Berry Supplement-Modified Human Microbiome Improves Immunotherapy Response in Mouse Models

Berry Supplement-Modified Human Microbiome Improves Immunotherapy Response in Mouse Models | medRxiv /* */ /* */ <!-- <!-- /*! * yepnope1.5.4 * (c) WTFPL, GPLv2 */ (function(a,b,c){function d(a){return"[object Function]"==o.call(a)}function e(a){return"string"==typeof a}function f(){}function g(a){return!a||"loaded"==a||"complete"==a||"uninitialized"==a}function h(){var a=p.shift();q=1,a?a.t?m(function(){("c"==a.t?B.injectCss:B.injectJs)(a.s,0,a.a,a.x,a.e,1)},0):(a(),h()):q=0}function i(a,c,d,e,f,i,j){function k(b){if(!o&&g(l.readyState)&&(u.r=o=1,!q&&h(),l.onload=l.onreadystatechange=null,b)){"img"!=a&&m(function(){t.removeChild(l)},50);for(var d in y[c])y[c].hasOwnProperty(d)&&y[c][d].onload()}}var j=j||B.errorTimeout,l=b.createElement(a),o=0,r=0,u={t:d,s:c,e:f,a:i,x:j};1===y[c]&&(r=1,y[c]=[]),"object"==a?l.data=c:(l.src=c,l.type=a),l.width=l.height="0",l.onerror=l.onload=l.onreadystatechange=function(){k.call(this,r)},p.splice(e,0,u),"img"!=a&&(r||2===y[c]?(t.insertBefore(l,s?null:n),m(k,j)):y[c].push(l))}function j(a,b,c,d,f){return q=0,b=b||"j",e(a)?i("c"==b?v:u,a,b,this.i++,c,d,f):(p.splice(this.i++,0,a),1==p.length&&h()),this}function k(){var a=B;return a.loader={load:j,i:0},a}var l=b.documentElement,m=a.setTimeout,n=b.getElementsByTagName("script")[0],o={}.toString,p=[],q=0,r="MozAppearance"in l.style,s=r&&!!b.createRange().compareNode,t=s?l:n.parentNode,l=a.opera&&"[object Opera]"==o.call(a.opera),l=!!b.attachEvent&&!l,u=r?"object":l?"script":"img",v=l?"script":u,w=Array.isArray||function(a){return"[object Array]"==o.call(a)},x=[],y={},z={timeout:function(a,b){return b.length&&(a.timeout=b[0]),a}},A,B;B=function(a){function b(a){var a=a.split("!"),b=x.length,c=a.pop(),d=a.length,c={url:c,origUrl:c,prefixes:a},e,f,g;for(f=0;f<d;f++)g=a[f].split("="),(e=z[g.shift()])&&(c=e(c,g));for(f=0;f<b;f++)c=x[f](c);return c}function g(a,e,f,g,h){var i=b(a),j=i.autoCallback;i.url.split(".").pop().split("?").shift(),i.bypass||(e&&(e=d(e)?e:e[a]||e[g]||e[a.split("/").pop().split("?")[0]]),i.instead?i.instead(a,e,f,g,h):(y[i.url]?i.noexec=!0:y[i.url]=1,f.load(i.url,i.forceCSS||!i.forceJS&&"css"==i.url.split(".").pop().split("?").shift()?"c":c,i.noexec,i.attrs,i.timeout),(d(e)||d(j))&&f.load(function(){k(),e&&e(i.origUrl,h,g),j&&j(i.origUrl,h,g),y[i.url]=2})))}function h(a,b){function c(a,c){if(a){if(e(a))c||(j=function(){var a=[].slice.call(arguments);k.apply(this,a),l()}),g(a,j,b,0,h);else if(Object(a)===a)for(n in m=function(){var b=0,c;for(c in a)a.hasOwnProperty(c)&&b++;return b}(),a)a.hasOwnProperty(n)&&(!c&&!--m&&(d(j)?j=function(){var a=[].slice.call(arguments);k.apply(this,a),l()}:j[n]=function(a){return function(){var b=[].slice.call(arguments);a&&a.apply(this,b),l()}}(k[n])),g(a[n],j,b,n,h))}else!c&&l()}var h=!!a.test,i=a.load||a.both,j=a.callback||f,k=j,l=a.complete||f,m,n;c(h?a.yep:a.nope,!!i),i&&c(i)}var i,j,l=this.yepnope.loader;if(e(a))g(a,0,l,0);else if(w(a))for(i=0;i (function(w,d,s,l,i){w[l]=w[l]||[];w[l].push({'gtm.start':new Date().getTime(),event:'gtm.js'});var f=d.getElementsByTagName(s)[0];var j=d.createElement(s);var dl=l!='dataLayer'?'&l='+l:'';j.src='//www.googletagmanager.com/gtm.js?id='+i+dl;j.type='text/javascript';j.async=true;f.parentNode.insertBefore(j,f);})(window,document,'script','dataLayer','GTM-P4HH5NV'); Skip to main content Home About Submit ALERTS / RSS Search for this keyword Advanced Search Berry Supplement-Modified Human Microbiome Improves Immunotherapy Response in Mouse Models Shiva Jahanbahkshi , Amna Bibi , Rebecca Hoyd , Caroline Dravillas , Nyelia Williams , Shiqi Zhang , Aaditya Pallerla , Shankar Suman , Joseph Amann , Mounika Goruganthu , Tamio Okimoto , Yangyang Liu , Marisa A. Bittoni , Ni Shi , Alvin Anand , Bailey Conrad , Lane Nevers , Kristen Heitman , Maxine Webb , Elizabeth M Grainger , Madison Grogan , Christian Quiles , Tong Chen , Carolyn J. Presley , Lang Li , Patrick Bradley , Yael Vodovotz , David P. Carbone , Steven K. Clinton , Jiangjiang Zhu , View ORCID Profile Daniel Spakowicz doi: https://doi.org/10.1101/2025.01.16.25320666 Shiva Jahanbahkshi 1 Department of Food Science and Technology, College of Food, Agriculture, and Environmental Sciences, The Ohio State University ; Columbus, OH, USA Find this author on Google Scholar Find this author on PubMed Search for this author on this site Amna Bibi 2 Division of Medical Oncology, Department of Internal Medicine, The Ohio State University Comprehensive Cancer Center ; Columbus, OH, USA Find this author on Google Scholar Find this author on PubMed Search for this author on this site Rebecca Hoyd 2 Division of Medical Oncology, Department of Internal Medicine, The Ohio State University Comprehensive Cancer Center ; Columbus, OH, USA Find this author on Google Scholar Find this author on PubMed Search for this author on this site Caroline Dravillas 2 Division of Medical Oncology, Department of Internal Medicine, The Ohio State University Comprehensive Cancer Center ; Columbus, OH, USA Find this author on Google Scholar Find this author on PubMed Search for this author on this site Nyelia Williams 2 Division of Medical Oncology, Department of Internal Medicine, The Ohio State University Comprehensive Cancer Center ; Columbus, OH, USA Find this author on Google Scholar Find this author on PubMed Search for this author on this site Shiqi Zhang 3 Department of Human Sciences and Comprehensive Cancer Center, The Ohio State University College of Medicine ; Columbus, OH, USA Find this author on Google Scholar Find this author on PubMed Search for this author on this site Aaditya Pallerla 2 Division of Medical Oncology, Department of Internal Medicine, The Ohio State University Comprehensive Cancer Center ; Columbus, OH, USA Find this author on Google Scholar Find this author on PubMed Search for this author on this site Shankar Suman 2 Division of Medical Oncology, Department of Internal Medicine, The Ohio State University Comprehensive Cancer Center ; Columbus, OH, USA Find this author on Google Scholar Find this author on PubMed Search for this author on this site Joseph Amann 2 Division of Medical Oncology, Department of Internal Medicine, The Ohio State University Comprehensive Cancer Center ; Columbus, OH, USA Find this author on Google Scholar Find this author on PubMed Search for this author on this site Mounika Goruganthu 2 Division of Medical Oncology, Department of Internal Medicine, The Ohio State University Comprehensive Cancer Center ; Columbus, OH, USA Find this author on Google Scholar Find this author on PubMed Search for this author on this site Tamio Okimoto 2 Division of Medical Oncology, Department of Internal Medicine, The Ohio State University Comprehensive Cancer Center ; Columbus, OH, USA Find this author on Google Scholar Find this author on PubMed Search for this author on this site Yangyang Liu 4 Pelotonia Institute for Immuno-Oncology, The Ohio State University Comprehensive Cancer Center ; Columbus, OH, USA Find this author on Google Scholar Find this author on PubMed Search for this author on this site Marisa A. Bittoni 2 Division of Medical Oncology, Department of Internal Medicine, The Ohio State University Comprehensive Cancer Center ; Columbus, OH, USA Find this author on Google Scholar Find this author on PubMed Search for this author on this site Ni Shi 2 Division of Medical Oncology, Department of Internal Medicine, The Ohio State University Comprehensive Cancer Center ; Columbus, OH, USA Find this author on Google Scholar Find this author on PubMed Search for this author on this site Alvin Anand 2 Division of Medical Oncology, Department of Internal Medicine, The Ohio State University Comprehensive Cancer Center ; Columbus, OH, USA Find this author on Google Scholar Find this author on PubMed Search for this author on this site Bailey Conrad 5 The Ohio State University College of Medicine , Columbus, OH, USA Find this author on Google Scholar Find this author on PubMed Search for this author on this site Lane Nevers 4 Pelotonia Institute for Immuno-Oncology, The Ohio State University Comprehensive Cancer Center ; Columbus, OH, USA Find this author on Google Scholar Find this author on PubMed Search for this author on this site Kristen Heitman 5 The Ohio State University College of Medicine , Columbus, OH, USA Find this author on Google Scholar Find this author on PubMed Search for this author on this site Maxine Webb 2 Division of Medical Oncology, Department of Internal Medicine, The Ohio State University Comprehensive Cancer Center ; Columbus, OH, USA Find this author on Google Scholar Find this author on PubMed Search for this author on this site Elizabeth M Grainger 2 Division of Medical Oncology, Department of Internal Medicine, The Ohio State University Comprehensive Cancer Center ; Columbus, OH, USA Find this author on Google Scholar Find this author on PubMed Search for this author on this site Madison Grogan 2 Division of Medical Oncology, Department of Internal Medicine, The Ohio State University Comprehensive Cancer Center ; Columbus, OH, USA Find this author on Google Scholar Find this author on PubMed Search for this author on this site Christian Quiles 6 Department of Microbiology, The Ohio State University ; Columbus, OH, USA Find this author on Google Scholar Find this author on PubMed Search for this author on this site Tong Chen 2 Division of Medical Oncology, Department of Internal Medicine, The Ohio State University Comprehensive Cancer Center ; Columbus, OH, USA Find this author on Google Scholar Find this author on PubMed Search for this author on this site Carolyn J. Presley 2 Division of Medical Oncology, Department of Internal Medicine, The Ohio State University Comprehensive Cancer Center ; Columbus, OH, USA Find this author on Google Scholar Find this author on PubMed Search for this author on this site Lang Li 7 Department of Biomedical Informatics, The Ohio State University College of Medicine ; Columbus, OH, USA Find this author on Google Scholar Find this author on PubMed Search for this author on this site Patrick Bradley 6 Department of Microbiology, The Ohio State University ; Columbus, OH, USA Find this author on Google Scholar Find this author on PubMed Search for this author on this site Yael Vodovotz 1 Department of Food Science and Technology, College of Food, Agriculture, and Environmental Sciences, The Ohio State University ; Columbus, OH, USA Find this author on Google Scholar Find this author on PubMed Search for this author on this site David P. Carbone 2 Division of Medical Oncology, Department of Internal Medicine, The Ohio State University Comprehensive Cancer Center ; Columbus, OH, USA Find this author on Google Scholar Find this author on PubMed Search for this author on this site Steven K. Clinton 2 Division of Medical Oncology, Department of Internal Medicine, The Ohio State University Comprehensive Cancer Center ; Columbus, OH, USA Find this author on Google Scholar Find this author on PubMed Search for this author on this site Jiangjiang Zhu 3 Department of Human Sciences and Comprehensive Cancer Center, The Ohio State University College of Medicine ; Columbus, OH, USA Find this author on Google Scholar Find this author on PubMed Search for this author on this site Daniel Spakowicz 2 Division of Medical Oncology, Department of Internal Medicine, The Ohio State University Comprehensive Cancer Center ; Columbus, OH, USA 3 Department of Human Sciences and Comprehensive Cancer Center, The Ohio State University College of Medicine ; Columbus, OH, USA Find this author on Google Scholar Find this author on PubMed Search for this author on this site ORCID record for Daniel Spakowicz For correspondence: daniel.spakowicz{at}osumc.edu Abstract Full Text Info/History Metrics Supplementary material Data/Code Preview PDF Abstract Cancer outcomes have improved with immune checkpoint inhibitor (ICI) treatment; however, less than half of tumors respond. Emerging data show that some responses to ICI depend on the host’s microbiome. Here, we explore a dietary intervention to modify the microbiome and determine the response to ICIs. Following pre-clinical studies showing the benefit of black raspberries, we conducted a human intervention trial called the BEWELL Study ( NCT04267874 ). The intervention increased the abundance of pro-ICI-response microbes (PIRMs). In mouse models, participants’ post-dietary intervention stool led to smaller tumor volumes following treatment with ICIs than pre-dietary intervention samples. One PIRM, Blautia obeum , was sufficient to improve ICI response. These results suggest that black raspberry nectar can modify the human gut microbiome to promote an improved response to ICIs. Introduction Cancer is a major public health problem worldwide and the second leading cause of death in the United States ( 1 ). Immune checkpoint inhibitors (ICIs) have significantly improved clinical outcomes in various cancers ( 2 ), particularly monoclonal antibodies targeting PD-1, PD-L1, or CTLA-4, which block T cell activity. However, despite their success, responses to ICI treatment remain heterogeneous, with 0–80% (median 30%) of tumors decreasing in size following treatment ( 3 , 4 ). There is an urgent need to increase the fraction of patients whose tumors respond to ICI treatment. One area of emerging interest in improving ICI efficacy is the gut microbiome. Pre-treatment stool samples of cancer patients can predict tumor response to ICIs ( 5 – 7 ), and fecal transplants can resensitize treatment-resistant tumors ( 8 ). Many efforts are underway to understand how microbes affect ICI response and to modify the microbiome to improve ICI treatment outcomes. Dietary interventions are particularly attractive, as they are accessible and patient-controlled, but have limited evidence regarding their ability to alter the microbiome on treatment-relevant timescales or with sufficient specificity ( 9 ). Here, we investigated a high-polyphenol, whole-food intervention (black raspberries (BRB)) for its ability to modify the gut microbiome to improve ICI treatment response. We demonstrated that BRB powder increases the abundance of pro-ICI-response microbes (PIRMs) in mouse models. In a human clinical trial, we observed that four weeks of 354 mL BRB nectar per day altered the gut microbiomes of study participants, largely by increasing the abundance of microbes in the family Lachnospiraceae . We further discovered that the BRB-modified microbiomes improve treatment outcomes in an ICI-response mouse model, relative to those study participants’ pre-intervention samples. Finally, we demonstrated isolated Lachnospiraceae strains are sufficient to improve ICI response in mice when supplemented into a human’s pre-BRB gut microbiome. Explorations of the mechanism suggest a role for altered L-carnitine signaling. Results Preclinical model exploration for food products that enrich gut Pro-Immunotherapy Response Microbes (PIRMs) We began testing food supplements in mouse models to find dietary interventions to enrich microbes with a literature precedence for affecting ICI response in humans, labeled here as PIRMs. We fed rats a standard synthetic diet (AIN-76A) alone or supplemented with 5% whole BRB powder ad libitum for 35 weeks ( Fig. 1A ). We collected stool at the end of the study to test for differences in the gut microbiomes by diet. Clustering by total 16S abundance revealed no separation between the two dietary groups (p-value = 0.096). The black raspberry group showed tighter clustering than the control group, suggesting uniform alterations with the diet (p-value = 0.344) ( Fig. 1B ). We tested for specific taxonomic changes, aggregating to every taxonomic level and correcting for multiple hypothesis tests. We observed significant enrichment of the PIRM Akkermansia in the black raspberry group (log2fc = 5.29, adjusted p-value = 0.049), along with its family (formerly Verrucomicrobiaceae, now Akkermansiaceae ) and order ( Verrucomicrobiales ). The cross-taxonomy enrichment demonstrates the selective enrichment of Akkermansia but not closely related taxa ( Fig. 1C , Supplementary Table S1) . The genus has been linked to improved ICI response in several studies ( 5 – 7 , 10 ). The BRB group showed depletion of a few genera, including Ruminiclostridium 5 (log2fc = −4.80, adjusted p-value = 0.049) and Clostridium sensu stricto 1 (log2fc = −8.21, adjusted p-value = 0.049), supporting specific effects of the intervention ( Fig. 1D ). This suggests that BRB supplementation may be a specific dietary intervention for enriching PIRMs. Download figure Open in new tab Fig. 1. Black raspberry diet supplementation in a rat model enriches for gut PIRMs. (A) Schema of dietary supplementation studies in rat models fed with AIN-76A synthetic diet +/− 5% lyophilized black raspberry powder and the collection of gut microbiome samples. (B) Amplicon sequencing showed an increased abundance of A. muciniphila in the treatment group. (C) The change in microbiome composition was narrowly restricted to A. muciniphila , with the only other enriched taxonomic groups being from the same lineage. Human dietary intervention clinical trial in a cohort at high risk of developing lung cancer Following the animal BRB diet intervention study results, we began a human clinical trial to explore whether similar changes in PIRMs could be obtained. The intervention delivered 340 mL of BRB nectar daily for four weeks ( Figure 2A ). The study population was recruited from a lung cancer screening clinic; they were cancer-free, but phenotypically similar to patients with lung cancer to maintain as much relevance to cancer as possible while reducing treatment-derived variation. We used a crossover design, where participants were randomized first to receive the intervention or a taste- and texture-matched placebo control. Participants drank their respective treatments twice daily for four weeks, followed by a 2-week washout. After washout, participants switched to the other treatment for another four weeks, making the total study duration ten weeks. Stool samples were collected before and after each intervention ( Fig. 2A ) . Overall, the composition of the participants’ gut microbiomes remained similar, with Bacteroidetes and Firmicutes predominating ( Fig. 2B ). We used mixed-effects models to identify the individual taxa enriched after only the BRB time point. We observed an increased abundance of several taxa, including Blautia obeum and Agathobacter rectalis . These taxa, as well as several other of the most significantly enriched organisms, are members of the family Lachnospiraceae (e.g., Roseburia sp. CAG 309 , Lachnospiraceae unclassified , Lachnospira pectinoschiza ). ( Fig. 2C , Supplementary Table S2 ). The effect size of BRB was largest for Roseburia sp. CAG 309 ( Fig. 2D ). Download figure Open in new tab Fig. 2. BRB nectar increases Lachnospiraceae abundance in the BEWELL human trial. (A) A crossover trial tested BRB nectar or placebo to participants for four weeks, with stool samples collected before and after each phase. (B) BRB treatment increased Firmicutes and decreased Bacteroidetes compared to placebo. (C) BRB significantly enriched Lachnospiraceae members, including Blautia obeum and Agathobacter rectalis . (D) Roseburia sp CAG 309 showed the largest BRB-induced effect size. (E) Comparing the BEWELL gut microbiome communities to publicly available clinical trial data from cancer patients who responded or did not respond to ICIs showed no clear similarity to either group. However, after BRB supplementation, the total community was slightly more similar to a “Responder” type microbiome than pre-BRB or either placebo category (F) . We next sought to put these changes into the context of cancer treatment outcomes. Previous studies have demonstrated the ability to predict whether an individual would respond to ICIs based on pre-treatment gut microbiome samples. We assembled publicly available data from five ICI clinical trials (n = 211) that assessed patients’ pre-treatment gut microbiome communities and related them to treatment response ( 5 , 6 , 11 – 13 ). As reported previously, the uniformly processed metagenomic sequencing data showed distinct clusters for responders and non-responders (adonis p-value = 0.007, Fig. 2F ) ( 5 – 7 ). Overlaying the BEWELL trial data showed no major shifts in the gut microbiome communities, consistent with the relatively small number of altered microbes ( Fig 2B & C ). However, comparing the distance to the centroids of the non-responder or responder clusters showed that the post-BRB samples were more responder-like ( Fig. 2E ). Extending the human dietary intervention to cancer using preclinical models Next, we sought to test whether the human trial’s dietary intervention modified the microbiome in a way that would affect the response to ICIs. We turned to a model system whereby a group of tumor-bearing mice were given a study participant’s microbiome from before the dietary intervention, and another group was given that person’s post-dietary intervention microbiome. We then monitored the effects of the different microbiomes on ICI response ( Fig. 3A ). We selected stool samples from study participants who exemplified the strongest changes across the cohort (i.e., those who showed large changes in the Lachnospiraceae , which had the most statistically significant enrichment by BRB), as well as two individuals who did not show these changes ( Fig. 3B ). As an additional control, we included stool from patients with lung cancer whose tumors responded well to ICIs or did not. Linear mixed effects models showed a significant negative effect on tumor volume of the gavage in the lung cancer patient whose tumor responded well to ICI treatment but had no significant association with the NR patient ( Fig. 3C ). Study participants with higher Lachnospiraceae in their post-BRB microbiome showed significantly smaller tumor volumes. Participants who did not show Lachnospiraceae showed no such effect. This suggests that the BRB-modified microbiomes, most strongly enriched for Lachnospiraceae , promoted tumor response to ICIs ( Fig. 3C ). Download figure Open in new tab Fig. 3. BRB-Modified Microbiomes Enhance ICI Response. (A) Tumor growth curves show significant tumor suppression in mice gavaged with post-dietary intervention microbiome and treated with anti-PD1 therapy compared to controls. (B) The abundance of Lachnospiraceae in samples gavaged into mouse models. (C) Study participants with higher Lachnospiraceae in their post-BRB microbiome showed significantly smaller tumor volumes. Participants who did not show Lachnospiraceae showed no such effect. Control-NR and Control-R microbiomes were from patients whose lung cancer was treated with ICIs and whose tumors did or did not respond to treatment. Blautia enrichment improves ICI response Following the improvement in ICI response in mouse models that received high Lachnospiraceae samples ( Fig. 3B & C ), we aimed to evaluate whether Blautia alone could improve ICI response. We established a mouse model where one group received a fecal slurry from a representative pre-dietary intervention sample (Participant 85, Fig. 4A ), while another group was gavaged with the same slurry supplemented with Blautia . All mice were injected with a cancer cell line and treated with anti-PD1. Monitoring tumor growth over time indicated that mice receiving the Blautia -supplemented slurry in conjunction with anti-PD1 treatment exhibited a marked reduction in tumor growth compared to those receiving the slurry alone (p-value= 0.012, Fig. 4B ). Moreover, a higher proportion of mice in the Blautia -supplemented group remained tumor-free, emphasizing its potential to bolster therapeutic responses ( Fig. 4C ). Download figure Open in new tab Fig. 4. Blautia enrichment improves ICI response and alters metabolic profiles. (A) Mice gavaged with participant 85’s pre-BRB fecal slurry did not contain Blautia . (B) Blautia -supplemented mice showed reduced tumor growth. (C) More mice in the Blautia group were tumor-free. (D) B. obeum and B. massiliensis improved ICI response more than A. rectalis . (E) SCFA levels were unchanged across groups. (F) Elevated L-carnitine levels correlated with smaller tumors To understand if the ICI effects we observed with Blautia are general across the Lachnospiraceae , we tested two closely related Blautia species ( obeum and massiliensis ) as well as a more distantly related family member that was enriched by BRB, Agathobacter rectalis . Results demonstrated that both B. obeum and B. massiliensis were more effective in slowing tumor growth than A. rectalis , suggesting that these microbes share the mechanism augmenting the benefits of immunotherapy ( Fig. 4D ). Then we conducted a metabolomics analysis to assess the impact of microbial treatments on metabolic profiles. We measured short-chain fatty acids (SCFAs) like butyric acid, heptanoic acid, and valeric acid across different groups of mice treated with A. rectalis , B. obeum , and B. massiliensis . We observed no difference in the SCFA production across the groups ( Fig. 4E ), nor in other molecules that have been associated with ICI response, e.g., inosine or tryptophan derivatives ( Supplementary Fig. S1 ). However, the mouse groups with smaller tumor volumes showed significantly greater L (−) carnitine levels ( Fig. 4F ). Discussion In our study, BRB supplementation led to microbiome changes that may enhance ICI treatment outcomes. In rat feeding studies, BRB supplementation enriched for previously reported PIRMs like Akkermansia . In the human trial, a small BRB dietary intervention was sufficient to alter participants’ microbiomes and increase the abundance of the family Lachnospiraceae . When transferred to mouse models, these altered microbiomes led to improved tumor response to ICI treatment. Supplementation with Blautia alone enhanced ICI efficacy. Metabolomics suggests a role for increased L(−) carnitine in driving improved tumor responses to ICI treatment. In recent years, the microbiome has been shown to play a causal role in the response to ICIs, leading many to study how best to alter the microbiome to improve treatment outcomes. Groups have explored the use of Fecal Microbiota Transplant (FMT), which has shown promise in several tumor types ( 14 – 16 ). Others have explored the use of single probiotics or microbial consortia ( 17 ), and several clinical trials are underway. We and others have pursued dietary interventions; here, we focus on polyphenols, but others have studied the effect of increased fiber ( 9 ) or specific fiber supplements like inulin ( 18 ) or pectin ( 19 ). These dietary approaches aim to provide a patient-accessible option for enhancing ICI efficacy through gut microbiome modulation. High polyphenol dietary interventions have been used to modify health outcomes in several contexts. The source of the polyphenols are typically plants and include fruits (BRB (Rubus occidentalis), Camu camu (Myrciaria dubia) ( 20 )), leaves (green tea (Camellia sinensis) ( 21 , 22 ), and seeds (walnuts (Juglans regia) ( 23 )). A recent study by Messaoudene et al. (2022) demonstrated the potential of Camu camu to enhance antitumor activity and overcome resistance to ICI treatment through its effects on the gut microbiome ( 20 ). Previous work involving BRB has demonstrated broad anticancer properties. Chen et al. showed reduced tumorigenesis in a colon cancer mouse model fed BRB and suggested a mechanism involving demethylation of the gene Secreted frizzled-related protein 2 (SRFB2) ( 24 ). In clinical trials, BRB supplementation has led to reduced inflammatory cytokine circulation in patients with precancerous lesions or cancers of the oral cavity ( 25 ), esophagus ( 26 – 30 ), and colon ( 31 , 32 ). Here, we show a relatively small dietary intervention, without additional control of the diet, was sufficient to alter the gut microbiome. These findings underscore the potential of dietary interventions to improve cancer treatment outcomes, particularly in combination with ICI therapies. The mechanism by which polyphenols alter health is expected to be highly varied but may be due to changes in microbial composition. We used preclinical models to relate the altered microbiome to treatment outcomes and showed that mice gavaged with the stool from individuals with BRB-enriched Lachnospiraceae had smaller tumor volumes. However, the altered microbes varied depending on the berry and conditions. When we fed BRB powder to rats, non- Lachnospriaceae PIRMs, including Akkermansia, were enriched. Messaoudene et al. showed that Camu camu berry increased the abundance of Ruminococcus . In our human trial, the BRB most strongly increased the abundance of Lachnospiraceae members. Lachnospiraceae have been strongly associated with ICI response in multiple studies. McCulloch et al. (2022) analyzed microbial signatures across five melanoma cohorts, finding Lachnospiraceae most strongly linked with favorable outcomes to ICI treatment ( 12 ). In addition, Davar et al. (2021) also showed that FMT from donors whose tumors had responded to ICI treatment with high gut microbiome Lachnospiraceae abundance led to improved responses in PD-1–refractory melanoma patient recipients. The expected mechanism included increasing CD8+ T cell activation and modulating immunosuppressive myeloid cells ( 15 ). Studies in colorectal cancer provide further support for the benefits of Lachnospiraceae , with tissue-resident species like Ruminococcus gnavus and Blautia producta shown to promote immune surveillance by activating CD8+ T cells through the degradation of lyso-glycerophospholipids. This process restores CD8+ T cell function by counteracting the immunosuppressive effects of these metabolites ( 33 ). Lastly, a high abundance of Lachnospiraceae in colorectal cancer patients has been associated with elevated RNAseq-derived “immunoscores”, suggesting greater lymphocyte infiltration and a more favorable prognosis ( 34 ). Collectively, these studies provide strong correlative evidence for Lachnospiraceae ’s role in enhancing ICI efficacy and its potential as a microbial biomarker for treatment response. The precise mechanism by which Lachnospiraeae alter ICI response remains unclear. Several groups have reported the production of SCFA’s, notably butyrate, by Lachnospiraceae members, including Roseburia and Eubacterium . Higher levels of butyrate have been associated with improved ICI response in mouse and human studies, likely due to butyrate’s ability to enhance immune function by promoting the activation of cytotoxic T cells and NK cells. This modulation helps to improve immune surveillance and response to tumors, as butyrate has been shown to directly activate immune pathways such as NF-κB signaling in T cells ( 8 , 35 , 36 ). However, no increase in butyrate or other SCFAs was observed in the Blautia -supplemented mouse feces or blood. Other mechanisms include inosine and indole-3-aldehyde, but no differences in indole molecules correlated with tumor response in the mouse models. However, we did observe altered carnitine levels in mice gavaged with Blautia , leading to smaller tumor volumes, but not in mice gavaged with Agathobacter rectale , which showed larger tumor volumes. Carnitine appears to play a multifaceted role in animal biology, with its effects varying based on the context and cancer type. As a vital molecule for fatty acid transport into mitochondria, carnitine supports energy production, which is necessary for maintaining gut epithelial barrier function and intestinal homeostasis ( 37 ). However, certain cancers that rely on lipid metabolism may exploit carnitine to fuel their growth and progression. For instance, the carnitine palmitoyltransferase (CPT) system, crucial for fatty acid oxidation, has been identified as a potential target for anti-cancer therapies ( 38 ). Our study highlights promising associations between BRB supplementation, microbiome enrichment, and improved ICI responses; however, it has some limitations. While BRB supplementation selectively enriched beneficial microbes like Akkermansia and Lachnospiraceae , the specific mechanisms driving improved ICI outcomes remain unclear. Although metabolomics revealed changes in L(−) carnitine levels, the role of carnitine in ICI efficacy is context-dependent, with both beneficial and potentially tumor-promoting effects reported. Conclusion A BRB whole-food intervention shows promise as a means to modify the microbiome to improve ICI responses by selectively enriching beneficial microbes like Lachnospiraceae and modulating metabolic pathways. These findings contribute to the growing body of evidence supporting the role of the gut microbiome in shaping ICI outcomes. While our data suggest a role for metabolites such as L(−) carnitine in influencing ICI efficacy, further research is needed to unravel the underlying mechanisms and resolve conflicting reports regarding its impact. By offering a patient-accessible strategy, dietary interventions like BRB have the potential to complement existing ICIs and provide personalized treatment options. Moving forward, integrating microbiome modulation into ICI-based cancer care will require mechanistic studies, larger trials, and exploration of its applicability across diverse patient populations and cancer types. These efforts could pave the way for transformative advances in cancer treatment through microbiome-driven approaches. Data Availability All data produced are available online at https://github.com/spakowiczlab/dmm21 https://github.com/spakowiczlab/dmm21 Funding Pelotonia, clinical trial award (DS) OSUCCC Division of Medical Oncology, seed grant (DS) Association for the Study of Lung Cancer, Lung Cancer Foundation of America and the Bristol Meyers Squibb Foundation, Young Investigator in Immuno-Oncology Award (DS) National Institutes of Aging grant 1K01AG070310 (DS) The Ohio State University Wexner Medical Center and The Ohio State University College of Medicine Clinical Research Center/Center for Clinical Research Management American Lung Association Innovator Award (DS) Author contributions Conceptualization: Methodology: Investigation: Visualization: Funding acquisition: Project administration: Supervision: Writing – original draft: Writing – review & editing: Competing interests Data and materials availability Supplementary Materials Materials and Methods Figs. S1 to S5 Tables S1 to S3 Acknowledgments We would like to thank Angela Dahlberg, editor in The Ohio State University Division of Medical Oncology, for editing and proofreading this manuscript. We also thank the study participants for their effort and dedication. References 1. ↵ R. L. Siegel , A. N. Giaquinto , A. Jemal , Cancer statistics, 2024 . CA: A Cancer Journal for Clinicians 74 , 12 – 49 ( 2024 ). OpenUrl CrossRef PubMed 2. ↵ T. A. Yap , E. E. Parkes , W. Peng , J. T. Moyers , M. A. Curran , H. A. Tawbi , Development of Immunotherapy Combination Strategies in Cancer . Cancer Discovery 11 , 1368 – 1397 ( 2021 ). OpenUrl Abstract / FREE Full Text 3. ↵ A. H. Sharpe , K. E. Pauken , The diverse functions of the PD1 inhibitory pathway . Nature Reviews Immunology 18 , 153 – 167 ( 2018 ). OpenUrl CrossRef PubMed 4. ↵ M. L. Y. Wan , V. A. Co , H. El-Nezami , Dietary polyphenol impact on gut health and microbiota . Critical reviews in food science and nutrition 61 , 690 – 711 ( 2021 ). OpenUrl PubMed 5. ↵ V. Gopalakrishnan , C. N. Spencer , L. Nezi , A. Reuben , M. C. Andrews , T. V. Karpinets , P. Prieto , D. Vicente , K. Hoffman , S. C. Wei , Gut microbiome modulates response to anti– PD-1 immunotherapy in melanoma patients . Science 359 , 97 – 103 ( 2018 ). OpenUrl Abstract / FREE Full Text 6. ↵ V. Matson , J. Fessler , R. Bao , T. Chongsuwat , Y. Zha , M.-L. Alegre , J. J. Luke , T. F. Gajewski , The commensal microbiome is associated with anti–PD-1 efficacy in metastatic melanoma patients . Science 359 , 104 – 108 ( 2018 ). OpenUrl Abstract / FREE Full Text 7. ↵ B. Routy , E. Le Chatelier , L. Derosa , C. P. Duong , M. T. Alou , R. Daillère , A. Fluckiger , M. Messaoudene , C. Rauber , M. P. Roberti , Gut microbiome influences efficacy of PD-1– based immunotherapy against epithelial tumors . Science 359 , 91 – 97 ( 2018 ). OpenUrl Abstract / FREE Full Text 8. ↵ Z. Peng , S. Cheng , Y. Kou , Z. Wang , R. Jin , H. Hu , X. Zhang , J. Gong , J. Li , M. Lu , The gut microbiome is associated with clinical response to anti–PD-1/PD-L1 immunotherapy in gastrointestinal cancer . Cancer Immunology Research 8 , 1251 – 1261 ( 2020 ). OpenUrl Abstract / FREE Full Text 9. ↵ C. N. Spencer , J. L. McQuade , V. Gopalakrishnan , J. A. McCulloch , M. Vetizou , A. P. Cogdill , M. A. W. Khan , X. Zhang , M. G. White , C. B. Peterson , M. C. Wong , G. Morad , T. Rodgers , J. H. Badger , B. A. Helmink , M. C. Andrews , R. R. Rodrigues , A. Morgun , Y. S. Kim , J. Roszik , K. L. Hoffman , J. Zheng , Y. Zhou , Y. B. Medik , L. M. Kahn , S. Johnson , C. W. Hudgens , K. Wani , P.-O. Gaudreau , A. L. Harris , M. A. Jamal , E. N. Baruch , E. Perez-Guijarro , C.-P. Day , G. Merlino , B. Pazdrak , B. S. Lochmann , R. A. Szczepaniak-Sloane , R. Arora , J. Anderson , C. M. Zobniw , E. Posada , E. Sirmans , J. Simon , L. E. Haydu , E. M. Burton , L. Wang , M. Dang , K. Clise-Dwyer , S. Schneider , T. Chapman , N.-A. A. S. Anang , S. Duncan , J. Toker , J. C. Malke , I. C. Glitza , R. N. Amaria , H. A. Tawbi , A. Diab , M. K. Wong , S. P. Patel , S. E. Woodman , M. A. Davies , M. I. Ross , J. E. Gershenwald , J. E. Lee , P. Hwu , V. Jensen , Y. Samuels , R. Straussman , N. J. Ajami , K. C. Nelson , L. Nezi , J. F. Petrosino , P. A. Futreal , A. J. Lazar , J. Hu , R. R. Jenq , M. T. Tetzlaff , Y. Yan , W. S. Garrett , C. Huttenhower , P. Sharma , S. S. Watowich , J. P. Allison , L. Cohen , G. Trinchieri , C. R. Daniel , J. A. Wargo , Dietary fiber and probiotics influence the gut microbiome and melanoma immunotherapy response . Science 374 , 1632 – 1640 ( 2021 ). OpenUrl CrossRef PubMed 10. ↵ X. Xu , J. Lv , F. Guo , J. Li , Y. Jia , D. Jiang , N. Wang , C. Zhang , L. Kong , Y. Liu , Gut microbiome influences the efficacy of PD-1 antibody immunotherapy on MSS-type colorectal cancer via metabolic pathway . Frontiers in Microbiology 11 , 814 ( 2020 ). OpenUrl PubMed 11. ↵ A. E. Frankel , L. A. Coughlin , J. Kim , T. W. Froehlich , Y. Xie , E. P. Frenkel , A. Y. Koh , Metagenomic Shotgun Sequencing and Unbiased Metabolomic Profiling Identify Specific Human Gut Microbiota and Metabolites Associated with Immune Checkpoint Therapy Efficacy in Melanoma Patients . Neoplasia 19 , 848 – 855 ( 2017 ). OpenUrl CrossRef PubMed 12. ↵ J. A. McCulloch , D. Davar , R. R. Rodrigues , J. H. Badger , J. R. Fang , A. M. Cole , A. K. Balaji , M. Vetizou , S. M. Prescott , M. R. Fernandes , Intestinal microbiota signatures of clinical response and immune-related adverse events in melanoma patients treated with anti-PD-1 . Nature medicine 28 , 545 – 556 ( 2022 ). OpenUrl CrossRef PubMed 13. ↵ B. A. Peters , M. Wilson , U. Moran , A. Pavlick , A. Izsak , T. Wechter , J. S. Weber , I. Osman , J. Ahn , Relating the gut metagenome and metatranscriptome to immunotherapy responses in melanoma patients . Genome Med 11 , 61 ( 2019 ). OpenUrl CrossRef PubMed 14. ↵ E. N. Baruch , I. Youngster , G. Ben-Betzalel , R. Ortenberg , A. Lahat , L. Katz , K. Adler , D. Dick-Necula , S. Raskin , N. Bloch , D. Rotin , L. Anafi , C. Avivi , J. Melnichenko , Y. Steinberg-Silman , R. Mamtani , H. Harati , N. Asher , R. Shapira-Frommer , T. Brosh-Nissimov , Y. Eshet , S. Ben-Simon , O. Ziv , M. A. W. Khan , M. Amit , N. J. Ajami , I. Barshack , J. Schachter , J. A. Wargo , O. Koren , G. Markel , B. Boursi , Fecal microbiota transplant promotes response in immunotherapy-refractory melanoma patients . Science 371 , 602 – 609 ( 2021 ). OpenUrl Abstract / FREE Full Text 15. ↵ D. Davar , A. K. Dzutsev , J. A. McCulloch , R. R. Rodrigues , J.-M. Chauvin , R. M. Morrison , R. N. Deblasio , C. Menna , Q. Ding , O. Pagliano , Fecal microbiota transplant overcomes resistance to anti–PD-1 therapy in melanoma patients . Science 371 , 595 – 602 ( 2021 ). OpenUrl Abstract / FREE Full Text 16. ↵ J. Erdmann , How gut bacteria could boost cancer treatments . ( 2022 ). 17. ↵ V. Sankarapandian , B. A. Venmathi Maran , R. L. Rajendran , M. P. Jogalekar , S. Gurunagarajan , R. Krishnamoorthy , P. Gangadaran , B.-C. Ahn , An update on the effectiveness of probiotics in the prevention and treatment of cancer . Life 12 , 59 ( 2022 ). OpenUrl PubMed 18. ↵ K. Han , J. Nam , J. Xu , X. Sun , X. Huang , O. Animasahun , A. Achreja , J. H. Jeon , B. Pursley , N. Kamada , Generation of systemic antitumour immunity via the in situ modulation of the gut microbiome by an orally administered inulin gel . Nature biomedical engineering 5 , 1377 – 1388 ( 2021 ). OpenUrl PubMed 19. ↵ S.-L. Zhang , Y.-Q. Mao , Z.-Y. Zhang , Z.-M. Li , C.-Y. Kong , H.-L. Chen , P.-R. Cai , B. Han , T. Ye , L.-S. Wang , Pectin supplement significantly enhanced the anti-PD-1 efficacy in tumor-bearing mice humanized with gut microbiota from patients with colorectal cancer . Theranostics 11 , 4155 ( 2021 ). OpenUrl PubMed 20. ↵ M. Messaoudene , R. Pidgeon , C. Richard , M. Ponce , K. Diop , M. Benlaifaoui , A. Nolin-Lapalme , F. Cauchois , J. Malo , W. Belkaid , A natural polyphenol exerts antitumor activity and circumvents anti–PD-1 resistance through effects on the gut microbiota . Cancer Discovery 12 , 1070 – 1087 ( 2022 ). OpenUrl PubMed 21. ↵ G. Deb , V. S. Thakur , A. M. Limaye , S. Gupta , Epigenetic induction of tissue inhibitor of matrix metalloproteinase-3 by green tea polyphenols in breast cancer cells . Molecular carcinogenesis 54 , 485 – 499 ( 2015 ). OpenUrl PubMed 22. ↵ I. A. Siddiqui , M. Asim , B. B. Hafeez , V. M. Adhami , R. S. Tarapore , H. Mukhtar , Green tea polyphenol EGCG blunts androgen receptor function in prostate cancer . The FASEB Journal 25 , 1198 ( 2011 ). OpenUrl CrossRef PubMed 23. ↵ H.-S. Chen , M.-H. Bai , T. Zhang , G.-D. Li , M. Liu , Ellagic acid induces cell cycle arrest and apoptosis through TGF-β/Smad3 signaling pathway in human breast cancer MCF-7 cells . International journal of oncology 46 , 1730 – 1738 ( 2015 ). OpenUrl PubMed 24. ↵ L. Chen , B. Jiang , C. Zhong , J. Guo , L. Zhang , T. Mu , Q. Zhang , X. Bi , Chemoprevention of colorectal cancer by black raspberry anthocyanins involved the modulation of gut microbiota and SFRP2 demethylation . Carcinogenesis 39 , 471 – 481 ( 2018 ). OpenUrl CrossRef PubMed 25. ↵ B. C. Casto , L. A. Kresty , C. L. Kraly , D. K. Pearl , T. J. Knobloch , H. A. Schut , G. D. Stoner , S. R. Mallery , C. M. Weghorst , Chemoprevention of oral cancer by black raspberries . Anticancer research 22 , 4005 – 4015 ( 2002 ). OpenUrl PubMed Web of Science 26. ↵ L. A. Kresty , M. A. Morse , C. Morgan , P. S. Carlton , J. Lu , A. Gupta , M. Blackwood , G. D. Stoner , Chemoprevention of esophageal tumorigenesis by dietary administration of lyophilized black raspberries . Cancer Research 61 , 6112 – 6119 ( 2001 ). OpenUrl Abstract / FREE Full Text 27. J. F. Lechner , R. K. Reen , A. A. Dombkowski , D. Cukovic , S. Salagrama , L.-S. Wang , G. D. Stoner , Effects of a black raspberry diet on gene expression in the rat esophagus . Nutrition and cancer 60 , 61 – 69 ( 2008 ). OpenUrl CrossRef PubMed Web of Science 28. B. W. Liston , A. Gupta , R. Nines , P. S. Carlton , L. A. Kresty , G. K. Harris , G. D. Stoner , Incidence and effects of Ha-ras codon 12 G→ A transition mutations in preneoplastic lesions induced by N-nitrosomethylbenzylamine in the rat esophagus . Molecular Carcinogenesis: Published in cooperation with the University of Texas MD Anderson Cancer Center 32 , 1 – 8 ( 2001 ). OpenUrl 29. D. S. Peiffer , N. P. Zimmerman , L.-S. Wang , B. W. Ransom , S. G. Carmella , C.-T. Kuo , J. Siddiqui , J.-H. Chen , K. Oshima , Y.-W. Huang , Chemoprevention of esophageal cancer with black raspberries, their component anthocyanins, and a major anthocyanin metabolite, protocatechuic acid . Cancer prevention research 7 , 574 – 584 ( 2014 ). OpenUrl Abstract / FREE Full Text 30. ↵ G. D. Stoner , T. Chen , L. A. Kresty , R. M. Aziz , T. Reinemann , R. Nines , Protection against esophageal cancer in rodents with lyophilized berries: potential mechanisms . Nutrition and cancer 54 , 33 – 46 ( 2006 ). OpenUrl CrossRef PubMed Web of Science 31. ↵ G. Harris , A. Gupta , R. Nines , L. Kresty , S. Habib , W. Frankel , K. LaPerle , D. D. Gallaher , S. Schwartz , G. Stoner , Effects of lyophilized black raspberries on azoxymethane-induced colon cancer and 8-hydroxy-2′-deoxyguanosine levels in the Fischer 344 rat . Nutrition and cancer 40 , 125 – 133 ( 2001 ). OpenUrl CrossRef PubMed Web of Science 32. ↵ L.-S. Wang , C.-T. Kuo , T. H.-M. Huang , M. Yearsley , K. Oshima , G. D. Stoner , J. Yu , J. F. Lechner , Y.-W. Huang , Black raspberries protectively regulate methylation of Wnt pathway genes in precancerous colon tissue . Cancer Prevention Research 6 , 1317 – 1327 ( 2013 ). OpenUrl Abstract / FREE Full Text 33. ↵ X. Zhang , D. Yu , D. Wu , X. Gao , F. Shao , M. Zhao , J. Wang , J. Ma , W. Wang , X. Qin , Tissue-resident Lachnospiraceae family bacteria protect against colorectal carcinogenesis by promoting tumor immune surveillance . Cell host & microbe 31 , 418 – 432 ( 2023 ). OpenUrl CrossRef PubMed 34. ↵ Z. Hexun , T. Miyake , T. Maekawa , H. Mori , D. Yasukawa , M. Ohno , A. Nishida , A. Andoh , M. Tani , High abundance of Lachnospiraceae in the human gut microbiome is related to high immunoscores in advanced colorectal cancer . Cancer Immunology, Immunotherapy 72 , 315 – 326 ( 2023 ). OpenUrl PubMed 35. ↵ X. Kang , C. Liu , Y. Ding , Y. Ni , F. Ji , H. C. H. Lau , L. Jiang , J. J. Sung , S. H. Wong , J. Yu , Roseburia intestinalis generated butyrate boosts anti-PD-1 efficacy in colorectal cancer by activating cytotoxic CD8+ T cells . Gut 72 , 2112 – 2122 ( 2023 ). OpenUrl Abstract / FREE Full Text 36. ↵ N. Liu , L. Chen , M. Yan , Q. Tao , J. Wu , J. Chen , X. Chen , W. Zhang , C. Peng , Eubacterium rectale improves the efficacy of anti-PD1 immunotherapy in melanoma via l-serine-mediated NK cell activation . Research 6 , 0127 ( 2023 ). OpenUrl PubMed 37. ↵ K. Lin , W. Zheng , M. Guo , R. Zhou , M. Zhang , T. Liu , The intestinal microbial metabolite acetyl l-carnitine improves gut inflammation and immune homeostasis via CADM2 . Biochimica et Biophysica Acta (BBA)-Molecular Basis of Disease 1870 , 167089 ( 2024 ). OpenUrl 38. ↵ Q. Qu , F. Zeng , X. Liu , Q. Wang , F. Deng , Fatty acid oxidation and carnitine palmitoyltransferase I: emerging therapeutic targets in cancer . Cell death & disease 7 , e2226 – e2226 ( 2016 ). OpenUrl View the discussion thread. Back to top Previous Next Posted January 17, 2025. Download PDF Supplementary Material Data/Code Email Thank you for your interest in spreading the word about medRxiv. NOTE: Your email address is requested solely to identify you as the sender of this article. 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