The aim of this study was to ascertain whether low grade innate inflammation contributes to a pathway of depression and anxiety via irritable bowel syndrome (IBS). We evaluated innate immune cell counts in colonic mucosa in normal subjects and those with IBS (Rome III) from a population based study in which 745 randomly selected subjects had a colonoscopy (mean age 51 years;57% women). Intraepithelial lymphocytes (IELs) per 100 enterocytes and eosinophils (eos) per five non-overlapping high power fields (HPF) were counted in 90 controls and 100 cases; immunocytochemistry (CD117) was performed for mast cells per 5HPF in 80 controls and 81 cases. IELs, mast cells and eos were individually summed over 5 sites (terminal ileum, caecum, transverse colon, sigmoid colon and rectum). Anxiety and depression scores were calculated from HADS. A causal model path model which hypothesises immune cells being associated with IBS which, in turn, is associated with elevated anxiety and depression was tested using path analysis implemented in the MPlus software. All hypothesised paths reached statistical significance (p < .05) supporting the individual hypothesized pathways. The overall model fit was reasonable although imperfect. In conclusion, a significant contribution of innate immune inflammatory load leading to anxiety and depression via IBS was found. Whether therapy directed to decreasing this inflammatory load also lifts depression and anxiety should be further explored.