In the last century, the global production of plastics has exponentially increased due to its widespread use in industry, agriculture, and daily life; thus, some plastics end up polluting the environment [1,2]. It is believed that large plastic polymers are inert and are not absorbed by the intestinal tract due to their size, so they are excreted unmetabolized. However, upon entering the environment and in biological systems, plastics breakdown into small particles by different transformation processes. This destruction produces massive amounts of smaller plastic particles, including microplastics (MPs) (size < 5 mm) and nanoplastics (NPs) (size < 1000 nm), [3] that are water, terrestrial, or airborne pollutants [4,5,6]. It is worrisome that several studies have found these smaller plastic particles in food [7,8,9,10,11,12,13,14] and in animal tissue samples [15,16]. In addition, MPs can serve as a vector for environmental pollutants or plastic additives and cause exposure to hazardous substances [17,18]. In humans, the ingestion and inhalation of MPs [6] and their presence in human stool [19] have been described. 

Plastics used in consumer products and discarded in the environment undergo slow degradation by oxidative processes and biodegradation, resulting in fragmentation into pieces of less than 5 mm, called secondary MPs. There are also primary MPs that are intentionally produced to be used in cosmetics or in different industries. Although plastics can be useful for human health when used in the manufacture of certain medical equipment, it is clear that MPs became ubiquitous environmental contaminants leading to inevitable human exposure, with hypothetical health implications [62].

Regarding the routes of human exposure to MPs, several studies have detected them in food, air, drinking water, wastewater, cosmetics, textiles, and dust [21,63,64]. Therefore, the main routes of entry of these materials into the body are the gastrointestinal and pulmonary routes. In this sense, these materials could pose a potential risk to the human population [65]. Ingestion is considered the major route of human exposure to MPs [66], and these particles have been reported in different food items [10,67,68]. Humans are estimated to ingest tens of thousands to millions of MP particles annually, or on the order of several milligrams daily. Because MPs are similar in size to the food of many aquatic organisms, MPs are often ingested by these organisms by mistake [69]. In humans, MPs may reach the gastrointestinal system through contaminated foods (aquatic organisms that ingest MPs, contaminated water or milk, and table salt, among others) or through mucociliary clearance after inhalation. As mentioned, it is generally believed that large plastic polymers are inert and are not absorbed by the intestinal system. Once ingested, >90% of MPs were reported to be excreted in faeces [70], especially large particles >150 μm; however, smaller particles may be absorbed systematically. It has been reported that MPs 0.1–10 μm in size can cross the blood-brain barrier and the placenta [71], particles < 150 μm can cross the gastrointestinal epithelium, and particles < 2.5 μm can enter the systemic circulation through endocytosis [71,72]. Upon entering in biological systems, plastics break down into small particles through biotic and abiotic weathering and transformation processes, creating massive amounts of smaller plastic particles in the environment, including plastic particles of <5 mm or MPs. Oral ingestion is followed by a number of steps that influence the particles and therefore their interactions, such as the contact with digestive fluids, the contact to intestinal cells, uptake and transport in the intestine and liver, and excretion [73,74]. In order to know if the MPs that have entered the digestive system have the capacity to cause detrimental effects on health, different works have been carried out. In this line, the toxic effects of MPs have been investigated in numerous aquatic species and inflammation, genotoxicity, and oxidative stress responses have been described [15]. However, data on effects in mammalian systems are limited [21]. In this sense, studies using in vivo models have described different effects as the accumulation of MPs in tissues such as the intestine, kidney, and liver [16]; the decreased colonic mucus secretion [75]; a minor uptake in intestinal cells [76]; an increase of bile acids and their metabolites in the liver [77]; the intestinal barrier dysfunction [78,79]; some fatty acid and metabolic disorders [75,78,79]; and also the appearance of intestinal dysbiosis [78,79]. In the same sense, it has been suggested that these changes in gut microbiota composition could increase gut permeability, alter metabolism, and favour an inflammatory response [80]. It is worth mentioning here, that MPs may have a different behaviour if there are intestinal diseases that induce inflammation of the intestinal mucosa, although more studies are needed in this regard [74].

The second route of exposure is the inhalation of suspended MPs in the air. MPs are released into the air by numerous sources, including synthetic textiles, the abrasion of materials, and the resuspension of MPs deposited on surfaces [81]. Air MPs deposit in the respiratory system, and clearance by macrophages or migration to the circulation or lymphatic system may lead to particle translocation. The development of airway and interstitial lung disease in occupational exposure to airborne MPs has been described in workers of the synthetic textile, flock, and vinyl chloride or polyvinyl chloride industries [82,83,84]. This probably occurs under conditions of high concentrations or high individual susceptibility.

Finally, dermal contact with MPs is considered a minimal significant route of exposure, and it has been speculated that NPs (<100 nm) could also transverse the dermal barrier [85].

There is scientific evidence in several species of rodents and mammals, including humans, that some of the MPs reach the bloodstream and are distributed to different organs and tissues, in addition to inducing variations in blood parameters [86,87,88]. The presence of MPs/NPs in the lymph, the portal vein, cerebrospinal fluid, milk (in lactating animals and women), and the human placenta has been detected [21]. MPs and NPs were detected in the human placenta at both foetal and maternal faces and in chorioamniotic membranes [88]. In addition, MPs of approximately 10 μm were also found in lung tissues from autopsies [89]. The removal of MPs from systemic fluids has also been reported to occur through splenic filtration and urine excretion, and MPs have also been detected in human faeces [19,21].

With regard to the main mechanisms of toxicity, it has been suggested that they are oxidative stress and cytotoxicity [16,90,91], deregulation of energy homeostasis and metabolism [92,93,94], translocation to the circulatory system [95,96,97], immune dysfunction [98], neurodegenerative disorders [16], or serving as vectors of microorganisms [99]. Regarding this last mechanism, it is important to note that alterations to the gut microbiome due to MPs could lead to adverse effects, such as the proliferation of harmful species, an increase in intestinal permeability, and endotoxaemia [22]. All these MPs toxic mechanisms are intrinsically interconnected, so that disruption of one process can initiate a cascade of chained toxicological responses [100].

The two most commonly given explanations for obesity, genetics and energy balance, cannot fully explain the substantial increases in the incidences of obesity that have been observed worldwide [101,102,103]. Multiple environmental factors can affect obesity susceptibility such as gut microbiome composition, stress, and disrupted circadian rhythms, among others [104]. In this line, in 2003, the idea of linking endocrine-disrupting chemicals and obesity was introduced [105]. Humans are exposed to an ever-increasing number of environmental toxicants, some of which are important risk factors for metabolic diseases, such as diabetes and obesity. These metabolism-sensitive diseases typically occur when key metabolic and signalling pathways are disrupted, which can be influenced by the exposure to contaminants such as endocrine-disrupting chemicals. Metabolomics has allowed and continues to allow the identification of potential metabolic targets of endocrine-disrupting chemicals [106].

In this sense, it was demonstrated that certain endocrine-disrupting chemicals could activate nuclear hormone receptors that are important to the maturation of white adipocytes, such as peroxisome proliferator-activated receptor γ (PPARγ) [107], or interfere with hormonal signalling in the hypothalamus, pancreas, and liver [108,109]. In addition, they can produce epigenetic modifications, activate retinoid X receptor (RXR) or PPARγ, produce an increase in dysfunctional adipocytes, interfere with other signalling pathways, such as glucagon-like peptide 1 (GLP-1) or nuclear receptors that could alter metabolism, or even modify gut microbiota composition [104]. These endocrine-disrupting chemicals coin the term “obesogens” [110]. It is important to note that some of these “obesogens” contaminate different MPs. We would also like to emphasize that the effects of early-life “obesogen” exposure can be transmitted to future generations and that many epigenetic modifications have been observed after “obesogen” exposure [104].

However, are the MPs truly related to NAFLD? If they are, through what mechanism could they act? Many studies have focused on the effects of MPs on marine organisms, and some reports have shown that MPs can enter the terrestrial food chain [111]. Moreover, it has been demonstrated that MPs interact with microbes in different media [112].

On the other hand, some studies have shown that some environmental chemicals, including antibiotics, pesticides, and several heavy metals, can effectively induce gut microbiota dysbiosis, change the mucus layer, and even result in lipid metabolism disorders in different experimental models, including mice [113,114,115,116,117]. In this sense, it has been reported that the intestine of mice fed high-concentration MPs showed obvious inflammation and higher TLR4 and interferon regulatory factor 5 (IRF5) expression. Thus, authors concluded that MPs can induce intestinal dysbacteriosis and inflammation [118]. Following the same line of research, Luo et al. investigated the impact and mechanism of MPs on dextran sodium sulfate (DSS)-induced colitis. The results demonstrated that gavage with MPs alone caused minimal effects on the intestinal barrier and liver status of mice. For mice with colitis, additional MPs exposure aggravated histopathological damage and inflammation, reduced mucus secretion, and increased the colon permeability. More importantly, MPs exposure also increased the risk of secondary liver injury associated with inflammatory cell infiltration [119].

More specifically, in relation to NAFLD (Table 1), in 2017 Deng et al. used fluorescent and pristine polystyrene microplastics (PS-MPs) particles with two diameters (5 μm and 20 μm) to investigate the tissue distribution, accumulation, and tissue-specific health risk of MPs in mice. They showed that MPs accumulated in the liver, kidney, and gut, have a tissue-accumulation kinetics and distribution pattern that was strongly dependent on the MPs particle size. In addition, the authors suggested that MPs exposure induced a disturbance of energy and lipid metabolism as well as oxidative stress [16]. Similar results have been reported in fish previously [90]. Subsequently, Lu et al. exposed male mice to two different sizes of polystyrene MPs. Their data showed that the polystyrene MPs could induce not only gut microbiota dysbiosis and hepatic lipid metabolism disorders but also decreased mucus secretion in the colon of these mice, providing new insights into the potential health risks caused by MPs in mammals [75]. Similarly, Li et al. aimed to investigate whether exposure to polystyrene-NPs has an impact on the development of NAFLD in chow- and HFD-fed mice. They demonstrated that polystyrene-NPs triggered the oxidative damage and proinflammatory response of hepatic tissue and accelerated the development of liver fibrosis in HFD-fed mice [120]. In this sense, increasing evidence indicates that the exposure of high-fat diet (HFD)-fed animals to other different pollutants, such as PM2.5, SiO2 NPs, or multiwalled carbon nanotubes, could also disrupt glucose tolerance and lipid metabolism, induce oxidative damage to hepatic tissue, and result in the occurrence of liver fibrosis [121,122,123]. It is also interesting to note that MPs serve as minor but efficient vectors for carrying other contaminants such as pesticides, pharmaceuticals, metals, and atmospheric pollutants (PM1, PM2.5), among others [124]. Therefore, it could be hypothesized that such interactions may alter the migration behaviour and exposure patterns of MPs, which could increase the impact on liver involvement.

It is important to point out here the results of the study of Huang et al. Although these authors do not investigate the relationship of MPs with NAFLD, they do investigate them in relation to insulin resistance and changes in the microbiota, which are two key pathogenic mechanisms in NAFLD. They evaluated the effects of polystyrene (PS) on insulin sensitivity in mice fed with normal chow diet (NCD) or high-fat diet (HFD) and explained the underlying mechanisms. Mice fed with NCD or HFD both showed insulin resistance after PS exposure accompanied by increased plasma LPS and pro-inflammatory cytokines such as tumor necrosis factor-α and interleukin-1β. Exposure to PS also resulted in a significant decrease in the richness and diversity of gut microbiota, particularly an increase in the relative abundance of Prevotellaceae and Enterobacteriaceae. Additionally, the experiment showed accumulation of MPs in the liver and other tissues and inhibition of the insulin signalling pathway in the liver of PS exposed mice. The authors suggest that the mechanism of PS exposure to induce insulin resistance in mice might be mediated through regulating gut microbiota and PS accumulation in tissues, stimulating inflammation and inhibiting the insulin signalling pathway [125].

On the other hand, as mentioned, recent studies have described the presence of MPs and NPs in human blood [71,72]. In this sense, the metabolic alterations, especially lipid ones, described in relation to the presence of MPs [16,75,124,126,127] could be indirectly related to the development of NAFLD. In other words, this circumstance should be considered among the possible mechanisms involved in the relationship between PMs and the development of NAFLD.

Nevertheless, to date, authors have not found human studies examining the relationships among MPs, the microbiota, and NAFLD pathogenesis. It is clear that humans are potentially exposed to these pollutants and that the deregulation of the intestinal microbiota by MPs is related to NAFLD and metabolic diseases associated with insulin resistance in mammals. However, to assess this risk, it is necessary to monitor their exposure. In this sense, future studies should assess this risk in humans by monitoring exposure and their presence in, for example, faeces samples [6,19,21] to determine if changes in the microbiota are detected and if they are related to the severity of NAFLD. If verified, efforts to eliminate these pollutants would be urgently needed and should be included in the personalized treatment of NAFLD patients.