Table 1.

Studies linking environmental chemical exposure and gut microbiome changes.

Publication	Animal model	Dosing regimen	Major gut microbiome and host findings
HEAVY METALS AND PARTICULATE MATTER
Lu et al., 2014a	6-week-old C57Bl6/6 female mice	Mic were treated with 10 ppm arsenic in the drinking water for 4 weeks.	•Arsenic exposure led to distinct β-diversity clustering in the intestinal flora. •Relative abundance of bacteria within the order Streptophyta; family unassigned, order Clostridiales; family unassigned, order Clostridiales; family Catabacteriaceae, order Clostridiales; family Clostridiaceae, and order Erysipelotrichales; family Erysipelotrichaeceae were decreased in arsenic-exposed individuals. •Relative abundance of bacteria within the order Bacillales; family other and order Clostridiales; family Clostridiales Family XIII Incertae Sedis were increased. •Indolelactic acid was decreased in arsenic-treated group, which positively correlated with changes in Erhysipelotrichaceae but negatively associated with Clostridiales Family XIII Incertae Sedis.
Guo et al., 2014	5-week-old ICR mice	Mice were treated with arsenic (3mg/L in drinking water), iron (5mg/L in drinking water) or both treatments at the same dosages for 90 days.	•All individuals exposed to one or both metals had an increase in the relative abundance of Firmicutes, Tenericutes, Proteobacteria, but decreases in Bacteroidetes and TM7. •Arsenic-treated mice had increases in Acidobacteria and Cyanobacteria/Chloroplast; •Verrucomicrobia was elevated in the iron and iron + arsenic groups. •Lactobacillus spp. was increased in those exposed to both heavy metals but decreased in individuals exposed to only one of the two metals. Barnesiella and Bacteroides were also reduced in those exposed to only one of the two metals.
Dheer et al., 2015	6–8 week-old C57Bl/6 Tac male mice	Mice were exposed for 2, 5, 19 weeks to 0, 10, or 250 ppb arsenite As(III).	•As(III) altered the gut microbial community, in particular for Bacteroidetes and Firmicutes. •Arsenic-treatment removed the bacterial biofilm residing along the mucosal lining •This treatment disrupted the diversity and abundance of microorganisms with bacterial spores increasing and intracellular inclusions reduced with the 250 ppb dose.
Lu et al., 2014b	Wild-type (WT) and IL10−/− mice	Mice were exposed to 10 ppm arsenic in the drinking water for 4 weeks.	•An increase in Bacteroidetes but a decrease in Firmicutes occurred in arsenic-treated IL10−/− mice. •These mice also had reduced ability to detoxify inorganic arsenic. •No histopathological changes were evident in the intestines due to genetic status or arsenic-treatment.
Chi et al., 2016	C57/BL6 male and female mice	Mice were exposed to 10 ppm arsenic in the drinking water for 4 weeks.	•Arsenic exposure induced more gut microbiome alterations in females. •In arsenic treated females, Dorea spp. decreased but Akkermansia spp. significantly increased. •Arsenic-treated males had an increase in Dorea spp. •In females, arsenic-induced gut microbiome changes correlated with metabolic pathways involved in metal resistance (including mercury resistance operon, zinc resistance, and the mdtABCD multidrug resistance cluster) and cell transport system (such as glutathione-regulated potassium-efflux system, ATP-dependent efflux pump transporter Ybh, general secretion pathway, and iron acquisition in Streptococcus). •In treated males, the gut microbiome changes were associated with nitrogen, carbon, and sulfate metabolism.
Wu et al., 2016	Non-agouti (a/a) mouse offspring	Female (a/a) mice were exposed from gestation through lactation to Pb (32 ppm in the drinking water), which resulted in a maternal blood lead level (BLL) of 32 μg/dL.	•Bacteroidetes and Firmicutes in the offspring gut microbiome were inversely associated with maternal Pb exposure.
			•Cultivable aerobes decreased but anaerobes increased in the Pb-exposed offspring. •Intestinal flora changes were associated with an increase in adult body weight in male but not female offspring.
Breton et al., 2013	6-week-old Balb/C female mice	Mice were exposed for 8 weeks to lead (PbCl2, 100 or 500 ppm- mg/L) or cadmium (CdCl2, 20 or 100 ppm- mg/L) in the drinking water.	•Exposure to either heavy metal reduced the numbers of Lachnospiraceae but elevated the relative amounts of Lactobacillaeceae and Erysipelotrichaeceacae with the latter primarily being due to changes in Turicibacter spp.
Gao et al., 2017	Adult C57Bl/6 female mice	Mice were exposed to 10 ppm PbCl2 in the drinking water for 13 weeks to a concentration of ~2 mg/kg body weight/day.	•PbCl2-treated animals did not show typical age-dependent increase in phylogenetic diversity. •Clostridiales, Ruminococcus spp., Ruminococcaceae, Oscillospira spp. decreased in treated mice. •Metabolic pathways involving vitamin E, bile acids, nitrogen metabolism, energy metabolism, oxidative stress, and defense/detoxification were disrupted in PbCl2-exposed mice.
Zhang W. et al., 2016	Mongolian toads (Bufo raddei)	The gut microbiome was assayed in toads living in a heavy-metal-polluted area (Baiyin- BY) and compared to those living in a relatively unpolluted area (Liujiaxia- LJX).	•Toads in the BY area had an overabundance of Bacteroidetes. •Tenericutes were over-represented in those from LJX. •In the BY toads, the ratio of Firmicutes/Bacteroidetes and the proportion of beneficial bacteria in the gut microbiome were decreased relative to LJX toads. •Species diversity and proportion of OTUs were also reduced in the toads subjected to heavy metal pollution.
Kish et al., 2013	WT 129/SvEv &IL10−/− mice	WT 129/SvEv mice were orally gavaged with Ottawa urban PM10 (EHC-93: 18 μg/g/day) for 7 or 14 days. Longer-term effects of PM10 exposure were assessed in IL10−/− mice who were subjected to the same treatment for 35 days.	•WT mice exposed to PM10 had alterations in immune gene expression, enhanced pro-inflammatory cytokine secretion into the small intestine, increased gut leakiness (permeability), and hyporesponsiveness in splenocytes to the PM. •IL10−/− mice exposed to PM10 had increased pro-inflammatory cytokine expression in the colon and significant changes in the relative amounts of Bacteroidetes spp., Firmicutes spp., and Verrucomicrobia spp. •The treated IL10−/− mice had bacterial-associated changes in SCFA production with increased abundance of branched chain fatty acids- isobutyrate and isovalerate in the cecum.
NANOPARTICLES
Williams et al., 2015	Male and female Sprague-Dawley rats	Rats were exposed orally for 13 weeks to various sizes (10, 75, and 110 nm) and doses (9, 18, and 36 mg/kg body weight/day) of AgNPs.	•AgNP-exposed rats had decreased populations of Firmicutes and Lactobacillus but greater proportion of potentially-pathogenic gram negative bacteria. •Rats treated with the lower doses and sizes of AgNPs showed increased intestinal-mucosal gene expression of immunomodulatory genes, Muc3, Tlr2, Tlr4, Gpr43, and Foxp3.
van den Brule et al., 2016	C57Bl/6 female mice	Mice were dosed orally for 28 days to AgNPs (0, 46, 460, 4,600 ppb).	•Bacterial sequences and populations in the gut microbiome changed in a dose-dependent manner with AgNP exposure.•AgNPs increased the ratio between Firmicutes (F) and Bacteroidetes (B) phyla because of changes in the distribution of Lachnospiraceae and the S24-7 family, respectively.
Javurek et al., 2017	Male Sprague-Dawley rats	Rats were exposed for 2 weeks to AgNPs (3.6 mg/kg body weight) in two forms: cubes and spheres.	•Clostridium spp., Bacteroides uniformis, Christensenellaceae, and Coprococcus eutactus were reduced in AgNC exposed rats. •Oscillospira spp., Dehalobacterium spp., Peptococcaeceae, Corynebacterium spp., Aggregatibacter pneumotropica were suppressed in the AgNS exposed individuals. •The gut microbiome changes correlated with behavioral responses observed when the same rats were tested in EPM.
Han et al., 2014	Fruit fly (Drosophila melanogaster) larvae	Larvae were exposed to AgNPs (50 μg/ml) or CuNPs (50 μg/ml).	•Larvae exposed to AgNPs show a less diverse gut microbiota, overgrowth of Lactobacillus brevis but a decrease in Acetobacter relative to controls or those exposed to CuNPs.
Merrifield et al., 2013	Zebrafish (Danio rerio)	Zebrafish were fed diets laced with AgNPs or CuNPs (500 mg/kg food for 14 days).	•Select beneficial microbes, e.g. Cetobacterium somerae, were reduced to undetectable levels in those exposed to CuNPs. •Two uncharacterized bacteria within the Firmicutes phylum were suppressed by CuNPs but not AgNPs. •CuNPs led to greater gut microbiome changes than AgNPs, although some OTUs were sensitive to AgNPs. •Neither type of NPs affected the intestinal epithelial lining of exposed zebrafish.
Sarkar et al., 2015	Early fingerlings of tilapia (Oreochromis nilticus L.)	Early fingerlings of tilapia were exposed to two sublethal concentrations of AgNPs (0.4 and 0.9 mg/L for 21 days).	•Histopathological analysis of the intestines showed reduced thickness of the intestinal wall, mucosal swelling, and increased catalase expression in AgNP-treated fish. •The overall amount of gut microflora (α-diversity) was reduced in a dose-dependent manner with AgNP exposure, which was accompanied by increase in glutamate dehydrogenase activity.
Das et al., 2014	Gut bacteria from a human donor	A defined bacterial community from a healthy human donor was subjected to 48 h of exposure to AgNPs (25, 100, and 200 mg/L).	•AgNP resulted in a negative influence on bacterial communities, as measured by gas production and changes in fatty acid methyl ester profiles. •AgNPs also induced bacterial community changes with Bacteroides ovatus, Roseburia faecalis, Eubacterium rectale, Roseburia intestinalis, and Ruminococcus torques significantly reduced. •Raoultella spp., Escherichia coli were increased after exposure to the various concentrations of AgNPs.
Yausheva et al., 2016	Redworms (Eisenia fetida)	ZnNPs were added at 1,000 mg/kg to the substrate soil provided to redworms.	•ZnNPs in the soil led to an increase in worm mortality rate (35%). •Exposure to ZnNPs also affected the gut microbiome within the worms with a reduction in β-diversity (303 OTUs in controls vs. 78 OTUs in treated individuals). •While Firmicutes was decreased in ZnNP-treated worms, there were overgrowths of Proteobacteria (primarily due to increases in Verminephrobacter spp. and Ochrobactrum spp.) in exposed individuals.
ENDOCRINE DISRUPTING CHEMICALS (EDCs)
Liu et al., 2016	Adult male zebrafish	Zebrafish were exposed for 5 weeks to BPA (200 μg/L or 2,000 μg/L) or E2 (500 ng/L or 2,000 ng/L).	•BPA or E2 exposure resulted in increased hepatic expression of vitellogenin expression. •BPA or E2 exposed zebrafish also had changes in composition of the intestinal flora with CKC4 increasing significantly.
Javurek et al., 2016	Adult male and female California mice (Peromyscus californicus) Juvenile (PND 30) male and female California mice offspring	Female California mice were exposed 2 weeks prior to mating to BPA (50 mg/kg feed weight), EE (0.1 ppb), or a control diet, and they were continued on the diets throughout gestation and lactation (PND 30). After pairing, reproductive male partners were exposed to these diets until offspring were weaned at PND 30. Male and female offspring were exposed to these above chemicals through the maternal diet and milk from periconception through lactation, respectively.	•Exposure to BPA and EE resulted in generational and sex-dependent gut microbiome changes. •Several of the bacteria whose relative abundance increased with BPA or EE exposure in the P0 or F1 generation, namely Bacteroides spp., Mollicutes, Prevotellaceae, Erysipelotrichaceae, Akkermansia, Methanobrevibacter, Sutterella spp., are associated with various diseases, such as inflammatory bowel disease (IBD), metabolic disorders, and colorectal cancer. •The relative abundance of the beneficial bacterium, Bifidobacterium spp., was elevated in fecal samples of BPA- and EE-exposed F1 females. •Gut microbiota alterations were also associated with alterations in various metabolic and other pathways.
Lai et al., 2016	3-week-old CD1 male mice	Mice were subjected for 10 weeks to one of these three treatments: BPA (120 μg/ml in the water), sucrose water solution (high sucrose diet- HSD, 200 mg/ml), or consumption of a high fat diet (HFD).	•Cecal contents from these three groups were similar in α- and β-diversity in terms of gut microbial community structure. •Both the BPA and HFD groups had relative overabundance of Proteobacteria •The BPA and HFD groups also had relative increases in Helicobacteraceae but reductions in relative abundance of Firmicutes and Clostridal spp.
Koestel et al., 2017	Adult dogs (Canis familiaris)	Adult gonadectomized male and female dogs were switched from being fed dry dog food and placed for 2 weeks on one of two brands of commercial canned dog food.	•After 2 weeks of being on either commercial brand canned dog food, dogs in this study had an increase of BPA concentrations by almost three-fold. •Relative abundance of Bacteroides spp., Streptophyta, Erysipelotrichaceae, and Flexispira spp. negatively correlated with greater circulating levels of BPA. •Bacteroides ovatus, Prevotella spp., Ruminococcus spp., and Cetobacterium somerae positively correlated with elevated concentrations of BPA.
Hu et al., 2016	Sprague-Dawley female rats	Sprague-Dawley female rats were chronically exposed from birth to adulthood to diethyl phthalate (DEP- 0.1735 mg/kg body weight), methylparaben (MPB- 0.1050 mg/kg body weight), triclosan (TCS- 0.05 mg/kg body weight), or the mixture of these three chemicals.	•Chronic exposure to these individual or combined chemicals led to microbiome changes by adolescence but many of these changes were abolished by adulthood •The changes observed in adolescence included the relative abundance of Bacteroidetes (Prevotella spp.) was increased but Firmicutes (Bacilli spp.) was reduced in all treated groups. •Rats treated with DEP or MPB showed reduced body weight at adolescence.