120] and (4) normal weight obese syndrome [Reference Di Renzo, Sarlo, Petramala, Iacopino, Monteleone, Colica and De Lorenzo123]. An insufficient, but significant, reduction in BMI, body resistance, fat mass (kg and %) and a substantial increase in free fatty mass (kg and %) were observed in all normal-weight/obese and pre-obese/obese subjects after probiotic intake. In the same groups, a reduction of bacterial overgrowth syndrome and lower psychopathological scores were observed after the intervention [Reference De Lorenzo, Costacurta, Merra, Gualtieri, Cioccoloni, Marchetti, Varvaras, Docimo and Di Renzo120].
The role of the gut microbiota composition
A relative abundance of Akkermansia muciniphila was shown to be negatively associated with BMI in the animal models of obese mice [Reference Everard, Belzer, Geurts, Ouwerkerk, Druart, Bindels, Guiot, Derrien, Muccioli and Delzenne124], in pregnant women [Reference Collado, Isolauri, Laitinen and Salminen125, Reference Santacruz, Collado, Garcia-Valdes, Segura, Martin-Lagos and Anjos126] and overweight children [Reference Karlsson, Tremaroli, Nielsen and Bäckhed127]. Interestingly, however, the same alteration was also observed in adults within the normal range of BMI: a stool sample of Korean twins who were either obese or diabetic but included a broad spectrum of phenotypes was analysed to explore the distribution of gut microbiota in relation to body weight [Reference Yassour, Lim, Yun, Tickle, Sung, Song, Lee, Franzosa, Morgan and Gevers128]. For both clinical and microbial phenotypes, longitudinal samples (samples of the same individual taken over time) were more similar than those of twins; however, the twins were more similar than unrelated individuals. The abundance of A. muciniphila was negatively associated with BMI, fasting blood sugar and insulin levels [Reference Yassour, Lim, Yun, Tickle, Sung, Song, Lee, Franzosa, Morgan and Gevers128].
Some changes in microbiota were shown to be causally related to obesity rather than the other way around, through clinical trials. A randomised, double-blind, placebo-controlled study to evaluate the efficacy of transglucosidase (TGD) in modulating blood glucose levels and body weight gain in patients with type-2 diabetes showed that the Bacteroidetes-to-Firmicutes ratio in the TGD groups significantly increased compared to the placebo group after 12 weeks. This, in turn, was associated with decreased blood glucose levels and prevention of body weight gain [Reference Sasaki, Ogasawara, Funaki, Mizuno, Iida, Goto, Koikeda, Kasugai and Joh129].
The role of epigenetics in explaining the association between gut microbiota and obesity
The abundance of specific phyla and bacteria in the microbiome in association with epigenetic changes was studied in a pilot study on pregnant women [Reference Kumar, Lund, Laiho, Lundelin, Ley, Isolauri and Salminen63]. The association between relative abundances of the predominant phyla in the gut microbiota and whole-genome methylation analysis was studied. DNA methylation patterns in white blood cells were associated with gut microbiota profiles, in particular comparing mothers with higher levels of Firmicutes with mothers with higher levels of Bacteroidetes and Proteobacteria. Pathway analysis revealed potential associations between gut microbiota relative abundance and cardiovascular diseases, inflammatory response, metabolic pathways and cancer.
Data from a Norwegian birth cohort of 552 children were used to sequence 16S rRNA genes on gut microbiota among 169 women, 4 days after delivery and 844 samples of their infants at six-time points during the first 2 years of life [Reference Stanislawski, Dabelea, Wagner, Sontag, Lozupone and Eggesbø130]. These data were used to measure how pre-pregnancy weight and gestational weight gain influence the gut microbiota of mothers during delivery and of their infants in early life. While maternal gut microbiota was found to vary according to pre-gestational weight and gestational weight change, these were only weakly associated with compositional differences in the gut microbiota of their infants [Reference Stanislawski, Dabelea, Wagner, Sontag, Lozupone and Eggesbø130].
Similarly, differences between 16S rRNA gene sequencing data across normal BMI, overweight and obese groups were found with diversity decreasing in the obese when compared with the normal group, with or without diet confounding factors, in a cross-sectional study in a Korean population [Reference Yun, Kim, Kim, Heo, Chang, Ryu, Shin and Kim131].
Finally, a placebo-controlled intervention study to evaluate the effect of supplementation with GLP-1 agonists (glucagon-like peptide-1 agonists) on the bacteria composition in insulin-dependent type-2 diabetic individuals, obese and lean non-diabetic individuals using a methylation analysis was evaluated. In comparison with lean individuals, the abundance of Faecalibacterium prausnitzii and microbiota diversity was remarkably lower in obese and type-2 diabetic subjects. The analysis of five CpGs in the promoter region of FFAR3 showed significant lower methylation in obese and type-2 diabetics. It increased in obese patients throughout the period. These results unveiled a substantial correlation between a higher BMI and lower methylation of FFAR3. Conversely, LINE-1, a marker of global methylation, indicated no significant differences between the three groups or the time points, although the methylation of type-2 diabetics tended to increase over time.
Interactions of the gut microbiota, obesity and epigenetic mechanisms in the Anthropocene
More research has pointed out how our microbiota has geographical characteristics, thereby indicating that the geographic origin and environment also play a role concerning human ecosystems [Reference Clemente, Pehrsson, Blaser, Sandhu, Gao, Wang, Magris, Hidalgo, Contreras and Noya-Alarcón56–Reference Smits, Leach, Sonnenburg, Gonzalez, Lichtman, Reid, Knight, Manjurano, Changalucha and Elias58, Reference Blackwell, Pryor, Pozo, Tiwia and Sugiyama132] and that geography and ethnicity play a role in microbial composition in humans [Reference Gupta, Paul and Dutta117]. People living in industrialised societies have shown to have a different bacteria composition and often to be less diverse than non-urbanised and indigenous populations [Reference Urlacher, Ellison, Sugiyama, Pontzer, Eick, Liebert, Cepon-Robins, Gildner and Snodgrass55, Reference Smits, Leach, Sonnenburg, Gonzalez, Lichtman, Reid, Knight, Manjurano, Changalucha and Elias58]. Moreover, De Filippo et al. [Reference De Filippo, Cavalieri, Di Paola, Ramazzotti, Poullet, Massart, Collini, Pieraccini and Lionetti133] analysed children from rural places in South-Saharan Africa eating a diet very high in fibre which showed a very different microbiota composition compared to European children, in which the children in Europe were more likely to have a dominance of Firmicutes compared to Bacteroidetes, which is similar to [Reference Smits, Leach, Sonnenburg, Gonzalez, Lichtman, Reid, Knight, Manjurano, Changalucha and Elias58]. What this literature had in common was describing the differences based on the so-called ‘culture’ concerning lifestyle, such as ‘westernisation’ and geography, in terms of industrialised, urban, rural and isolated contexts.
Geography in this sense could be seen as an indicator for a functioning ecosystem, disturbed and destructed ecosystem if one looks at isolated Amazonian contexts, rural contexts in Amazonia and Malawi and urban contexts in the USA respectively. Anthropogenic actions altering planetary processes characterise the Anthropocene. Indigenous anthropogenic impact on the Amazon overall biodiversity and soil biodiversity has been demonstrated as increasing biodiversity for 4500 years [Reference Demetrio, Conrado, Acioli, Ferreira, Bartz, James, da Silva, Maia, Martins and Macedo134, Reference Maezumi, Alves, Robinson, de Souza, Levis, Barnett, de Oliveira, Urrego, Schaan and Iriarte135]. Deforestation is decreasing soil biodiversity [Reference Franco, Sobral, Silva and Wall136]. None of soil diversity changes has been analysed in any of the studies. However, the consistency of the gut microbiota in humans have been developed and nurtured as a result of human interaction with nature, as in the form of early human settlement during the geographical epoch of the Holocene, with the development of agricultural practices and changes in dietary habits [Reference Rook25, Reference Rook and Knight27]. Rook's research [Reference Rook and Brunet24–Reference Rook and Knight27, Reference Bloomfield, Rook, Scott, Shanahan, Stanwell-Smith and Turner38, Reference Rook and Brunet40–Reference Rook43] has been essential to our understanding of the co-evolvement of the human gut microbiota with its environment. The importance of the soil diversity, particularly the existence of specific species ‘old friends’ as Rook points out and their loss during the Anthropocene need to be taken into account when analysing the development of human gut microbiota and geographical differences. Lifestyle seems to be a too simplistic explanation for a more systemic change with planetary consequences.
Moreover, research by Robinson et al. [Reference Robinson, Mills and Breed137] is advocating for landscape architecture from a microbiome-ecosystem perspective, which is also supported by a meta-analysis on the positive aspects of gardening on human health [Reference Soga, Gaston and Yamaura138]. These could then also be analysed from a One Health [Reference Zinsstag, Schelling, Waltner-Toews, Whittaker and Tanner139] perspective, including microbiota changes in different species and contexts, with a particular focus on obese cats and dogs [Reference Salas-Mani, Jeusette, Castillo, Manuelian, Lionnet, Iraculis, Sanchez, Fernández, Vilaseca and Torre140–Reference Pallotto, De Godoy, Holscher, Buff and Swanson143]. Under this circumstance, obesity needs to be analysed in context, and we suggest as a consequence of a global change in the Anthropocene, summing events such as urbanisation, deforestation, transportation, land-use change, changes in agricultural practices, use of pesticides and loss of soil biodiversity [Reference Rockström, Steffen, Noone, Persson, Chapin, Lambin, Lenton, Scheffer, Folke, Schellnhuber, Joachim, Nykvist, De Wit, Hughes, Van der Leeuw, Rodhe, Sörlin, Snyder, Costanza, Svedin, Falkenmark, Karlberg, Corell, Fabry, Hansen, Walker, Liverman, Richardson, Crutzen and Foley8, Reference Montag, Kuch, Rodriguez and Müller144, Reference Tasnim, Abulizi, Pither, Hart and Gibson145].
Conclusion
The role of the gut microbiota, obesity and epigenetic mechanisms is increasingly recognised. Obesity should be understood with environmental variables which are in turn embedded in the current context of global change and particularly biodiversity loss within the Anthropocene. Further research should take into account biodiversity, microbiota and epigenetic changes when developing new obesity research streams. These population-based approached based on a systemic response should complement incentives to combat the growing obesity prevalence at the individual level. All interventions, including systemic, public health response to obesity will need to focus on building intersectional and interdisciplinary strategies that seek to understand the complexity of obesity in the Anthropocene.
Conflict of interest
The authors declare no conflict of interest.
Ethical standards
Not applicable.