The Influence of Dysbiosis on Kidney Stones that Risk Up Renal Cell Carcinoma (RCC)

Nephrolithiasis is a frequent urological disease that has a high recurrence rate. It might lead to one of the most lethal urological malignancies i.e. renal cell carcinoma (RCC). Although diverse genetic and environmental factors have been considered responsible for nephrolithiasis or kidney stone formation, however, several studies suggest that dysbiosis may in part contribute to the increasing prevalence. The gut microbial composition greatly differed between kidney stone patients and healthy subjects with the former showing a drastic decrease in microbial diversity. A pro-inflammatory dysbiotic pattern characterized by a reduction in the total number of bacteria, a reduction in immunoregulating microbiota, and a large reduction in muconutritive microbiota was seen in calcium oxalate stone formers while the anti-inflammatory bacteria were very low in number.

The pro-inflammatory bacterial species Escherichia–Shigella, the leading member(s) of family Enterobacteriaceae, were higher in kidney stone formers than in normal control individuals. A highly intense decrease was observed in much muconutritive microbiota Akkermansia muciniphila and Faecalibacterium prausnitzii. F. prausnitziiis the largest producer of butyrate and the largest consumer of acetate and is the most important species inhabiting the intestine. Its depletion along with the reduction of Bifidobacterium (which is more reduced in patients with kidney stones) leads to a reduction in the intestinal butyrate levels, which thence leads to a functional instability in the gastrointestinal tract and urothelium thereby resulting in an inflammatory pattern. A. muciniphila depletion results in a poor protective layer formation in the epithelium which favors a pro-inflammatory dysbiosis pattern. PCR and culture-based investigations reveal remarkably reduced colonization of Oxalobacteria formigemes (an oxalate degrading species) in stone formers or patients with high lithogenic risk than observed in control groups.

Investigations suggested that patients with a history of kidney stones had a significantly increased overall RCC risk compared to participants without a history of kidney stones. Kidney stones were associated with an increased risk of papillary RCC but not clear-cell RCC. Similarly, the TCC risk was also elevated in participants with kidney stones. It was also reported that the diagnosis of kidney stones at an early age (< 40) was associated with increased RCC & TCC risk than at later ages. Therefore, a strong relationship between kidney cancers and kidney stone disease has been established which is mainly attributed to the chronic inflammation and infection which leads to an altered proliferation of urothelial cells often resulting in the development of tumors.

Although prolonged antibiotic exposure is mainly responsible for the nephrolithiasis associated gut and urinary microbiome dysbiosis which further leads to RCC & TCC, nutritional imbalances such as high salt and animal protein intake, poor hydration and low intake of food and vegetables are key factors that increase the lithogenic risk. Therefore, the nutritional intervention focused on manipulating the composition and functions of the intestinal microbiome is an assuring sphere for regulating lithogenic risk and determining the novel strategies for the prevention of nephrolithiasis and hence RCC.

Written by: Shruti Gupta and Shamsher Singh Kanwar, Department of Biotechnology, Himachal Pradesh University, Summer Hill, Shimla, India

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