Fungal Dysbiosis Correlates with the Development of Tumor-Induced Cachexia in Mice

Abstract

Cachexia (CC) is a devastating metabolic syndrome associated with a series of underlying diseases that greatly affects life quality and expectancy among cancer patients. Studies involving mouse models, in which CC was induced through inoculation with tumor cells, originally suggested the existence of a direct correlation between the development of this syndrome and changes in the relative proportions of several bacterial groups present in the digestive tract. However, these analyses have focus solely on the characterization of bacterial dysbiosis, ignoring the possible existence of changes in the relative populations of fungi, during the development of CC. Thus, the present study sought to expand such analyses, by characterizing changes that occur in the gut fungal population (mycobiota) of mice, during the development of cancer-induced cachexia. Our results confirm that cachectic animals, submitted to Lewis lung carcinoma (LLC) transplantation, display significant differences in their gut mycobiota, when compared to healthy controls. Moreover, identification of dysbiotic fungi showed remarkable consistency across successive levels of taxonomic hierarchy. Many of these fungi have also been associated with dysbioses observed in a series of gut inflammatory diseases, such as obesity, colorectal cancer (CRC), myalgic encephalomyelitis (ME) and inflammatory bowel disease (IBD). Nonetheless, the dysbiosis verified in the LLC model of cancer cachexia seems to be unique, presenting features observed in both obesity (reduced proportion of Mucoromycota) and CRC/ME/IBD (increased proportions of Sordariomycetes, Saccharomycetaceae and Malassezia). One species of Mucoromycota (Rhyzopus oryzae) stands out as a promising probiotic candidate in adjuvant therapies, aimed at treating and/or preventing the development of CC.

Modulation of Gut Microbiota and Neuroprotective Effect of a Yeast-Enriched Beer

“…In our study, although minor changes were observed in this group of microorganisms upon treatments, a relevant and interesting shift was detected in the order Sordariomycetes, which increased in the untreated 3xTg-AD mice compared to the wt animals, whereas its abundance was reduced by beer and beer/yeast treatments. This is the first report of a relationship between AD and this fungal taxon that was instead previously associated with dysbiosis detected in a series of gut inflammatory diseases including Crohn's disease, colorectal cancer, myalgic encephalomyelitis and inflammatory bowel disease [50,51]. Interestingly, beer treatment successfully reduced the amount of these fungi in the gut of 3xTg-AD mice, eventually contributing to a reduction in the gut inflammatory condition.…”

Mycobiota and C-Type Lectin Receptors in Cancers: Know thy Neighbors

“…Its prevalence in patients with different types of cancer significantly reduces their life quality and expectancy ( Bruera and Hui, 2012 ). Recently, Jabes et al (2020) explored the alterations of gut fungi in CC mice inducted by subcutaneous inoculation with Lewis lung carcinoma cells (a model widely employed for the study of CC) ( Bennani-Baiti and Walsh, 2011 ). They found that there were sufficient differences in the composition of intestinal fungi to distinguish the CC mice and control mice by beta diversity analysis.…”

Analysis of mouse faecal dysbiosis, during the development of cachexia, induced by transplantation with Lewis lung carcinoma cells

“…Next, the animals were transferred to sterile cages (two animals per cage) and kept, under the conditions described above, for a period of 28 days, when the development of CC was evaluated. Among these 20 LLC-injected animals, we obtained eight mice that displayed five different CC-related symptoms (and were, therefore, designated as 'fully cachectic'): (i) Cachexia Index>5 [16]; (ii) loss of muscle mass (gastrocnemius); (iii) increased expression of muscular atrophy and (iv) inflammation markers (atrogin and IL6R); and (v) histometric alterations in adipocytes (see [17] for details). These eight animals were designated the Cachectic Group, or CC, which was further used for subsequent microbiome analyses.…”

“…A group of 20 mice was submitted to LLC tumour cell transplantation and monitored for 28 days under controlled conditions, as described above (see also Jabes et al [17]). At the end of this period, a group of eight animals displayed a series of symptoms typically associated with the full development of cachexia, including Cachexia Index (CI) ≥5, reduced mass in the gastrocnemius muscle, morphometric changes in adipose tissue and increased expression of marker genes for muscular atrophy and inflammation (see Jabes et al for details [17]). In total, eight LLC-injected animals displayed all the above-mentioned cachexia characteristics and these mice were selected for further analyses, constituting the CC group.…”