Study Spotlight Take-Away with Chef Dr. Mike: Kidney disease, the gut microbiome, and forever chemicals

by Michael S. Fenster, MD

Interbeing is the understanding that nothing exists separately from anything else. We are all interconnected.”

Thich Nhat Hanh

Previously, in this column, the ubiquity of “forever chemicals,” perfluoroalkyl and polyfluoroalkyl substances, or PFAs, in our environment was discussed. Particularly concerning was the widespread dissemination of two specific PFAs, perfluorooctane sulfonic acid (PFOS) and perfluorooctanoic acid (PFOA), throughout the food chain, including fish, seafood, meat, eggs, dairy, and even drinking water. Add to the fact that other PFAs are FDA-approved for food contact application, and it is easy to understand why, as the lead researcher in this week’s Study Spotlight, Dr. Hailey Hampson, observed, “Nearly everyone has PFAs in their blood, and these chemicals are associated with a number of negative health effects.”

Prominent among the illnesses associated with increased levels of PFAs is kidney disease. Chronic kidney disease (CKD) affects over 10% of the world’s population, and an increased risk of developing CKD is associated with the presence of hypertension and diabetes, illnesses reaching epidemic proportions throughout the industrialized world. As organs that help the body eliminate toxins, the kidneys are particularly vulnerable to the effects of PFAs. However, the direct mechanism or mechanisms through which exposure to PFAs may lead to CKD is unknown. While there is evidence suggesting a direct nephrotoxic effect of PFAs, other research suggests that PFAs may negatively impact the gut microbiome and cause CKD through these means. If true, this would be particularly pertinent to those PFAs associated with dietary consumption.

Such foodborne PFAs were the focus of another previous column that detailed their association with particularly aggressive forms of colorectal cancer (see the previous column for more details regarding the potential pathways for PFAs’ entry into the US food supply). This week, we take a closer look at the most recent work from that same group of researchers who found that in a longitudinal analysis, a higher PFA burden was associated with reduced kidney function. Critically, they demonstrated that in addition to a potentially direct nephrotoxic effect, PFAs may cause kidney injury by altering the composition and metabolites of the human gut microbiome.

The Study:

  • The study examined 78 young adult participants of the longitudinal Children’s Health Study, who were between the ages of 17 and 22 and had a mean age of 20.
  • The study group was 56% Hispanic, 53% female, overweight/obese in early adolescence (2011 and 2012), but had no other underlying medical conditions, e.g., T2 diabetes.
  • Baseline and longitudinal PFA exposure were measured and expressed as a PFAs burden score, which estimates exposure to these chemicals.
  • Baseline and longitudinal plasma metabolomics were measured.
  • The gut microbiome was characterized at the genus level from stool samples.
  • Kidney function was expressed in terms of the estimated glomerular filtration rate (eGFR).
  • Each standard deviation increase in baseline PFA burden score was associated with a 2.4 % lower eGFR at follow-up, which represents a worsening of kidney function with increasing PFA exposure over just a four-year period.
  • The effect appeared to be significantly linked to alterations in the composition of the gut microbiota, a decrease in certain types of gut bacteria-associated metabolites, and an increase in other types of gut bacteria-associated metabolites.

The Caveat:

Previous research has shown an association between increased levels of certain gut microbiota metabolites like indoxyl sulphate, p-cresyl sulphate, and trimethylamine-N-oxide (TMAO) and the progression of kidney disease. This study suggests that a link between the environmental and food contaminants, PFAs, and CKD is mediated at least in part through a dysregulation of the gut microbiome.

The study identified 15 different gut microbial taxa that were associated with at least one PFA, 77 gut microbiome metabolites associated with at least one PFA, and 26 specific gut microbiota metabolites associated with the eGFR. This is the first study to identify an association between environmental and dietary contaminants, PFAs, and chronic kidney disease mediated by gut microbiome dysbiosis. It is also one of the first studies to show effects at PFA exposure levels observed in the general population.

The level of dysfunction appeared to involve alterations in both the gut microbial taxa (the type and number of certain bacteria) and metabolic profiles (increases and decreases in the compounds produced by the gut microbiota). Many of these bacterial products exert effects by circulating throughout the bloodstream. For example, a decrease in renal function was accompanied by a decrease in bacteria from the Lachnospiraceae family, a group that was previously observed to be reduced in individuals with CKD. These bacteria are known to produce beneficial short-chain fatty acids (SCFAs) that function to reduce inflammation and oxidative stress.

Conversely, increased levels of succinate, which has been shown to increase oxidative stress and cause renal injury, were observed. Increased levels of cystine, which is a risk factor for kidney stones and CKD, were recorded. Finally, increased levels of dodecanoic (or lauric) acid were noted. This medium-chain saturated fatty acid has been shown to be associated with renal damage and inflammation.

While there was an increase in some metabolites, others decreased. Decreased levels of D-pinitol were recorded. This is an anti-inflammatory compound that has anti-diabetic effects. There were also reduced levels of ureidopropionate, a compound that has been shown to be associated with a reduced risk of CKD progression. Decreased levels of 17-ß estradiol were observed, which is important because estrogen helps maintain the stability and function of the gut-epithelial barrier. Disruption of this barrier can facilitate the leakage of inflammatory toxins into the bloodstream and increase the risk of conditions like CKD. As endocrine disruptors, PFAs can affect estrogen levels systemically throughout the body. High PFA concentrations in the kidneys can directly cause renal injury via oxidative stress.

This study helps illustrate the multiple mechanisms by which environmental and dietary toxins like PFA can impact our health. It can be caused by a direct effect like oxidative stress that damages kidney cells. It may be through reducing beneficial bacteria that produce anti-inflammatory metabolites like short-chain fatty acids. It may be by creating conditions that increase the abundance and circulation of inflammatory metabolites.

And while that may complicate the story, as real life usually does, it also provides opportunities for multiple areas of positive intervention. It’s up to us to act on it!


The Study:

Hailey E. Hampson, Shiwen Li, Douglas I. Walker, Hongxu Wang, Qiran Jia, Sarah Rock, Elizabeth Costello, Petter Bjornstad, Laura Pyle, Jonathan Nelson, Frank D. Gilliland, Zhanghua Chen, Max Aung, Leda Chatzi, David V. Conti, Tanya L. Alderete, Jesse A. Goodrich. The potential mediating role of the gut microbiome and metabolites in the association between PFAS and kidney function in young adults: A proof-of-concept study.Science of The Total Environment. 2024. https://doi.org/10.1016/j.scitotenv.2024.176519.


Additional resources:

Chen, Y.Y., et al., 2019. Microbiome-metabolome reveals the contribution of gut-kidney axis on kidney disease. J. Transl. Med. 17 (1), 5.

Cui, L., et al., 2009. Studies on the toxicological effects of PFOA and PFOS on rats using histological observation and chemical analysis. Arch. Environ. Contam. Toxicol. 56 (2), 338–349.

Kovesdy, C.P., 2022. Epidemiology of chronic kidney disease: an update 2022. Kidney Int. Suppl. 12 (1), 7–11.

van der Giessen, J., et al., 2019. A direct effect of sex hormones on epithelial barrier function in inflammatory bowel disease models. Cells 8 (3).

Wu, I.W., et al., 2020. Compositional and functional adaptations of intestinal microbiota and related metabolites in CKD patients receiving dietary protein restriction. Nutrients 12 (9).

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