Antibiotic Exposure Aggravates Bacteroides-Linked Uremic Toxicity in the Gut-Kidney Axis

Abstract

Epidemiological and experimental evidence has implicated a potent link between antibiotic exposure and susceptibility to various diseases. Clinically, antibiotic treatment during platinum chemotherapy is associated with poor prognosis in patients with malignancy. In the present study, mucosal antibiotic exposure was assessed for its impact on renal distress as a sequela of platinum-based chemotherapy. Clinical transcriptome dataset-based evaluations demonstrated that levels of dysbiosis-responsive genes were elevated during renal distress, indicating pathological communications between gut and kidney. Experimentally, mucosal exposure to streptomycin aggravated platinum-induced renal tubular lesions in a mouse model. Moreover, antibiotic-induced dysbiosis increased susceptibility to gut mucosal inflammation, epithelial disruption, and bacterial exposure in response to cisplatin treatment. Further investigation of the luminal microbes indicated that antibiotic-induced dysbiosis promoted the dominance of Bacteroides species. Moreover, the functional assessment of dysbiotic microbiota predicted tryptophan metabolic pathways. In particular, dysbiosis-responsive Bacteroides acidifaciens was associated with the production of the uremic toxin indoxyl sulfate and renal injuries. The results of this study including bacterial community-based evaluations provide new predictive insights into the interorgan communications and interventions against dysbiosis-associated disorders.

Gut epithelial barrier dysfunction in lupus triggers a differential humoral response against gut commensals

“…B. acidifaciens has also been shown to promote IgA production in the colon and Peyer’s patches ( 39 , 42 ). However, it can also play a detrimental role in uremic toxicity induced by antibiotics and chemotherapy by producing indole sulfate ( 43 ). Similarly, B. acidifaciens negatively contributes to gut barrier disruption by inducing a decrease in the expression of zonulin-1 and claudin-1 ( 44 ).…”

Administration of Gracilariopsis lemaneiformis polysaccharide attenuates cisplatin‐induced inflammation and intestinal mucosal damage in colon‐26 carcinoma tumor‐bearing mice

“…Notably, analysis of the indicator species revealed that Bacteroides_acidifaciens was the main microbial marker in the cisplatin group, which aligns with previous findings. Specifically, cisplatin enhances the abundance of B. acidifaciens , a major producer of indoxyl sulfate, which is a key substance responsible for kidney damage 32 . Furthermore, the inflammatory responses caused by cisplatin exacerbates damage to the intestinal mucosal epithelium, thereby aggravating the toxic side effects of cisplatin‐induced renal injury.…”

“…Specifically, cisplatin enhances the abundance of B. acidifaciens, a major producer of indoxyl sulfate, which is a key substance responsible for kidney damage. 32 Furthermore, the inflammatory responses caused by cisplatin exacerbates damage to the intestinal mucosal epithelium, thereby aggravating the toxic side effects of cisplatininduced renal injury. Another study indicated that Bacteroides abundance was positively corrected with IL-6, TNF-⊍ and IL-1⊎ levels and negatively correlated with tight junction proteins.…”

Stress-responsive Gdf15 counteracts renointestinal toxicity via autophagic and microbiota reprogramming

“…The procedure was based on the previously published method 68 . In detail, C57BL/6 mice (6-week-old male, average weight 16–18 g) were purchased from Jackson Laboratories (Bar Harbor, ME, USA), and Gdf15 KO C57BL/6 mice were kindly provided by Dr. Se-Jin Lee (Johns Hopkins University, Baltimore, MD, USA).…”

“…The procedure was based on the previously published method 68 , 69 . Briefly, kidney sections were stained with PAS, and microphotographs of prepared sections were obtained using an inverted microscope (Nikon-Eclipse Ts2R, Tokyo, Japan).…”