## 5 Clues from Microbiome Studies on the Benef of Phytochemicals in Immunotherapy Efficacy  
The commensal bacteria residing in the gastrointestinal system and their genome is called the gastrointestinal (GI) microbiome. The GI microbiome plays significant roles in self-defense and inflammation [68]. Recently, the GI microbiome has emerged as a predictor of ICI efficacy, and several studies have demonstrated better survival in ICI-treated patients enriched with beneficial commensal bacteria, including _Akkermansia muciniphila_, _Bacteroides_ spp., and _Faecalibacterium prausnitzii_. _Akkermansia muciniphila_ in particular was associated with a response to ICIs in four studies conducted on patients with three different tumors (RCC, NSCLC, and HCC) [69; 70; 71; 72]. Whether the increases in these bacteria are secondary to a bystander effect or these bacteria play roles in ICI efficacy is highly debated. However, the restoration of ICI efficacy with _Akkermansia muciniphila_ transplantation in ICI non-responders mice [70] and the recent report of improved ICI efficacy with microbiome and ICI combination in metastatic renal cell carcinoma patients [73] point to an anti-tumor role of the microbiome rather than it only being a biomarker. Several phytochemicals such as curcumin and phenols could increase levels of beneficial commensal bacteria (Table 3) and correct the dysbiosis created by oxidative stress, as shown in alcoholic liver disease and fatty liver disease models. Similarly, phytochemicals could correct dysbiosis in patients treated with ICIs. These phytochemicals are most commonly found in fiber-rich diets (Table 3). [PERSON] et al. reported indirect evidence of this strategy's possible benefit in melanoma patients [14]. Metabolomic analyses in 39 ICI-treated melanoma patients revealed that the anacardic acid levels were increased in responders. Most of these patients (five out of six) had dietary habits that explained the high anacardic acid levels. Based on these points, we think using phytochemicals to correct dysbiosis and increase levels of bacteria associated with ICI efficacy should be exploited in clinical trials. Additionally, further research is needed to delineate the optimal fiber type to consume for ICI efficacy. Recently, [PERSON] et al. reported that a soluble fiber diet increased gut _Bacteroides fragilis_, previously associated with ICI response, while the insoluble fiber-rich diet reduced the _Bacteroides fragilis_ levels in a mice model [74]. In addition, [PERSON] et al. previously demonstrated the enrichment of beneficial commensal Actinobacteria and Akkermansia in obese mice fed with nondigestible fructans, which are found in higher concentrations in bananas, compared to mice fed with cellulose [75; 76]. Until the results of these trials become available, the recommendation of eating soluble fiber-rich diets and diets rich in phytochemicals that increase beneficial commensal bacteria could benefit ICI-treated patients. \begin{table}
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**Lead Author, Year Population/Patient Number (n)** & **Margin Findings** & **Candidate phytochemicalani** & **Pryochemical Enriched Nutrient** & **Bacteria Nutrient** \\ \hline [PERSON] et al. (2015) [78] & Melanoma/25 & Increased levels of _Rideroustics Indianapolis_ & Polyphenol/coumarin [79] and _Rideroustics_ & Soluble fiber-rich diet [74]/High coffee-consumption [80] & _Rideroustics Indianapolis_ \\  & & Improved response to CTLA-4 blockade with FM from patients with increased focal & & & \\  & & _Riderous_ spp. levels & & & \\ \hline [PERSON] et al. (2015) [81] & Melanoma/Mice in ICI responders & Increased levels of _Riderous_ spp. in ICI responders & Resveratrol [82] & Grapes, wine, and peanuts [63] & _Bifabactetermin_ spp. similar tumor control as PD-LI blockade with oral supplementation of _Bifabactetermin_ spp. \\ \hline [PERSON] et al. (2016) [84] & Melanoma/34 & Lower risk of colitis in _Riderous_ spp.