The unexpected discovery of H. pylori (Hp) as a cause of what were considered to be non-communicable diseases (chronic gastritis, peptic ulcer and gastric adenocarcinoma) shocked and transformed the field. It taught me, one doesn’t see (or find) what one isn’t trained to see (or find). Subsequently, with advances in high throughput sequencing and bioinformatics, there has been major interest in the gut microbiome and the ecological hypothesis of disease (various combinations of interacting microbes and their metabolic products can induce health or disease). Many studies have identified various alterations of the microbiome associated with disease. However, in terms of specific microbes, disparate results are the rule, and causation has been much more difficult to nail down given the microbiome is altered by diet, drugs and other environmental, and genetic factors. My group is interested in chronic unexplained gastrointestinal disorders that affect 1 in 3 Australians, this includes irritable bowel syndrome (IBS) and functional dyspepsia (FD). FD is characterised by very unpleasant postprandial symptoms (fullness, bloating, inability to finish a normal sized meal and/or epigastric pain). FD improves with Hp eradication therapy in a minority. We identified low-grade pathological inflammation in the duodenum in FD (increased activated eosinophils and mast cells), confirmed worldwide, and this is associated with increased permeability and neuronal damage. The duodenal inflammation is a strong risk factor for new onset (incident) gastro-oesophageal reflux disease, and anxiety. We also found FD induces immune activation (e.g. increased circulating homing small bowel T cells). Next we identified altered duodenal mucosa-associated microbiota profiles by 16S rRNA amplicon sequencing in FD, which was dominated by Streptococcci. We cultured novel Streptococcus isolates from duodenal biopsies of FD patients and one isolate (AGIRA0003) was taxonomically affiliated with S. salivarius CCHSS3 by genome-based analysis. Screening of Streptococci isolates revealed AGIRA0003 possesses two polypeptides (~75-100kDa and ~30-35kDa) that were seroreactive, with positivity observed for 90% of FD and 35% control sera, with a response at either molecular weight significantly associated with FD diagnosis (p<0.0001). Further, seroreactive (but not seronegative) patients had greater proportions of gut-homing T cells compared to controls (0.33±0.77 vs 0.84±4.26, p=0.04). Our data demonstrates that there are strain-specific bacterial-immune interactions associated with FD and suggest repeated exposure to microbial antigens may drive symptom onset in these patients. IBS is a common cause of abdominal pain but unexplained. We observed in colonic biopsies from a population-based colonoscopy cohort the presence of colonic spirochetes (CS) in 2.3%. The bacteria responsible for CS (Brachyspira spp.) are often considered commensals, however, we observed in two independent studies pain, diarrhoea and IBS were strongly associated with CS. Additionally, we observed subtle pathological changes in CS patients, namely, increased eosinophils, mast cells, and lymphoid aggregates in the lamina propria, since confirmed. We also observed that the “conventional” 16S rRNA amplicon sequencing approach is unable to detect human colonic spirochetes as the standard 16S rRNA primer sets are incompatible with spirochetes' 16S rRNA region. We speculate CS may be one of the causes of IBS-diarrhoea, a link that may have been otherwise overlooked despite sophisticated microbiome analyses. As such, our work suggests a subset of common chronic unexplained gut disorders may be bacterial diseases.