Diet and the Gut
Various dietary exposures, at different times of life, may be important in the development of type 1 diabetes (T1D). The "up" arrows indicate associations with an increased risk of type 1, and "down" arrows a decreased risk. These specific factors are discussed on other pages; this page summarizes how factors related to the gut, including gut microbiota, inflammation, and permeability may be a common thread among all these dietary factors.
Source: Slide courtesy of Dr. Jill Norris, Colorado School of Public Health.
Links Between The Gut and Diabetes/Obesity
Changes to the gut (intestine) and the gut microbiota, including inflammation and intestinal permeability (a "leaky gut") are linked to type 1, type 2, and gestational diabetes, as well as insulin resistance and obesity. This page summarizes the these findings, while specific dietary factors are described on the subpages Nutrition, Wheat and Dairy, and Breastfeeding.
The gut microbiome is a very active area of research in relation to diabetes (e.g., Aw and Fukuda 2018; Durazzo et al. 2019; Pitocco et al. 2020). Scientists are now looking into whether gut microbiota can be used for prevention or treatment of type 1 diabetes (Gülden et al. 2015), gestational diabetes (Isolauri et al. 2015), or type 2 diabetes (Brunkwall and Orho-Melander 2017; He et al. 2015; Homayouni-Rad et al. 2016). There has been one successful human randomized controlled trial that used fecal microbiota transplantation to halt the progression of type 1 diabetes in newly diagnosed patients! (de Groot et al. 2020).
A review on the gut microbiome and type 1 diabetes finds that people with type 1 diabetes have a less diverse gut microbiota and other gut differences as compared to people without diabetes, that there is an interplay between gut microbiota and the immune system which is implicated as an important factor in the development of type 1 diabetes, and that various environmental factors (e.g., diet, antibiotics) affect gut microbiota and could potentially contributes to type 1 diabetes (Dedrick et al. 2020). Other reviews also focus on the gut microbiota and type 1 diabetes development (Zhou et al. 2020a), on intestinal permeability in type 1 diabetes (Mønsted et al. 2021), on early life gut microbiota and type 1 diabetes (Zhou et al. 2020b), on gut microbiota and autoimmune disease in general (Jiao et al. 2020; Khan and Wang, 2020; Wu et al. 2020; Zhang et al. 2020), on interactions between gut microbiota/type 1 diabetes and genetics/epigenetics or other factors (Elhag et al. 2020; Giampaoli et al. 2020), and on diet/nutrition, microbiota, and type 1 (Hamilton-Williams et al. 2021).
Knip et al. (2010) review the findings of studies on infant feeding and type 1 diabetes, and conclude that while no specific dietary factor or nutrient has been conclusively found to play a role in the development of type 1 diabetes, data do indicate that certain dietary factors may predispose to or protect against the disease. Another more recent review of early-life exposures and type 1 diabetes also discusses a variety of dietary factors (Craig et al. 2019). However another recent review recommends "the encouragement of long-term breast-feeding for at least the first 6 months of life and the avoidance of early complementary foods and gluten introduction (before 4 months of age) as well as cow milk introduction before 12 months of life" (Verduci et al. 2020). Another review finds that "breastfeeding and late introduction of gluten, fruit, and cow's milk may reduce the risk of type 1 diabetes, whereas high childhood cow's milk intake may increase it (Lampousi et al. 2021).
Type 1 Diabetes
A number of dietary factors have been studied in association with the development of type 1 diabetes, including possible risk factors like cow's milk and the gluten in wheat, as well as possible protective factors such as breastfeeding and various nutrients. See the appropriate pages for information on these foods. (Other factors that also involve diet, including vitamin D deficiency and nitrate/nitrite, are covered in other sections). Much of the focus of these studies have been diet in early life, since the autoimmune antibodies that are associated with the development of type 1 diabetes can often be detected very early in life (Hummel and Zeigler, 2011).
The results of these studies have been mixed. After reading them, you might agree with the title of this editorial in the Journal of the American Medical Association (JAMA): "Infant diets and type 1 diabetes: too early, too late, or just too complicated?" (Atkinson and Gale 2003).
New techniques are now being used to analyze diet in relation to type 1 diabetes, because diet is complex. For example, scientists have looked at metabolites in the blood, to see if any are linked to type 1-related autoimmunity, and actually found that some are-- both for increasing or decreasing risk (Johnson et al. 2019). How exactly these metabolites relate to the intake of specific foods we don't know, but this is a new area of research that will be interesting to follow.
One factor linked in a few studies is the early introduction (before 3 months of age) of solid food. One long-term study found that early solid food was associated with type 1-related autoimmunity development by age 3, but not after that (Hakola et al. 2018).
A Leaky Gut?
It may be that foods like cow's milk and gluten have been associated with type 1 diabetes development for the same reason: because of a malfunctioning intestine (gut). Vaarala (2002) points out that the intestinal walls of people with type 1 diabetes have been found to be more permeable (leaky) than people without type 1, and their intestinal immune system seems to be more active as well, due to inflammation. Vaarala suggests that perhaps these irregularities in the gut immune system in people who develop type 1 diabetes underlie early dietary findings, such as the association of type 1 diabetes with the consumption of cow's milk formula in infancy.
Gut inflammation appears to increase the permeability (leakiness) of the gut. This inflammation has been found in both children with type 1 diabetes and in animal models of diabetes such as non-obese diabetic (NOD) mice, and its source is unknown. A leaky gut can allow the entrance of certain proteins such as are found in wheat or cow's milk, leading to inflammation and autoimmunity. Exposure to these foods alone, however, is not likely the cause of type 1 diabetes without underlying changes in the gut immune system and a leaky gut (Vaarala 2008). Other environmental factors may also contribute to a leaky gut, e.g., vitamin D deficiency (Villa et al. 2016), or environmental chemicals (see the section The Gut and Environmental Chemicals below). A leaky gut can also allow the entrance of bacteria or toxic chemicals into the body, which may trigger autoimmunity (Mu et al. 2017).
There is some discussion as to whether a leaky gut leads to diabetes, or if diabetes leads to a leaky gut. Either way, a leaky gut appears to be involved in type 1 diabetes (Li and Atkinson, 2015). Newer research, however, finds that microbes associated with proteins involved in intestinal inflammation and a compromised gut barrier can be found in people at high risk of type 1 even before diagnosis and also in new onset patients (Gavin et al. 2018), implying that the changes to the gut come before the diabetes. In animals, increased gut permeability can activate of immune system changes in the intestine, including the immune cells that target the islets and beta cells, and lead to autoimmune diabetes (Sorini et al. 2019).
Janet developed type 1 diabetes over 20 years ago at age 14. She has often suffered from a leaky gut, and couldn't tolerate formula as a baby. She also lived in the shadow of a chemical plant that emitted dioxin.
Gut Microbiota and Type 1 Diabetes
Gut inflammation and permeability are also likely accompanied by changes in gut microbiota (Vaarala 2011). The term ‘gut microbiota’ represents a complex microbial community within the body (Atkinson and Chervonsky, 2012). In fact, alterations in gut microbiota may very well explain the increased gut permeability, inflammation, and immune dysfunction in type 1 diabetes (Vaarala 2013).
The gut microbiota is intimately linked with the immune system. It is capable of affecting health by contributing to nutrition, prevention of infectious disease, and through influencing the development and maintenance of the immune system. The importance of the gut microbiota for autoimmunity has already been established (e.g., Xu et al. 2019), and most research now is looking into the mechanisms by which microbes specifically influence the development of autoimmune disease (e.g., epigenetic mechanisms, see for example Chen et al. 2017). In fact, transferring a single species of gut bacteria to certain tissues can trigger autoimmunity in mice and in human liver cells in those genetically prone to autoimmunity (Manfredo Vieira et al. 2018).
There has been one successful human randomized controlled trial that used fecal microbiota transplantation to halt the progression of type 1 diabetes in newly diagnosed patients! (de Groot et al. 2020). This trial shows that the gut microbiota can affect the development of type 1 diabetes, and gives us a path forward for more and larger trials. More trials on supplementing with beneficial gut microbiota in early life are upcoming (e.g., Ziegler et al. 2021).
An increasing body of evidence supports the idea that the gut microbiota may influence the development of type 1 diabetes (Atkinson and Chervonsky, 2012). A systematic review found a significant association between alterations in gut microbial composition and type 1 diabetes (Jamshidi et al. 2019). Specific gut microorganisms have also been identified that are linked to islet autoimmunity, a precursor to type 1 diabetes (Zhang et al. 2022). One hypothesis proposes that, "intestinal microbiota may contribute to the development of type 1 diabetes (T1D) via a two-phased process. The first phase of the process starts at birth and ends with the appearance of the first T1D-associated autoantibodies. During that phase, a successful training of the developing immune system is required in order to establish self-tolerance and to control inflammatory responses. If during that phase the gut microbiome tilts towards disproportion between the abundance of Bacteroides, Bifidobacteria, and Eschericia coli, the maturation of the immune system becomes distorted and susceptibility to immune-mediated diseases increases. The second phase from seroconversion [testing positive to autoantibodies] to overt T1D seems to be characterized by a reduced microbial diversity and a proinflammatory intestinal dysbiosis [gut inflammation]." (Siljander et al. 2019).
The TEDDY study, a large, international, long-term study, have found that a variety of factors were associated with gut microbiome composition, including breastfeeding, birth mode, geographical location, siblings, and furry pets. A sub-study has indeed revealed subtle associations between microbial taxonomy and the development of islet autoimmunity and type 1 diabetes (Stewart et al. 2018). A longitudinal Australian study found that children who test positive to multiple islet autoantibodies and who progress to diabetes, like those with recent-onset diabetes, have a different gut microbiome and increased intestinal permeability (Harbison et al. 2019).
Some research shows that the gut microbiome of people with prediabetes or diabetes is different to that of healthy people. However, these changes seem to emerge after the appearance of type 1-related autoantibodies, suggesting that the gut microbiota might be involved in the progression from beta-cell autoimmunity to clinical disease, rather than in the initiation of autoimmunity (Knip and Siljander 2016). Research does show, however, that gut microbiome development does differ in populations with differing rates of type 1 diabetes, and that the species involved are involved in immune system activation (Vatanen et al. 2016). Some authors have looked at interactions between diet, gut microbiome, and autoimmunity, and hypothesize that these together influence the development of type 1 diabetes (Endesfelder et al. 2016). And, some recent research has shown that there may be changes in the gut "virome"-- viruses in the gut-- that precede any other early signs of type 1 diabetes (Park and Zhao, 2018). Changes in fungal as well as bacterial levels in the gut are also linked to type 1 diabetes development in children (Honkanen et al. 2020).
Analyses of the gut microbiota from people with type 1 related autoimmunity found that these people have an aberrant gut microbiome, as compared to controls (Brown et al. 2011; de Goffau et al. 2013). An analysis of Spanish children with type 1 diabetes found that they had different gut microbiota than children without diabetes. Some of the gut microbiota species were also correlated with blood glucose levels in the children with diabetes (Murri et al 2013). Mexican children with type 1 diabetes also have an altered gut microbiota as compared to those without diabetes (Mejía-León et al. 2014), as do Turkish children (Soyucen et al. 2014), and newly diagnosed young children from the Netherlands (de Goffau et al. 2014), and in China (Qi et al. 2016). Italian children at risk of type 1 have different gut microbiota than healthy controls, and higher gut permeability as well (Maffeis et al. 2016). Italian people with type 1 also have different gut microbiota, as well as inflammation (Pellegrini et al. 2017). Changes in gut microbiota appear to affect susceptibility to type 1 diabetes in the U.S. Alkanani et al. 2015). Also note that geography can make a difference in gut microbiota; a study of type 1 diabetes in numerous countries worldwide found that there are strong differences in microbiota types in different countries around the world (Kemppainen et al. 2015). Having some sort of "gut distortion" of microbes in type 1 diabetes is found even in geographically distinct African and Asian countries (Cinek et al. 2018). There are additional studies on gut microbiota and type 1 development as well (Del Chierico et al. 2022; Luo et al. 2022).
Gut bacteria can influence the autoimmune response, in conjunction with genetic background, as seen in samples from people who developed type 1 diabetes (Paun et al. 2019; Luber and Kostic 2019). In fact, gut microbiota are linked to numerous autoimmune diseases, not just type 1 diabetes (reviewed by Gianchecchi and Fierabracci, 2019; Gobbo et al. 2022; Nogueira and Shoenfeld, 2019), as well as other diseases linked to the immune system (Yoo et al. 2020). A study of various autoimmune diseases found that there was a causal relationship between gut microbiota composition and both type 1 and celiac disease (Xu et al. 2022).
Differing gut microbes are also found in people with type 2 diabetes compared to people without diabetes; no difference was found in type 1 vs. type 2 in Candida species (Gosiewski et al. 2014). Differences in gut microbiota are also found between people with type 1 vs MODY, a non-autoimmune type of diabetes (Leiva-Gea et al. 2018).
In lab animals, gut microbiota clearly has an effect on the development of diabetes. In fact, transferring the microbiota from genetically resistant mice to genetically prone mice delayed the development of type 1-like diabetes in the prone mice (Peng et al. 2014). Some researchers propose that transferring certain microbiota into people may help prevent type 1 (and type 2) diabetes, and as well as the complications of diabetes (Ganesan et al. 2018). In diabetes-prone non-obese diabetic (NOD) mice, dietary prebiotics reduced gut permeability and inflammation, delaying the development of diabetes (Hansen et al. 2019).
Gut microbiota from children with new-onset type 1 diabetes increased fasting glucose levels and insulin resistance in antibiotic-treated mice (Yuan et al. 2022).
We may be able to use this research on the gut microbiota in type 1 to prevent disease development (Al Theyab et al. 2020).
The Gut in Early Life
A German study has looked at the gut microbiota in early life, comparing children with and without islet autoimmunity, a precursor to type 1 diabetes. In both sets of children, they found that the composition of the gut microbiota changed substantially during the first year of life, and was affected by breastfeeding, food introduction, and birth delivery (e.g., vaginal vs. C-section). They did not find any differences in diversity or composition of the gut microbiota in children with and without autoimmunity. Yet they did find changes in "microbial interaction networks" in children who went on the develop type 1-related autoimmunity (Endesfelder et al. 2014). However, another study, this time from Finland, did find differences in early life gut microbiota between those who ended up developing type 1 and those who did not. They found that certain species were higher in those who developed diabetes, that that these species peaked over 8 months before the appearance of autoantibodies. The timing seems to coincide with the introduction of solid food (Davis-Richardson et al. 2014). Another study from Finland also found that the gut microbiome differed among children who went on to develop autoimmunity and then type 1 diabetes, as compared to those who did not (Cinek et al. 2017). Interestingly, Finnish children have a greater higher rate of allergies than Estonian children, as well as different early life microbiota (Ruokolainen et al. 2020).
A group of authors that examined the gut microbiota over time in infants prone to type 1 found that an individual's microbiota remained relatively stable over time (although varied among people). And yet changes in the microbiota did appear between the development of autoimmunity and type 1 diabetes diagnosis (Kostic et al. 2015).
The mother's gut microbiota during pregnancy also appears to affect the development of autoimmunity in her offspring (Nyangahu and Jaspan, 2019), as well as fetal growth (Sato et al. 2019). The timing of early-life solid food intake affects the infant's gut microbiota (and BMI), although these differences are affected by breastfeeding status (Differding et al. 2020).
In mice, the development of diabetes is affected by exposures in early life-- exposures that have no effect in later life-- including gut microbiota (de Riva et al. 2017).
Some influential type 1 diabetes researchers think that we may be able to prevent type 1 by "restoring a disappearing microbe," B. Infantis (Insel and Knip 2018).
Gluten and Gut Microbiota
In lab animals, early life exposure to gut microbes can influence sex hormone levels and thereby the development of diabetes in non-obese diabetic (NOD) mice, an animal model of type 1 diabetes (Markle et al. 2013). Diabetes-prone NOD mice fed a gluten-free diet had a lower incidence of diabetes then those fed a gluten-containing diet, and this difference was associated with differences in their intestinal microbiota (Marietta et al. 2013). When pregnant and lactating NOD mice were fed a gluten-free diet, their offspring had a lower incidence of diabetes and different microbiota-- even when the pups ate a normal diet (Hansen et al. 2014).
Acidic Drinking Water and Gut Microbiota
Drinking water acidity was also shown to affect the development of diabetes in NOD mice, and was also associated with changes in intestinal microbiota (Sofi et al. 2014; Wolf et al. 2014). A study in Norway found that people whose drinking water was more acidic had four times as many cases of type 1 diabetes compared to people who drank less acidic water (Stene et al. 2002), and the prospective study from Germany mentioned above also found that autoantibody-positive children who drank more acidic water had a somewhat faster progression to type 1 diabetes (Winkler et al. 2008).
Antibiotics and Gut Microbiota
You might ask whether or not the use of antibiotics might be associated with the development of type 1 diabetes, since antibiotic use does affect gut microbiota composition (Korpela et al. 2016; Yassour et al. 2016).
A number of long-term, population-wide studies from Denmark have examined this possibility. One found that taking broad-spectrum antibiotics during the first two years of life was associated with an increased risk of type 1 diabetes in the next 13 years of life, but only in children delivered by C-section (not in children delivered vaginally) (Clausen et al. 2016). Another found no association overall, except filling 5 or more broad-spectrum antibiotic prescriptions in the first two years of life did result in a higher risk of type 1 diabetes (Mikkelsen et al. 2017). Maternal use of antibiotics during pregnancy was not associated with childhood type 1 diabetes (Haupt-Jorgensen et al. 2018). An older study also found no link between antibiotic use and type 1 diabetes development (Hviid and Svanström 2009), and a newer, large international study found no link between early life antibiotics and type 1 (or celiac disease) related autoimmunity (Kemppainen et al. 2017). Antibiotics during early childhood were also not associated with an increased risk of type 1 diabetes in Denmark (Antvorskov et al. 2020).
Also from Scandinavia, a large, population-based study from Norway found that antibiotic use during prenatal and early life was not associated with the development of childhood type 1 diabetes (Tapia et al. 2018). A study from Sweden, however, found that dispensed prescriptions of antibiotics, mainly for acute otitis media and respiratory tract infections, in the 1st year of life was associated with an increased risk of type 1 diabetes before age 10, most prominently in children delivered by cesarean section (Wernroth et al. 2020). In South Korea, antibiotics in the first two years of life were not associated with the development of type 1 diabetes during childhood (Lee et al. 2022).
Higher exposure to neonicotinoid pesticides and antibiotics (individually and combined) were found in Chinese children with new-onset type 1 diabetes as compared to healthy controls, and these exposures were also associated with changes in gut microbiota (Xu et al. 2022).
A review finds that while "some data suggest that widespread use of antibiotics may facilitate autoimmunity through gut dysbiosis, there are also data to suggest antibiotics may hold the potential to improve disease activity" (Vangoitsenhoven and Cresci, 2020). A large review found that taking antibiotics in childhood was not linked to type 1 diabetes or celiac disease, but were linked to an increased risk of overweight/obesity (and many other things, especially allergies) (Duong et al. 2022). In Finland, a large study found that broad-spectrum antibiotics were associated with an increased risk of childhood autoimmune disease, while penicillin-type antibiotics were not (Räisänen et al. 2022).
Animal studies do show that antibiotic use does affect the intestinal microbial composition of animals, and this is associated with changes in diabetes development, in diabetes-prone BB-rats. Curiously, however, the effect was largely protective (Brugman et al. 2006). Other rat studies have also shown that antibiotics can have beneficial effects on the immune system (Graversen et al. 2020). However, studies of NOD mice, another rodent strain prone to diabetes, did find that antibiotics (taken from conception through adulthood) increased the risk of diabetes (Brown et al. 2016; Candon et al. 2015; Livanos et al. 2016). Low-dose antibiotics given starting at birth transiently alters the gut microbiota leading to long-term changes metabolism, and affecting immune system genes (Cox et al. 2014). In NOD mice, the prenatal period is the most critical for antibiotic exposure, as compared to later in life. Scientists were able to prevent diabetes from appearing by targeting certain bacteria that cause infections (Hu et al. 2015). Another study by the same authors shows that prenatal antibiotics affects the gut microbiota early in life and is critical for education of the immune system after that (Hu et al. 2016). In NOD mice, even one dose of antibiotics early in life alters intestinal immunity and accelerates and enhances diabetes development (Zhang et al. 2018). Additional studies have also found that antibiotics increase diabetes in NOD mice, as well as change the gut microbiota (Pearson et al. 2019).
Other authors have looked at the effect of early life antibiotics on pigs, to better mimic humans than rodents do. They found that that early life antibiotic exposure affects glucose metabolism 5 weeks after antibiotic withdrawal, and was associated with changes in pancreatic development. The antibiotics had a temporary effect on postnatal gut microbiota, and the changes in pancreatic development only appeared later in life (Li et al. 2017). Early life exposure to antibiotics increases autoimmunity in rats as well (Stanisavljević et al. 2019).
As an aside, rats with type 1 diabetes respond to antibiotics differently than rats without diabetes, implying that perhaps people with type 1 may respond differently to antibiotics than other people, but this remains to be seen (Zheng et al. 2019).
Probiotics and Prebiotics and Type 1 Diabetes
By changing the gut microbiota in a positive way, we may be able to reduce the risk of developing of type 1 diabetes (Knip and Honkanen 2017). Since probiotics (e.g., the beneficial microorganisms found in yogurt) can support proper gut maturation in animals (Calcinaro et al. 2005), the PRODIA study is studying whether using probiotics during the first six months of life decreases the appearance of autoantibodies in children at genetic risk of type 1 diabetes (Ljungberg et al. 2006).
A systematic review and meta-analysis of probiotic/prebiotic/synbiotic supplementation trials on blood glucose control in people with diabetes found no benefit to those with type 1 diabetes, although beneficial effects in those with type 2 or gestational diabetes (Wang et al. 2022).
One intervention trial has found that giving probiotics to infants did not prevent autoimmunity or type 1 diabetes, unfortunately (Savilahti et al. 2018). Another intervention trial found that giving probiotics to children newly diagnosed with type 1 had no significant effect in maintaining residual pancreatic beta cell function (Groele et al. 2021). However a study from India did find benefits of probiotics in children newly diagnosed, including lower HbA1c, lower insulin requirements, and higher rates of remission (Kumar et al. 2021).
One type of probiotic, Lactobacillus johnsonii, has been found to delay the development of diabetes in diabetes-prone rats (Valladares et al. 2010). Another probiotic prevents diabetes in mice (Dolpady et al. 2016). Supplementation with probiotics in the first month of life successfully reduced the risk of type 1-related autoimmunity in children with high genetic risk of type 1 diabetes (Uusitalo et al. 2016). The authors however are not yet recommending widespread supplementation-- they feel more research is needed first. Also note that the probiotics had no effect in children with lower genetic risk. And, while confirming the lower risk of IAA autoimmunity in another publication, the researchers did not find an association between early probiotics and type 1 diabetes development by age 6 (Krischer et al. 2017).
A Canadian study is seeing whether or not prebiotics (which help the growth of microorganisms) improve blood sugar control in children who had had type 1 diabetes for at least a year (Ho et al. 2016). It found that they do-- prebiotics were even associated with an improvement in c-peptide level, which is a measure of beta cell function (Ho et al. 2019).
Probiotics during the first year of life did not appear to affect the risk of developing celiac disease (which is often associated with type 1 diabetes) in children at genetic risk (Uusitalo et al. 2019).
In NOD mice, probiotics can reduce the incidence of autoimmune diabetes, reduce gut permeability, and improve beta cell function (Kim et al. 2020).
Other Factors That May Affect Gut Microbiota
Other factors can also affect gut microbiota-- scientists have identified at least 126 factors that are associated with gut microbiota, and those all together explain less than 20% of the variation among individuals (Zhernakova et al. 2016). For example, in infants, umbilical cord blood vitamin D levels, as well as race, breastfeeding and mode of delivery are associated with gut microbiota composition (Sordillo et al. 2017). Exercise is another factor that affects gut microbiota (Codella et al. 2018). People with type 1 who have good blood glucose control and who exercise have similar microbiota to people without diabetes (Stewart et al. 2017). Diet is a major factor; a variety of dietary factors affect microbiota (reviewed in Singh et al. 2017). Food additives (including artificial sweeteners), food contaminants, trace minerals, polyphenols (present in food), flavonols, and many more (stress, age, climate...) (reviewed in Roca-Saavedra et al. 2018). Diabetes medications may also affect gut microbiota in a beneficial way (Montandon and Jornayvaz 2017). And genetic background also affects gut microbiota (Russell et al. 2019).
Environmental factors that interfere with the gut immune system can probably influence the incidence of type 1 diabetes (Vaarala 2002). Viruses, for example, may be able to increase gut inflammation and permeability. Altered gut microbiota may also explain why children who develop type 1 diabetes are prone to stomach virus infections, or do not develop tolerance to cow's milk proteins (Vaarala 2012). Just the presence of some viruses are associated with intestinal permeability (in people with type 2 diabetes) (Pedersen et al. 2018).
Effects of PCBs on the Gut and Disease
Exposure to PCB 126 increases intestinal inflammation, disrupts gut microbiota, alters metabolism, and increases indicators of cardiometabolic disease, such as insulin and blood glucose levels. Source: Image created by Jennifer Moylan. Gut microbe image courtesy of Pacific Northwest National Laboratory. From NIH Research Brief 287, based on Petriello et al. 2018.
Dietary emulsifiers (found in processed foods) have been shown to affect the gut microbiota, resulting in low-grade inflammation, and promoting the metabolic syndrome in mice (Chassaing et al. 2015).
Pharmaceutical drugs that are used to treat diabetes can affect the gut microbiota (and microbiota can also affect the metabolism and efficacy of drugs) (reviewed by Whang et al. 2019). Traditional Chinese medicine may be able to help prevent or treat type 2 diabetes by improving gut health (reviewed by Nie et al. 2019). The drug salsalate may prevent diabetes in lab animals due to its effects on the gut microbiota and by preventing intestinal inflammation (Zhang et al. 2020).
The endocrine system is affected by the gut microbiota and vice versa (Williams et al. 2020). There is also a question of whether pancreatic beta cells and insulin secretion are affected by gut microbiota (Liu et al. 2020).
Environmental chemicals can also affect gut microbiota (and vice versa); see the section below, The Gut and Environmental Chemicals. Microplastics, which can contain or bond with many chemicals, also affect gut microbiota (Fackelmann and Sommer 2019).
Scientific Symposium: Diabetes and the Microbiome
In late 2014, the American Diabetes Association and JDRF co-sponsored a symposium, Diabetes and the Microbiome, which included a discussion of the microbiome in relation to type 1 and type 2 diabetes as well as obesity. You can read the full text of the workshop proceedings online for free. Some highlights (Semenkovich et al. 2015):
"Several lines of evidence suggest that the microbiome may influence the development of type 1 diabetes."
"The immune system and the gut microbiome develop coordinately, and the close functional relationship raises the possibility that microbes or microbial metabolites could be used in the diagnosis, prevention, or treatment of type 1 diabetes."
"Increasing evidence suggests that microbiome-host interactions may be one environmental factor that influences type 2 diabetes risk and progression."
"The microbiome is modifiable through genetic and environmental circumstances, including method of birth, breast-feeding, antibiotics, diet, exposure to toxins, and hygiene."
In some people, an inflamed, leaky gut with improper microbiota may contribute to the development of type 1 diabetes. The fundamental causes of these changes are unknown. Further studies should consider how environmental chemicals can affect gut inflammation, permeability, and microbiota. While we await the results of some intervention trials, we can support the gut immune system with probiotics and appropriately introduce suspected foods such as wheat and dairy products in our children. There is no evidence yet that these actions will prevent type 1 diabetes, but they are safe and not likely to lead to any harm.
Type 2 Diabetes, Insulin Resistance, and Body Weight
As in type 1 diabetes, disturbances in the composition and function of gut microbiota, and even a leaky gut, may also be involved in type 2, diabetes, obesity, and insulin resistance (Allin et al. 2015; Crommen and Simon 2017; Diener et al. 2021; Federico et al. 2017; Holst et al. 2017; Komaroff 2017; Leite et al. 2017; Meijnikman et al. 2018; Nuli et al. 2019; Pascale et al. 2019; Rainone et al. 2016; Sedighi et al. 2017; Serino 2018; Sircana et al. 2018; Wu et al. 2020), in addition to Non-Alcoholic Fatty Liver Disease (NAFLD) (Cui et al. 2019; Safari and Gérard, 2019).
Interestingly, people who are not obese and have type 2 diabetes have low-grade inflammation in the intestinal tract (Zhou et al. 2018).
A variety of factors have been linked to gut microbiota and type 2 diabetes and/or obesity, many listed below. Others include things like protein in the diet (Madsen et al. 2017).
Amazingly, gastric bypass (bariatric) surgery often leads to remission of type 2 diabetes, even before or without weight loss (Pournaras et al. 2010). There must be something going on in the gut that can contribute to type 2 diabetes; we don't yet know what it is. You may believe that scientists are scrambling to figure this out-- it was an entirely unexpected finding-- and there are many ideas as to why it happens (e.g., gut hormones, Sala et al. 2014, or inflammation/gut microbiota Debédat et al. 2019; Debédat et al. 2022).
Bariatric surgery has also been used in obese people with type 1 diabetes. In this case, the diabetes is usually not put into remission, and patients still need to take insulin, although often much less insulin. Some have better glucose control (lower HbA1c) after the surgery than before (Brethauer et al. 2014; Chow et al. 2016; Middelbeek et al. 2014), but not necessarily, and there is also a risk of both hypoglycemia and ketoacidosis (Kirwan et al. 2016; Rottenstreich et al. 2016). One person has had her type 1 diabetes put into remission with bariatric surgery and without insulin (Hironaka et al. 2018).
Gut Microbiota and Type 2 Diabetes or Obesity
Gut microbiota may be involved in the development of obesity and type 2 diabetes (Cani and Delzenne 2010; Ma et al. 2019). The gut microbiota plays a significant role in the development of the metabolic syndrome as well (Mazidi et al. 2016). Gut microbial composition and functions are strongly influenced by diet, and affect metabolism via energy absorption, gut motility, appetite, glucose/lipid metabolism, as well as fat storage in the liver. An impairment of gut microbes can cause inflammation and insulin resistance (Festi et al. 2014). Animal studies show that gut microbiota can affect the development of obesity, insulin resistance, and diabetes through a variety of mechanisms. A Western diet can promote microbiota that promote obesity (Musso et al. 2010).
A study of Danish adults found that those who had a low bacterial richness in their gut were more likely to be heavier and insulin resistant. Those who were obese and had low bacterial richness also tended to gain more weight over time (Le Chatelier et al. 2013). In Korea, researchers have found changes in the composition and function of "gut microbial markers" that could be used for early diagnosis of an inflamed gut (Yassour et al. 2016). A U.S. study found that people with high blood sugar and insulin resistance had more encroachment of microbiota into the outer layer of the intestinal tract (Chassaing et al. 2017). A study comparing the gut microbiota in people with prediabetes from both India and Denmark found commonalities, despite the geographic differences (Pinna et al. 2021).
In fact, researchers are finding that they may be able to predict type 2 diabetes -- that is, identify women who have a type 2 diabetes-like metabolism by examining the gut "metagenome" -- that is, the genetic material from the gut microbiota. They compared the genetic material from women with diabetes, impaired glucose tolerance, and with normal blood glucose levels. They found differences among these groups, and then used these differences to create a model to predict the risk of type 2 diabetes. These methods also show that the metagenome markers for type 2 diabetes differ between European and Chinese women, so these tools may have to be developed depending on the age and geographic location of the people studied (Karlsson et al. 2013).
Gut microbiota in the first two years of life are strongly associated with BMI at age 12 (Stanislawski et al. 2018).
In lab animals, abnormal gut microbiota can contribute to the development of type 2 diabetes (Yu et al. 2019). Scientists can cause (or prevent) obesity by altering the gut microbiota. They can transfer gut microbiota from a fatter mouse to a thinner mouse and the thinner mouse gains weight (Ridaura et al. 2013; Turnbaugh et al. 2006). Certain beneficial microbiota can also reduce weight gain and improve glucose tolerance in mice (Stenman et al. 2014). Feeding prebiotics to mice can reduce insulin resistance, glucose intolerance, intestinal inflammation and gut permeability (Ahmadi et al. 2019). In humans, we still need more trials, but a review suggests that probiotics/prebiotics could be a promising approach to reduce insulin resistance (Kim et al. 2018).
Fecal microbiota transplantation is being looked at as a potential treatment option for metabolic syndrome (de Groot et al. 2017). Danish adults with certain microbiota had more success on a diet than those with other microbiota (Hjorth et al. 2018). Another trial found that people with type 2 diabetes who had higher levels of gut microbiota that were promoted by dietary fiber had lower average blood glucose levels (Zhao et al. 2018).
In mice, probiotic supplementation reduced body weight and fat mass. Probiotic strains isolated from the a gold medalist Olympic weightlifter were most effective, and also increased exercise performance (Lin et al. 2022).
There are microbiota elsewhere in the body aside from the gut. Interestingly, oral microbiota types have been associated with insulin resistance (Demmer et al. 2017).
Antibiotics and Type 2 Diabetes or Obesity
A large analysis of data from the U.K. found that taking antibiotics was associated with an increased risk of developing type 2 diabetes, the risk increasing with the number of antibiotic courses taken (Boursi et al. 2015). However, a study from Canada did not find a link (Ye et al. 2018).
Antibiotics in Pregnant Women and Effects of Offspring
Antibiotic use during pregnancy is associated with an increased the risk of obesity by 84% in U.S. children at age 7 (Mueller et al. 2015). It is also associated with lower birth weight and higher levels of the hormone leptin in umbilical cord blood (Mueller et al. 2017). Antibotic use during the second trimester was associated with an altered infant gut microbiome composition at 3 and 12 months of age, and with higher infant weight-for-length at 12 months (Zhang et al. 2019). In China, antibiotic use during pregnancy was linked to a 4% higher risk of obesity in children at age 5 (Zhuang et al. 2021).
Antibiotics During Infancy
A longitudinal study of U.K. children found that antibiotic use during the first six months of life was associated with higher body weight during early childhood (Trasande et al. 2013). A U.S. study found that antibiotic use during the first six months of life (but not at older ages) was associated with rapid infant weight gain and obesity at age 2 in Latino children in San Francisco (Ville et al. 2017). A very large U.S. study found that use of antibiotics in the first 2 years of life was associated with a higher BMI at age 5 (Block et al. 2018). In Finnish children, antibiotic use in the first six months of life, or repeated antibiotic use during infancy, was associated with excess weight gain in the first 2 years of life (Saari et al. 2015).
Other studies also show that antibiotic use in the first year or two of life is associated with a higher risk of childhood obesity (Aversa et al. 2020; Bailey et al. 2014; Chen et al. 2020; Dawson-Hahn and Rhee, 2019; Li et al. 2022; Scott et al. 2016), as did a systematic review and meta-analysis (Aghaali and Hashemi-Nazari, 2019).
However, not all studies show a link-- one found that antibiotic use in the first six months of life was not associated with excess weight gain in U.S. children through age 7 (Gerber et al. 2016). And, a large U.S. study found that it was infection-- but not antibiotics-- that was associated with the risk of childhood obesity (Li et al. 2017).
Antibiotics During Childhood
In New Zealand, repeated antibiotic use during the first four years of life was associated with increased BMI at age 4.5 (Chelimo et al. 2020).
In a large, long-term study, researchers found that in healthy U.S. children, antibiotic use was associated with persistent weight gain throughout childhood. Children who had used antibiotics 7 or more times weighed about 3 pounds heavier at age 15 than those who did not use antibiotics (Schwartz et al. 2016). The use of macrolide antibiotics during childhood are associated with weight gain in Finnish children (Korpela et al. 2016).
A study from China has raised another issue-- whether antibiotics given to animals (veterinary antibiotics) are a health issue for humans. This study found that although human antibiotic levels were not associated with obesity in children, veterinary antibiotic levels were (Wang et al. 2016). Another Chinese study also found that exposure to certain antibiotic for veterinary use mainly from food or drinking water was associated with an increased risk of overweight/obesity in children (Li et al. 2022).
In animals, low-dose antibiotics given starting at birth transiently alters the gut microbiota leading to long-term changes in metabolism, enhancing the effect of diet-induced obesity (Cox et al. 2014). Lifelong antibiotics plus a high-fat diet led to different gut microbiota, higher weight, fat mass, and insulin resistance than in mice only exposed to a high-fat diet (Mahana et al. 2016). The effects of antibiotics on obesity also depends on animal genetics (Fujisaka et al. 2016). A review finds that here is strong evidence supporting the role of antibiotics in the development of obesity in animals, but that human evidence is still inconclusive (Leong et al. 2018).
In a study of rats the animals given probiotics had a lower body weight and more diverse intestinal biota than the controls and those who received E coli (a harmful microorganism) (Karlsson et al. 2011).
Scientists screened major types of antibiotics to examine their effects on fat cells, and found that azithromycin suppressed brown and beige fat cell function, accumulated in fatty tissue, was associated with a higher BMI in humans, and increased diet-induced obesity in mice (Yu et al. 2022).
Probiotics and Type 2 Diabetes or Obesity
A systematic review of 33 articles (5 human, 28 animal) concluded that probiotics (especially Lactobacillus) have beneficial effects on glycemic control (Razmpoosh et al. 2016). A systematic review of 6 studies and meta-analysis of 5 studies found that probiotics are associated with lower fasting blood glucose levels in people with type 2 diabetes (Samah et al. 2016). Two separate systematic reviews and meta-analyses found that probiotic and synbiotic supplementation helped to improve markers of inflammation and oxidative stress in people with diabetes (Tabrizi et al. 2019; Zheng et al. 2019). Additional reviews also find benefits of probiotics for people with type 2 diabetes (Bock et al. 2020; Kesika et al. 2019; López-Moreno et al. 2021) and type 2, prediabetes, and gestational diabetes (Cao et al. 2021, Wang et al. 2022). Animal studies also find that probiotics reduce insulin resistance, inflammation, intestinal permeability, and glucose intolerance (Bagarolli et al. 2017).
The gut microbiome has been linked to the development of gestational diabetes as well (Cortez et al. 2018; Hu et al. 2021; Huang et al. 2021; Kuang et al. 2017; Kunasegaran et al. 2021; Ma et al. 2020; Mokkala et al. 2017; Ponzo et al. 2019; Zheng et al. 2020).
Reviews of Trials
A systematic review and meta-analysis of 38 randomized controlled trials found probiotic supplementation may help reduce gestational diabetes occurrence (Ari et al. 2022).
A systematic review and meta-analysis of 12 randomized controlled trials found benefits of probiotics and symbiotics in the treatment of gestational diabetes (Hao et al. 2021).
A systematic review and meta-analysis of 20 randomized controlled trials found that probiotic supplements improved blood glucose and reduced insulin resistance in pregnant women with or without gestational diabetes (Pan et al. 2021).
A systematic review and meta-analysis of 17 randomized controlled trials of the effect of probiotics in pregnancy on the incidence of gestational diabetes found no effect of probiotics on gestational diabetes incidence but did find a small but significant reduction of fasting glucose levels and insulin levels in those who took probiotics (Masulli et al. 2020).
A meta-analysis of 12 randomized, controlled trials found that probiotics reduce the blood glucose level of pregnant women, especially those without gestational diabetes (Peng et al. 2018).
A systematic review and meta-analysis of 11 randomized controlled trials of probiotics in women with gestational diabetes found that supplementation improved blood sugar control and other factors in these women, and helped the babies as well (Zhang et al. 2019).
A systematic review and meta-analysis of 8 randomized controlled trials of probiots in women with gestational diabetes found that supplementation decreased fasting glucose and insulin levels and reduced insulin resistance, and that synbiotics reduced insulin resistance (Çetinkaya Özdemir et al. 2022).
A meta-analysis of 7 randomized controlled trials found that probiotic supplementation might reduce fasting blood glucose levels in women with gestational diabetes (Chen et al. 2019).
A review and meta-analysis of four high-quality trials found that probiotic supplementation did not decrease fasting blood glucose or LDL ("bad") cholesterol, but did reduce insulin resistance. Probiotics did not affect gestational weight gain, delivery method or neonatal outcomes between experimental and control groups, and no adverse effects of the probiotics were reported (Taylor et al. 2017).
However, another review and meta-analysis found that probiotics did reduce insulin resistance and insulin levels in women with gestational diabetes, but had no effect on glucose levels, gestational age, or gestational weight (Pan et al. 2017).
A review found that probiotics may help prevent gestational diabetes (Homayouni et al. 2019).
A review found that probiotics did not help prevent gestational diabetes (Chen et al. 2022).
A number of double-blind, placebo-controlled, randomized clinical trials have tried to determine the effects of probiotics on women with gestational diabetes:
One from Iran found that those who took a probiotic had less weight gain and lower fasting blood glucose levels than those who received a placebo (Dolatkhah et al. 2015).
Another from Iran found that those who took probiotics for 6 weeks had better glucose control, lower insulin resistance, and better triglyceride levels than those who received a placebo (Karamali et al. 2016).
A third, also from Iran, found that probiotics lowered inflammation and insulin levels, and improved insulin resistance (Jafarnejad et al. 2016).
A fourth found that probiotics combined with vitamin D had numerous beneficial effects in women with gestational diabetes (Jamilian et al. 2018).
A fifth found that probiotics lowered fasting glucose levels in overweight/obese pregnant women (Asgharian et al. 2019).
Another found probiotics had beneficial effects on gene expression related to insulin and inflammation, blood glucose control, cholesterol levels, inflammatory markers, and oxidative stress (Babadi et al. 2018).
Yet another found no beneficial effects, however (Shahriari et al. 2021).
A trial from New Zealand, found that women who took lactobacillus supplements in early pregnancy had a lower risk of gestational diabetes, especially if they were older or had had prior gestational diabetes (Wickens et al. 2017).
A trial from Australia in overweight and obese women found that probiotics did not prevent gestational diabetes; rates were actually higher in those who took them (Callaway et al. 2019).
A trial from Finland found that neither probiotics nor fish oil nor their combination lowered the risk of gestational diabetes in overweight or obese pregnant women (Pellonperä et al. 2019).
In China, probiotic use was associated with improved glucose and lipid metabolism in the pregnant women, and might also contribute to the reduced risk of gestational diabetes (Han et al. 2019).
Also in China, probiotic yogurt during pregnancy helped reduce the risk of gestational diabetes, but probiotic yogurt before pregnancy did not (Chen et al. 2019).
When researchers transferred microbiota from women with gestational diabetes to germ-free mice, the mice developed high blood sugar (Liu et al. 2020). Probiotic supplements can alleviate gestational diabetes in rats by restoring gut microbial diversity (Zheng et al. 2021).
The Gut and Environmental Chemicals
One significant environmental factor that may be able to affect the gut immune system, intestinal permeability, and gut microbiota is environmental chemicals. The relationship goes both ways-- chemicals can affect the gut microbiome structure and function, and the gut microbiome can transform chemicals (and this applies to pharmaceutical drugs also) (Collins and Patterson 2020; Elmassry et al. 2020; Giambò et al. 2022; Hampl and Stárka 2020; Li et al. 2020; Lu et al. 2015; Mousavi et al. 2021; Nakov and Velikova, 2020; Sandys and Te Velde, 2022).
For an article describing research on gut microbiota and autoimmune disease (including type 1 diabetes), and factors such as chemicals that may influence the gut microbiota, see The Environment Within: Exploring the Role of the Gut Microbiome in Health and Disease, (Konkel, 2013). Also see Navigating a Two-Way Street: Metal Toxicity and the Human Gut Microbiome, (Schmidt, 2022) both published in Environmental Health Perspectives.
A review of the topic finds that when the gut is exposed to chemicals, the microbiota undergo a series of changes that cause the transformation of chemicals, which are are taken up by the body and affect glucose levels, often by influencing glucose production by the liver. We may be able to prevent these changes by using therapies that affect the microbiota, and thereby help control and prevent diabetes (Velmurugan et al. 2017). Another review discusses how heavy metal exposure alters the composition and metabolic profile of the gut microbiota, and in turn, the gut microbiota alter the uptake and metabolism of heavy metals. It also discusses how probiotics have been shown to reduce the absorption of heavy metals in the intestinal tract (Duan et al. 2020).
A review finds "good evidence that exposure to heavy metals, pesticides, nanoparticles, polycyclic aromatic hydrocarbons, dioxins, furans, polychlorinated biphenyls, and non-caloric artificial sweeteners affect the gut microbiome and which is associated with the development of metabolic, malignant, inflammatory, or immune diseases," and that mixtures of these chemicals may also be important (Tsiaoussis et al. 2019). Another review focuses specifically on autoimmune diseases, discussing how changes in the gut microbiome composition could contribute to autoimmune disease development, especially in response to exposure to environmental chemicals (Khan and Wang, 2020). Environmental chemicals also affect the gut and thereby influence the development of type 2 diabetes and obesity, as well as other diseases related to metabolism (reviewed by Gálvez-Ontiveros et al. 2020). An additional review finds that "major classes of environmental chemicals (bisphenols, phthalates, persistent organic pollutants, heavy metals, and pesticides)" can impact the gut microbiome by causing "alterations in microbial composition, gene expression, function, and health effects in the host" and "changes in metabolism, immunity, and neurological function." (Chiu et al. 2020). A review looks at how gut microbiota might change in response to environmental chemicals, and influence diabetes-related conditions like insulin resistance (Huang 2022). There are additional reviews on environmental chemicals and gut microbiota as well (Campana et al. 2022; Ortiz et al. 2022).
Animal studies show that environmental chemicals affect the gut and the gut microbiota (reviewed by Rosenfeld 2021 and Rosenfeld 2017). For example, when rats are given a chemical called streptozotocin (STZ) which can induce insulin-dependent diabetes, their microbiota changes drastically as diabetes develops. The diversity of the microbiota diminishes over time (Patterson et al. 2015). The microbiota changes induced by STZ also vary depending on where they are in the digestive tract (Wirth et al. 2014).
Early life exposure is especially important. Many environmental chemicals can affect gut microbiota when exposure occurs early, which affects the maturation of the gut (see reviews by Sarron et al. 2020 and Calatayud Arroyo et al. 2020).
Chemicals have not been adequately tested for their effect on the gut, and many chemicals come in contact with food (e.g., pesticides, plastic packaging, and food additives). Many of these may affect the gut microbiota or gut barrier (Groh et al. 2017). Chemicals found in food can affect gut microbiota, lipid metabolism, and inflammation as well (Defois et al. 2018).
PCBs Affect Gut Permeability
Exposure to PCBs disrupts intestinal permeability in intestinal cells. (A) Intestinal permeability assessed 24 hours after PCB administration. B and C show staining of intestinal cells of PCB-exposed mice and unexposed controls ("vehicle"). Sections show individual villi; immunoreactivity is indicated by brown staining. In control animals, immunoreactivity is visible at the borders of adjacent epithelial cells (white arrows). PCB-126 disrupted the morphology of villi, as indicated by loss of the villus epithelium (B; black arrow).
Researchers are beginning to look at the role of the intestine on the fate of contaminants in food. These contaminants can include things like pesticides, heavy metals, and persistent organic pollutants (POPs) such as organochlorine insecticides, PCBs, dioxin, and polycyclic aromatic hydrocarbons (PAHs). Many chemicals enter the body through the intestine, exposing the intestinal cells to significant concentrations. Some of these chemicals can affect the absorption of other, possibly unrelated, substances, and are likely to influence intestinal inflammation as well (some are reviewed in Sergent et al. 2008). For example, the heavy metal cadmium affects the gut microbiota and causes gut inflammation in rodents (He et al. 2019; Ninkov et al. 2015); heavy metals also affect gut microbiota (Richardson et al. 2018) and the intestinal barrier (Jeong et al. 2020). The pesticide carbendazim reduces the richness and diversity of gut microbiota in mice (Jin et al. 2015), the pesticides chlorpyrifos and glyphosate (Roundup) affect the gut microbiota of rats (Fang et al. 2018; Dechartres et al. 2019), and the pesticide trichlorfon damages the intestinal barrier, triggers inflammation, and alters the gut microbiota of fish (Chang et al. 2019).
In a review, Snedeker and Hay (2012) look at how interactions between gut ecology and environmental chemicals may contribute to the development of diabetes and obesity. The microorganisms in the gut may affect an individual's exposure to environmental chemicals; these microorganisms can affect the absorption, distribution, metabolism, and excretion of environmental chemicals, including chemicals linked to diabetes and obesity. For an article describing this review, see Gut check: Do interactions between between environmental chemicals and intestinal microbiota affect obesity and diabetes? published in Environmental Health Perspectives (Holtcamp 2012). You can also listen to Drs. Snedeker and Hay discuss this research on the call, Gut microbiota and environmental chemicals in diabetes and obesity, sponsored by the Collaborative on Health and the Environment (2012).
Human and Animal Studies on Specific Chemicals
A longitudinal study from the Faroe Islands looked at chemical levels over time (starting at birth) and their gut microbiota at age 28. They found that the earlier life contaminant levels didn't have a direct effect on the microbiome of adults, but some current PFAS levels were somewhat related to current gut microbiome composition (Thompson et al. 2022).
In a study of Korean women, those with higher levels of certain bacteria in their guts had higher body mass index and waist circumference. They also had higher levels of persistent organic pollutants in their bodies, suggesting that there may be an interaction among all of these factors (Lee et al. 2011). This research is also discussed on the CHE call, Gut microbiota and environmental chemicals in diabetes and obesity.
More and more studies are examining the effects of chemicals directly on the intestine and gut microbiota. In U.S. infants, arsenic exposure is associated with gut microbiota composition (Hoen et al. 2018), and that arsenic and other chemicals interact with nutrients as well as with antibiotics to influence the gut microbiome (Laue et al. 2020). Lu et al. (2014) found that mice who drank arsenic-laced water developed an altered gut microbiome as well as functional differences in their gut. A study on intestinal cells found that exposure to arsenic causes inflammation and loss of microvilli, and reduces the intestinal barrier (Chiocchetti et al. 2018).
In Norwegian women, levels of various POPs (including PCBs, PBDEs, and PFASs) in breastmilk were were associated with less microbiome diversity and with microbiome functionality in their 1 month old infants (Iszatt et al. 2019).
Ishida et al. (2005) found that dioxin damages the intestinal epithelium in one strain of mice (but not another) by increasing intestinal permeability. The dioxin-treated mice also had higher glucose levels after a glucose tolerance test. The authors suggest that dioxin initially damages the intestine, and the tissues respond by facilitating the absorption of glucose.
Another study found that some PCBs can disturb the intestinal barrier and alter gut permeability (in animals and in experiments using human intestinal cells) (Choi et al. 2010). In mice, PCBs can intestinal inflammation and disrupt gut microbiota (Petriello et al. 2018). PCB-induced changes to the gut microbiome could even influence their toxicity. Interestingly, exercise reduced the severity of these changes (Choi et al. 2013). Another persistent organic pollutant (POP), TCDF, was found to alter the gut microbiota of mice in ways that may contribute to diabetes and obesity (Zhang et al. 2015). For an article explaining this study, see the article, POPs and gut microbiota: Dietary exposure alters ratio of bacterial species, published in Environmental Health Perspectives (Potera 2015). Dioxin (TCDD), also a POP, changes the gut microbiome in mice treated with a chemical to induce type 1-like diabetes, also causing liver toxicity (Lefever et al. 2016). The POP tributyltin also affects the gut microbiota in mice, in conjunction with weight gain (Guo et al. 2018), and the flame retardants PBDEs also affect gut microbiota (Cruz et al. 2020; Li et al. 2018). In adult mice, exposure to the POP and PFAS PFOS perturbed gut metabolism, inducing changes associated with inflammation and metabolic functions (Lai et al. 2018). The POP TCDF also causes gut inflammation in mice (Nichols et al. 2019).
Pesticides can be a food contaminant, as a result of their use in agriculture. Daily ingestion of low doses of diquat, an extensively used herbicide, induces intestinal inflammation in rats. The authors of this study suggest that repeated ingestion of small amounts of pesticides, as could be found in food, may have consequences for human health and may be involved in the development of gastrointestinal disorders (Anton et al. 2000). Chronic exposure during early life to the pesticide chlorpyrifos increases gut permeability in rats pups at the time of weaning (but not in adulthood) (Joly Condette et al. 2014). Chlorpyrifos also affects the gut microbiota, impairs the intestinal lining, and stimulates the immune system of pup rats (Joly Condette et al. 2015). Interestingly, researchers have found that giving the prebiotic inulin, which helps support gut microbiota, can actually correct the metabolic effects of early life exposure to the pesticide chlorpyrifos in lab animals (Reygner et al. 2016). Other pesticides also appear to affect the gut; the organophosphorous pesticide monocrotophos induces intestinal dysfunction in rats (Vismaya and Rajini, 2014), and the pesticide diazinon disrupts the gut microbiota of mice (Gao et al. 2017). A study from rural India shows a high prevalence of diabetes in people directly exposed to organophosphates, as well as higher long-term blood glucose (HbA1c) levels. The authors also show that these pesticides affect the gut microbiota, and confirm these findings in animal studies. They conclude that the pesticides degrade the gut microbiota and thereby cause high blood glucose levels and diabetes (Velmurugan et al. 2017). The pesticide atrazine and PCBs both affect the gut microbiota and intestinal permeability in adult zebrafish (Chen et al. 2018). Yuan et al. (2019) review the effects of pesticides on gut microbiota. A pesticide precursor/metabolite, 3-methyl-4-nitrophenol (MNP), reduced the frequency of regulatory T cells (Tregs) which control autoimmunity in the intestine in mice (Hu et al. 2022).
Food is also a major exposure route of BPA because it can leach out of food containers into food. BPA exposure can increase inflammatory gut microbiota in non-obese diabetic (NOD) mice, an animal model of type 1 diabetes, thus leading to increased (or decreased) incidence of type 1 diabetes in these mice-- depending on the timing of exposure and the sex of the mice (Xu et al. 2019). In other mice, BPA has been shown to detrimentally affect gut microbiota, in the same way a high-sugar or high-fat diet does (Lai et al. 2016). In rats, BPA affected gut microbiota, caused intestinal dysfunction, and higher blood glucose levels (Ambreen et al. 2019). In dogs, who eat canned dog food, BPA affects the gut microbiota (Koestel et al. 2017). BPA has been shown to affect gut microbiota in both exposed rodents and their offspring (Jaruvek et al. 2016). In rats, perinatal exposure to BPA was found to promote the development of intestinal inflammation in adult female offspring, although it decreased intestinal permeability (Braniste et al. 2010). A different study, however, found that in mice, developmental exposure to BPA increased gut permeability, and weakens the protective gut immune system, causing increased susceptibility to inflammation (Malaisé et al. 2018; Malaisé et al. 2017), and more widespread inflammation as well (Reddivari et al. 2017). Other authors have also found that in mice, BPA not only affected gut microbiota, but also increased intestinal permeability (Feng et al. 2019). BPA also makes intestinal cells absorb more cholesterol (Feng et al. 2017). Bisphenol A diglycidyl ether (BADGE), a stabilizing compound that can also leach out of food containers, may also increase apoptosis (programmed cell death) of intestinal cells (Ramilo et al. 2006). Nonylphenol, another compound found in plastics, can disrupt the permeability of intestinal cells (Isoda et al. 2006). A more recent study found that early-life exposure to BPA made rats more susceptible to intestinal infection than those unexposed, and impaired their ability to respond to food antigens (Ménard et al. 2014).
Cadmium, another chemical that can enter the body via food, induces intestinal inflammation in mice, and in high doses can disrupt permeability in intestinal cells (Zhao et al. 2006). Cadmium can also disrupt the gut microbiota (Ba et al. 2017; Zhang et al. 2015). Mercury can increase gut permeability, at levels found in food (Vázquez et al. 2014). The polycyclic aromatic hydrocarbon benzo[a]pyrene, found in barbecued food, increases intestinal inflammation caused by a high fat diet in mice (Khalil et al. 2010).
POP Disturbs Gut Microbiota
Even air pollution is linked to changes in gut microbiota (reviewed by Dujardin et al. 2020 and Bailey et al. 2020). A study from Southern California found that traffic-related air pollution levels were associated with higher fasting blood glucose levels, and different gut microbiota in overweight and obese adolescents (Alderete et al. 2018). In mice, air pollution can affect gut microbiota as well as glucose tolerance (Wang et al. 2018). A review finds that air pollution can affect gut inflammation and gut microbiota (Feng et al. 2020).
And water pollution is also linked to changes in gut microbiota in aquatic organisms (Evariste et al. 2019). Microplastics, found in water, caused multiple toxic effects in fish intestine, including damaging the gut mucosa, affecting gut microbiota, and increasing gut permeability, inflammation and metabolism disruption (Qiao et al. 2019).
Nano- and micro-plastics are also linked to disturbances in gut microbiota and the gut barrier (reviewed by Hirt and Body-Malapel, 2020).
Some researcher propose using probiotics or other gut interventions to counteract the effects of environmental chemicals on the gut or on health in general (Garcia-Gonzalez et al. 2020; Le Magueresse-Battistoni 2020).
Exposure During Development
Some of the studies described above include exposures during development in early life; sometimes these effects can be more severe than exposures during later life. Additional studies also suggest that early life exposure to chemicals can affect the gut. In human infants, phthalate levels are associated with changes in the gut microbiota that are linked to later-life effects on the immune system (Yang et al. 2019). In rats, exposure to phthalates during development negatively impacts the development of the small intestine (Setti Ahmed et al. 2018). Interestingly, exposure to phthalates during puberty also affects the gut microbiota in mice (Wang et al. 2018).
Gut Microbiota Can Affect Chemical Metabolism
Some chemicals can be metabolized by the gut microbiota, and made toxic. For example, alcohol or pharmaceutical drugs can be converted into toxic compounds by certain microbiota. Numerous environmental chemicals can also be made more toxic by gut microbiota, including arsenic, persistent organic pollutants such as PCBs and furans, the pesticides chlorpyrifos and glyphosate (Round-up), and air pollutants (Roca-Saavedra et al. 2018).
Changes to the gut microbiome can make arsenic, for example, fore toxic (Chi et al. 2018). Changes in the gut microbiome caused by an infection affected the absorption and metabolism of arsenic in mice (Lu et al. 2013). The gut microbiome can also turn less-harmful varieties of arsenic into more-harmful varieties (D.C. Rubin et al. 2014). For an article on this topic, see Fire in the belly? Sulfur-Reducing Gut Microbes Fuel Arsenic Thiolation, published in Environmental Health Perspectives (Potera 2014). Thus, there may be interactions between the microbiome, chemicals, and other factors such as infections that may all be important.
Probiotics/Antibiotics and Environmental Chemicals
Interestingly, probiotics can reduce the toxicity of several chemicals. According to a review of this topic, Lactobacilli can reduce the accumulation and toxicity of heavy metals and pesticides in animal tissues by reducing the intestinal absorption of these contaminants, and by enhancing intestinal barrier function. Probiotics can also improve immune function by reducing inflammation (Feng et al. 2018). Similarly, antibiotics can affect the microbiome and the toxicity of arsenic in lab animals (Roggenbeck et al. 2021).
To download or see all the references on this and other diet-related pages, including breastfeeding, cow's milk, gluten, and more, see the collection Diet, nutrition, gut, microbiome and diabetes/obesity in PubMed.