In this prospective cohort study, vegetarian diet (versus non-vegetarian diet) is associated with a lower risk of UTI particularly in female, non-smokers, and mainly for the uncomplicated-subtype of UTI. To the best of our knowledge, this is the first study that evaluated the prospective association between a vegetarian diet and UTI.

Previous research suggested that meat-related foodborne ExPECs may be the main cause of uncomplicated UTIs and a half of complicated UTIs (Table 1)2,3,4,5,6,7,8. Consistent with this finding, we found that the protective association between vegetarian diet and UTI risk was mainly in uncomplicated rather than complicated UTI, and this association is independent of diseases and risk factors predisposing conditions to complicated UTI including hypertension12, diabetes13, and hyperlipidemia14. This suggests that the effect of vegetarian diet is not mediated through these related diseases. The test of interaction showed that vegetarian diet (versus non-vegetarian diet) was associated with protection among the never smoking group, but not the ever smoking group (P-interaction = 0.029, Table 5). It is possible that smoking compensates the benefit of vegetarian diet by increasing blood pressures (which predisposing to renal failure)12,15, renal stone formation16, and urinary tract cancers17. All of which are also the disease conditions predisposing to complicated UTI2,3,4. However, the number of smokers in our study is small and the significant interaction could arise from chance that further confirmation from other studies is needed.

The principal pathogenic strains causing UTIs are ExPECs (accounting for 65~75% UTIs), a group of strains distinct from the intestinal pathogenic and normal commensal E. coli3,4. ExPECs express many characteristic virulent factors which are not present in other strains of non-ExPECs2,3,4,18. Many studies have illustrated that meat, including poultry and pork, as the major reservoirs for ExPECs5,6,7,8,19. Vincent et al. identified the E. coli strains by using O:H serotype and sequence type (ST) and discovered the O25:H4-ST131 and O114:H4-ST117 strains acquired from retail chicken were very similar to, if not indistinguishable from E. coli of UTI patients5. Jacobsen et al. performed the phylogenetic analysis by triplex polymerase chain reaction using three DNA markers showed the UTI-associated B2 and D phylogroups are found among isolates from broiler chicken meat, broiler chickens, pork, and pigs. Further, antimicrobial resistance phenotypes of E. coli from meat were very similar to isolates from UTI patients7. In addition, sequencing analysis of ExPECs showed UTI-causing ST10, ST69, ST95, ST117, and ST131 are associated with poultry and retail poultry meat8,19. Vegetarians do not consume meat and therefore avoid uptake of animal-food-associated ExPECs.

Recent studies discovered the gut and fecal microbiotas were different between vegetarians and non-vegetarians20,21,22,23. The high fiber contents in vegetarian diet may modulate the intestinal microbiota in humans20,21. Fiber is metabolized by intestinal anaerobic microflora to produce short-chain fatty acids, which decrease intestinal pH20,21. Vegans or vegetarians were shown to have lower total counts of E. coli and Enterobacteriaceae spp. and lower stool pH than non-vegetarians, and the lower stool pH could prevent the growth of E. coli and Enterobacteriaceae22. The shifts in the gut and fecal microbiotas in vegetarians may potentially contribute to the protection from UTI.

Vegetarians consume predominantly plant foods and with more frequent consumption of vegetables, fruits, and nuts than non-vegetarians in most cohorts24,25, as in our cohort study, published previously26. Briefly, vegetarians in this present study had previously been shown to have a distinct overall dietary pattern, with a more frequent consumption of a variety of vegetables, fruits, nuts, soy products and beans, while avoiding all types of meat, fish, and seafood, compared with non-vegetarians26. Plant foods contain phytochemicals (major classes including terpenoids, phenolics, alkaloids) which have been demonstrated to have antibacterial activities27,28,29,30,31,32,33,34,35,36,37,38,39,40, in addition to anti-carcinogenic, anti-mutagenic, anti-inflammatory, and anti-oxidative factors27. Among the phytochemicals, phenolics compounds are related to the antibacterial activities27,28,29,30,31,32,33,34,35,36,37,38,39,40, and are abundant in vegetables, whole grains, fruits, and nuts28,29, and some of which had been demonstrated with antimicrobial effect27,30,31,32,33,34,35,36,37,38,39,40. Cranberry (Vaccinium macrocarpon), belong to the Ericaceae family, is one of the most well-known fruit against UTI as evidenced in many trials30,31,32,33,34,35,36. Besides cranberry, fresh juice (berry or fruit) have been was associated with a decreased risk of recurrence of UTI (odds ratio: 0.66, 95% CI: 0.48–0.92, per 2 dL juice)33. Proanthocyanidins (PAC), a member of tannins belong to phenolics found in cranberry and other fruits may defend against microbes30. PAC inhibits the adhesion of P fimbriae in vitro via conformational changes and decrease in adhesion forces30,34,36, and this in vitro anti-adherence effect is dose-dependent30. Moreover, fructose found in fruits may also inhibit the adherence of type 1 fimbriae30. These fimbriae-mediated adhesions are the key step for infection2. In addition to ExPEC, in vitro studies have shown that cranberry may inhibit adherence of other common UTI pathogens including Klebsiella pneumoniae, Staphylococcus aureus, Proteus spp., Pseudomonas aeruginosa, and Enterococcus faecalis30,36. Clinical research suggests the dose of cranberry as follows30: (1) cranberry juice cocktail 240–300 ml daily (preventing 50% of recurrences of UTIs and reducing bacteriuria), (2) dried, concentrated juice extract 600 to 1,200 mg per day divided into two or three daily doses, or (3) total 36 mg of PAC in twice-daily manner. In addition to cranberry, other berries and fruits, such as elderberry (Sambucus nigra), blueberry (Vaccinium corymbosum), strawberries (Fragaria ananassa), blackberries (Rubus spp.), red raspberry (Rubus idaeus), blackcurrant (Ribes nigrum), and redcurrants (Ribes rubrum), also contain phenolics and may have similar properties against p-fimbriated E. coli37. Another plant with studies showing an effect against UTI is roselle (Hibiscus sabdariffa)38,39,40. Roselle, commonly consumed in the form of tea or jam in Taiwan, belongs to the Malvaceae family and is rich in phytochemical phenolics especially anthocyanins38. Alshami et al. had demonstrated the antimicrobial activity of roselle extract against uropathogenic E. coli, K. pneumoniae, and Candida albicans isolated from recurrent urinary tract infection, through inhibiting the biofilm forming capacity39,40. Moreover, commonly consumed nuts including almond, Brazil nut, cashew, chestnut, hazelnut, heartnut, macadamia, peanut, pecan, pine nut, pistachio, and walnut also contain a variety of phytochemicals including PAC, although there is no study demonstrating the antibacterial effect so far41. Studies about medicinal plants had shown many of them with broad spectrum antimicrobial activity against uropathogenic E. coli and other UTI pathogens42,43. However, the component contributing to the effect remains to be investigated. In sum, vegetarian diets comprise abundant phytochemicals, which may contain anti-microbial properties and protect against UTI.

ExPECs isolated from animal food products and UTI patients are very similar in antibiotic resistant patterns and virulence factor profiles5,6,8,44,45. Antibiotics use in animal agriculture may contribute to the increasing antibiotic resistance in humans44. The extended spectrum β-lactamase (ESBL)-producing and fluoroquinolone-resistant ExPECs, most of which are globally disseminated E. coli strain O25:H4-ST131 (accounting for 78%), are a major problem with resistance to penicillins, cephalosporins, and fluoroquinolones2,8,46. Moreover, the ESBLs encoded on plasmids typically carry other antibiotic resistance genes against aminoglycosides, sulfonamides, and quinolones, leading to multidrug resistant2. The high recurrence rates and increasing multidrug resistance in ExPECs2 make antibiotic treatment of UTI challenging. Therefore, alternative non-antibiotic management for UTI is important. High phytochemical content in a healthy vegetarian diet may provide an alternative prophylaxis from and bactericidal effect against UTI27,30,31,32,33,34,35,36,37,38,39,40, and a study had demonstrated the PAC from cranberry also exhibited the anti-adherence property in the multidrug resistant strains of uropathogenic P-fimbriated E. coli47.

Several limitations must be noted in our study. (1) Our case definition is based on ICD-9 code rather than the gold standard, which should be clinical symptoms and laboratory examination including pyuria and urine culture with a more than 100,000 colony forming units per milliliter48,49. (2) Residual confounding may still remain as several known confounders, including water intake50, sexual intercourse33,51, intake of honeydew melon (which may also contain ExPEC5, though evidence is insufficient), were not measured. (3) Although ExPEC is found mainly from meat sources, one study reported the detection of ExPEC isolates from a honeydew melon sample of restaurant/ready-to-eat foods in North America5. To the best of our knowledge, E. Coli or ExPEC had never been reported in plant based foods in Taiwan. The sporadic case of ExPEC in non-meat product may be due to contamination and will require further research. However, if plant-based foods were a major source of ExPEC contributing to UTI, the protective association between vegetarian diet and UTI would have been attenuated, strengthening the null association. (4) Another limitation lies in our FFQ, which did not ask specifically about intake of honeydew melon, cranberries, or roselle. Thus, we were unable to conduct further analysis on the association between UTI and these plant foods. In addition, the FFQ was self-administered with some degree of missing values, that it is difficult to calculate the exact intake of specific phytochemicals known to contribute to UTI-protection.

In conclusion, vegetarian diet is protectively associated with UTI particularly in female and for uncomplicated UTI. Further study with identification of pathogens from urine culture is needed to clarify the relationship among UTI risk, pathogens, and vegetarian diet.