## 3 Discussion
On the other hand, non-response was associated with increased proportions of _Streptococcus_, _Actinomyces_, _Veillonella_, _Dorea_, _Fusobacterium_, higher neutrophil levels (and neutrophil-to-lymphocyte ratios), and higher fecal levels of butyric acid and its derivatives, which also correlated with decreased survival. muscle mass and function is strongly associated with poor outcomes and adverse events in several oncological contexts [28]. However, the mechanisms underlying the association between sarcopenia and poor response to anticancer therapy remain to be elucidated. In a clinical trial of advanced melanoma patients treated with anti-PD1 checkpoint inhibitors, [PERSON] et al. [29] observed that sarcopenia female patients had 6.5-fold higher anti-PD-1-related early acute limiting toxicity and no improvement in anti-tumor response. The authors hypothesized that this outcome may be related to weight-based dosing, which indicates high-dose drug administration, as it is assumed that pharmacokinetic parameters are altered in patients with high BMI, while drug distribution may be impaired due to loss of lean mass in sarcopenia patients. As for GM, responders were discriminated based on the presence of high proportions of _Phascalorctobacterium_ and _Oscillospira_, as well as low proportions of _Actinomyces_, _Streptococcus_, _Fusobacterium_, _Clostridium_, _Veillonella_, and _Dorea_. Interestingly, _Phascalorctobacterium_ was recently listed among the consistent taxonomic biomarkers associated with responsiveness to melanoma immunotherapy [30]. It should be mentioned that _Phascalorctobacterium_ was also part of the 11-strain commensal consortium that was shown to robustly elicit interferon gamma-producing CD8 T cells in the intestine and improve the therapeutic efficacy of immunotherapy in tumor models [31]. The association between the opportunistic pathogens _Fusobacterium_ and _Streptococcus_ and poor prognosis (i.e., failure to respond to therapy) also confirms the validity of the available literature [9; 14; 32]. On the other hand, conflicting data are reported in the literature for _Veillonella_. Indeed, increased relative abundance of the family _Veillonella_ has been suggested to be an immunotherapy-favorable feature, though non-responder melanoma patients have been found to be enriched in _Veillonella atypica_[10]. These observations suggest the importance of high-resolution taxonomic profiling (down to the species level) in drawing reliable conclusions. With respect to metabolites, the most intriguing finding is arguably the over-representation of the short-chain fatty acid butyrate acid and its derivatives (i.e., methyl and propyl esters) in the feces of non-responders. In addition to being present in some foods, particularly those containing bovine milk fat [33], butyrate is universally recognized as a microbiota metabolite (resulting from fiber fermentation) that is crucial for whole-body health [34]. Similarly, its derivatives are typically produced during polysaccharide fermentation processes and are generally recognized to have anti-inflammatory effects [35; 36]. However, butyrate (and propionate) has recently been shown to limit the efficacy of immunotherapy (anti-CTLA-4). The mechanism behind this phenomenon is probably related to its immunomodulatory activity, i.e., induction of Treg cells, reduced accumulation of memory T cells, and lower inducible T cell co-stimulator induction in T cells [37]. Consistently, in our study, higher basal fecal levels of butyric acid were associated with decreased survival. Regarding the biochemical basis of high butyrate (and derivatives) levels in non-responders, it should be noted that no significant differences in fiber intake were found between responders and non-responders, suggesting a limited contribution of diet. On the other hand, butyrate is also produced via amino acid metabolic pathways by some pathobitons, including _Fusobacterium_[38], which was found to be enriched in non-responders.