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New fecal microbiota for cancer patients The composition of the gut microbiome influences the response of cancer patients to immunotherapies. Baruch et al. and Davar et al. report first-in-human clinical trials to test whether fecal microbiota transplantation (FMT) can affect how metastatic melanoma patients respond to anti–PD-1 immunotherapy (see the Perspective by Woelk and Snyder). Both studies observed evidence of clinical benefit in a subset of treated patients. This included increased abundance of taxa previously shown to be associated with response to anti–PD-1, increased CD8 + T cell activation, and decreased frequency of interleukin-8–expressing myeloid cells, which are involved in immunosuppression. These studies provide proof-of-concept evidence for the ability of FMT to affect immunotherapy response in cancer patients. Science , this issue p. 602 , p. 595 ; see also p. 573

Objective To evaluate the synergic effects of a novel oral supplement formulation, containing prebiotics, yeast β-glucans, minerals and silymarin (Silybum marianum), on lipid and glycidic metabolism, inflammatory and mitochondrial proteins of the liver, in control and high-fat diet-induced obese mice. Methods After an acclimation period, 32 male C57BL/6 mice were divided into the following groups: nonfat diet (NFD) vehicle, NFD supplemented, high-fat diet (HFD) vehicle and HFD supplemented. The vehicle and experimental formulation were administered orally by gavage once a day during the last four weeks of the diet (28 consecutive days). We then evaluated energy homeostasis, inflammation, and mitochondrial protein expression in these groups of mice. Results After four weeks of supplementation, study groups experienced reduced glycemia, dyslipidemia, fat, and hepatic fibrosis levels. Additionally, proliferator-activated receptor-α, AMP-activated protein kinase-1α, peroxisome proliferator-activated receptor γ co-activator -1α, and mitochondrial transcription factor A expression levels were augmented; however, levels of inhibitor of nuclear factor-κB kinase subunit α and p65 nuclear factor-κB expression, and oxidative markers were reduced. Notably, the cortisol/C-reactive protein ratio, a well-characterized marker of the hypothalamic–pituitary–adrenal axis immune interface status, was found to be modulated by the supplement. Conclusion We discovered that the novel supplement was able to modify different antioxidant, metabolic and inflammatory pathways, improving the energy homeostasis and inflammatory status, and consequently alleviated hepatic steatosis.

Summary Cancer-associated cachexia is a complex metabolic syndrome characterized by weight loss and systemic inflammation. Muscle loss and fatty infiltration into muscle are associated with poor prognosis in cancer patients. Skeletal muscle secretes myokines, factors with autocrine, paracrine and/or endocrine action, which may be modified by or play a role in cachexia. This study examined myokine content in the plasma, skeletal muscle and tumor homogenates from treatment-naive patients with gastric or colorectal stages I-IV cancer with cachexia (CC, N = 62), or not (weight stable cancer, WSC, N = 32). Myostatin, interleukin (IL) 15, follistatin-like protein 1 (FSTL-1), fatty acid binding protein 3 (FABP3), irisin and brain-derived neurotrophic factor (BDNF) protein content in samples was measured with Multiplex technology; body composition and muscle lipid infiltration were evaluated in computed tomography, and quantification of triacylglycerol (TAG) in the skeletal muscle. Cachectic patients presented lower muscle FSTL-1 expression (p = 0.047), higher FABP3 plasma content (p = 0.0301) and higher tumor tissue expression of FABP3 (p = 0.0182), IL-15 (p = 0.007) and irisin (p = 0.0110), compared to WSC. Neither muscle TAG content, nor muscle attenuation were different between weight stable and cachectic patients. Lumbar adipose tissue (AT) index, visceral AT index and subcutaneous AT index were lower in CC (p = 0.0149, p = 0.0455 and p = 0.0087, respectively), who also presented lower muscularity in the cohort (69.2% of patients; p = 0.0301), compared to WSC. The results indicate the myokine profile in skeletal muscle, plasma and tumor is impacted by cachexia. These findings show that myokines eventually affecting muscle wasting may not solely derive from the muscle itself (as the tumor also may contribute to the systemic scenario), and put forward new perspectives on cachexia treatment targeting myokines and associated receptors and pathways.

Aim The influence of thyroid hormones on exocrine pancreas function is poorly understood, and limited to the postnatal development period. Here, we evaluated the effects of hypo- and hyperthyroidism on the morphology and enzyme content of this tissue. Main methods To induce hypothyroidism male Wistar rats were subjected to a thyroidectomy (Tx) or sham operated (SO). After 40 days, some of the Tx and SO rats were treated with T3 for 7 days. Following euthanization, the pancreas was removed and evaluated for morphology, as well as amylase, lipase and trypsin content, using histological and immunoreactive techniques analyses, respectively. Serum amylase levels were also evaluated. Key findings The pancreatic acinar cells of Tx rats were smaller, exhibited reduced Haematoxyllin stained areas, and contained lower amylase and lipase levels, indicative of low cell activity. Tx rats also presented higher collagen levels, and high trypsin content in pancreatic extracts. Interestingly, T3 administration reversed the observed acinar cell alterations and restored pancreatic enzyme content, by augmenting amylase and lipase and attenuating trypsin levels, but failed to change collagen content. Increased levels of lipase and decreased trypsin were also observed in T3-treated SO rats. Significance Thyroid hormones play an important role in acinar cell morphology and function. In the hypothyroid state there is a decrease in pancreatic enzyme levels that is restored with T3 treatment. In addition to participating in insulin sensitivity and glycemic control, THs also modulate enzyme expression and activity in the exocrine pancreas, consequently, delivering metabolic substrates to specific organs and tissues.

Background: Monoclonal antibodies (mAb) targeting the programmed cell death protein 1 (PD-1) receptor provide durable long-term benefit in a subset of patients (pts) with advanced melanoma with response rates of 35-42% and 4-year progression-free survival (PFS) rate of 27%. Separately, the composition of the gut microbiota has been shown to correlate with anti-PD-1 efficacy in human cancer pts with melanoma, renal cell cancer and non-small cell lung cancer (NSCLC) although the precise organisms differ considerably across various studies. In preclinical models, responder-derived fecal microbiome and microbiome consortia produce anti-tumor responses. The effect of microbiome modulation in pts with anti-PD-1 refractory melanoma has not been evaluated. Methods: To evaluate whether primary resistance to anti-PD-1 immunotherapy could be overcome by intestinal microbiome modulation, we designed and conducted a phase II study (NCT03341143). We enrolled pts with primary refractory metastatic melanoma with best response of short-term stable disease (≤6 months) or progressive disease (PD) to prior anti-PD-1 based immunotherapy. Pts received single-administration of responder-derived fecal microbiota transplantation (R-FMT) together with pembrolizumab. Candidate donors were pts with advanced melanoma treated with anti-PD-1 immunotherapy with durable partial or complete response (PR, CR). Pembrolizumab was continued till intolerable toxicity or disease progression. Safety and clinical activity (based on RECIST v1.1) were main objectives; while progression-free survival (PFS) was a key secondary endpoint. Results: As of December 1, 2020, 16 pts with primary refractory melanoma were enrolled, of whom 15 were evaluable. LDH was elevated in 14/15 pts; and the median number of prior therapies was 2. Recipient pts were seromatched to receive a single R-FMT from one of eight candidate donors (5 CR; 3 PR; median PFS 58 months, range 43-70). R-FMT was administered via colonoscopy after bowel preparation with no use of antibiotics. Pembrolizumab was administered IV per label. R-FMT/pembrolizumab was well-tolerated, with no unusual toxicity signals. R-FMT induced rapid and durable microbiota perturbation in most pts; while 6 of 15 evaluable pts had evidence of clinical benefit. Response to R-FMT/pembrolizumab was associated with an increased abundance of taxa previously shown to be associated with response to anti-PD-1, increased CD8+ T cell activation, and decreased frequency of IL-8 expressing myeloid cells. Responders had distinct proteomic and metabolomic signatures, and transkingdom network analyses confirmed that the gut microbiome regulated these changes. Conclusions: In pts with anti-PD-1 primary refractory melanoma, R-FMT/pembrolizumab changed the gut microbiome and reprogrammed the tumor microenvironment to overcome resistance to anti-PD-1 immunotherapy. Response was associated with CD8 T cell induction and reduction of IL-8 expressing myeloid cells. Citation Format: Diwakar Davar, Amiran Dzutsev, John A. McCulloch, Richard R. Rodrigues, Joe-Marc Chauvin, Robert M. Morrison, Richelle N. Deblasio, Carmine Menna, Quanquan Ding, Ornella Pagliano, Bochra Zidi, Shuowen Zhang, Jonathan H. Badger, Marie Vetizou, Alicia M. Cole, Miriam R. Fernandes, Stephanie Prescott, Raquel G. Costa, Ascharya K. Balaji, Andrey Morgun, Ivan Vujkovic-Cvijin, Hong Wang, Amir A. Borhani, Marc B. Schwartz, Howard M. Dubner, Scarlett J. Ernst, Amy Rose, Yana G. Najjar, Yasmine Belkaid, John M. Kirkwood, Giorgio Trinchieri, Hassane M. Zarour. Efficacy of Responder-derived Fecal Microbiota Transplant (R-FMT) and Pembrolizumab in Anti-PD-1 Refractory Patients with Advanced Melanoma [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2021; 2021 Apr 10-15 and May 17-21. Philadelphia (PA): AACR; Cancer Res 2021;81(13_Suppl):Abstract nr LB062.

Background: Gastric glands grow and cells reach differentiation at weaning in rats. By considering that early weaning (EW) can affect the timing of development, we aimed to compare molecular and cellular markers of differentiation in pups and adults. Methods: Wistar rats were separated into suckling-control (S) and EW groups at 15 days. Stomachs were collected at 15, 18, and 60 days for RNA and protein extraction, and morphology. Results: After EW, the expression of genes involved in differentiation (Atp4b, Bhlha15 and Pgc) augmented (18 days), and Atp4b and Gif were high at 60 days. EW increased the number of zymogenic cells (ZC) in pups and adults and augmented mucous neck cells only at 18 days, whereas parietal and transition cells (TC) were unchanged. Conclusions: EW affected the gastric mucosa mostly in a transient manner as the changes in gene expression and distribution of differentiated cells that were detected in pups were not fully maintained in adults, except for the size of ZC population. We concluded that though most of EW effects were immediate, such nutritional change in the infancy might affect part of gastric digestive functions in a permanent manner, as some markers were kept unbalanced in the adulthood.

Colorectal cancer affects the large intestine, leading to loss of white adipose tissue (WAT) and alterations in adipokine secretion. Lower incidence of colorectal cancer is associated with increased fibre intake. Fructooligosaccharides (FOS) are fibres that increase production of butyrate by the intestinal microbiota. Tributyrin, a prodrug of butyric acid, exerts beneficial anti-inflammatory effects on colorectal cancer. Our aim was to characterise the effects of diets rich in FOS and tributyrin within the context of a colon carcinogenesis model, and characterise possible support of tumorigenesis by WAT. C57/BL6 male mice were divided into four groups: a control group (CT) fed with chow diet and three colon carcinogenesis-induced groups fed either with chow diet (CA), tributyrin-supplemented diet (BUT), or with FOS-supplemented diet. Colon carcinogenesis decreased adipose mass in subcutaneous, epididymal, and retroperitoneal tissues, while also reducing serum glucose and leptin concentrations. However, it did not alter the concentrations of adiponectin, interleukin (IL)-6, IL-10, and tumour necrosis factor alpha (TNF)-&alpha, in WAT. Additionally, the supplements did not revert the colon cancer affected parameters. The BUT group exhibited even higher glucose tolerance and levels of IL-6, VEGF, and TNF-&alpha, in WAT. To conclude our study, FOS and butyrate supplements were not beneficial. In addition, butyrate worsened adipose tissue inflammation.

Background Cachexia is a multifactorial and multiorgan syndrome associated with cancer and other chronic diseases and characterized by severe involuntary body weight loss, disrupted metabolism, inflammation, anorexia, fatigue, and diminished quality of life. This syndrome affects around 50% of patients with colon cancer and is directly responsible for the death of at least 20% of all cancer patients. Systemic inflammation has been recently proposed to underline most of cachexia‐related symptoms. Nevertheless, the exact mechanisms leading to the initiation of systemic inflammation have not yet been unveiled, as patients bearing the same tumour and disease stage may or may not present cachexia. We hypothesize a role for gut barrier disruption, which may elicit persistent immune activation in the host. To address this hypothesis, we analysed the healthy colon tissue, adjacent to the tumour. Methods Blood and rectosigmoid colon samples (20 cm distal to tumour margin) obtained during surgery, from cachectic (CC = 25) or weight stable (WSC = 20) colon cancer patients, who signed the informed consent form, were submitted to morphological (light microscopy), immunological (immunohistochemistry and flow cytometry), and molecular (quantification of inflammatory factors by Luminex® xMAP) analyses. Results There was no statistical difference in gender and age between groups. The content of plasma interleukin 6 (IL‐6) and IL‐8 was augmented in cachectic patients relative to those with stable weight (P = 0.047 and P = 0.009, respectively). The number of lymphocytic aggregates/field in the gut mucosa was higher in CC than in WSC (P = 0.019), in addition to those of the lamina propria (LP) eosinophils (P