Here, we show that autophagy is activated in the intestinal epithelium in murine and human colorectal cancer and that the conditional inactivation of Atg7 in intestinal epithelial cells inhibits the formation of pre-cancerous lesions in Apc(+/-) mice by enhancing anti-tumour responses. The antibody-mediated depletion of CD8(+) T cells showed that these cells are essential for the anti-tumoral responses mediated by the inhibition of autophagy. We show that Atg7 deficiency leads to intestinal dysbiosis and that the microbiota is required for anticancer responses. In addition, Atg7 deficiency resulted in a stress response accompanied by metabolic defects, AMPK activation and p53-mediated cell-cycle arrest in tumour cells but not in normal tissue. This study reveals that the inhibition of autophagy within the epithelium may prevent the development and progression of colorectal cancer in genetically predisposed patients.

Simple SummaryHorses are mainly housed in individual boxes. This housing system is reported to be highly detrimental with regard to welfare and could trigger the expression of four behavioural indicators of a compromised welfare state: stereotypies, aggressiveness toward humans, unresponsiveness to the environment, and stress-related behaviours. The aim of this study was to investigate whether several factors commonly observed in boxes (e.g., the presence of a window toward the external environment) and management practices (e.g., time spent being ridden) could alleviate the negative effects of individual boxes on welfare. The results show that the majority of the factors studied did not influence the expression of the indicators. In addition, the longer the horses spent in individual boxes, the more likely they were to express unresponsiveness to the environment. Overall, the main conclusion of this study is that the detrimental effects caused by the spatial, social, and dietary deprivations of this housing system could not be alleviated by small facilities in the box or changes in management practices. To preserve the welfare of horses, it seems necessary to allow free exercise, interactions with conspecifics, and fibre consumption as often as possible, to ensure the satisfaction of the species’ behavioural and physiological needs.AbstractHorses are mainly housed in individual boxes. This housing system is reported to be highly detrimental with regard to welfare and could trigger the expression of four behavioural indicators of a compromised welfare state: stereotypies, aggressiveness toward humans, unresponsiveness to the environment, and stress-related behaviours. The aim of this study was to identify housing and management factors that could alleviate the detrimental effects of individual boxes on welfare. A total of 187 horses were observed over 50 days by scan sampling. The impact of 12 factors was investigated on the expression of the four behavioural indicators in three different analyses. The results show that the majority of factors tested did not influence the expression of the behavioural indicators. Only three (straw bedding, a window opening onto the external environment, and a reduced quantity of concentrated feed) would have beneficial, although limited, effects. Furthermore, the longer the horses spent in individual boxes, the more likely they were to express unresponsiveness to the environment. To preserve the welfare of horses, it seems necessary to allow free exercise, interactions with conspecifics, and fibre consumption as often as possible, to ensure the satisfaction of the species’ behavioural and physiological needs.

The intestinal epithelium acts as a barrier between the organism and its microenvironment, including the gut microbiota. It is the most rapidly regenerating tissue in the human body thanks to a pool of intestinal stem cells (ISCs) expressing Lgr5. The intestinal epithelium has to cope with continuous stress linked to its digestive and barrier functions. Epithelial repair is crucial to maintain its integrity, and Lgr5-positive intestinal stem cell (Lgr5+ISC) resilience following cytotoxic stresses is central to this repair stage. We show here that autophagy, a pathway allowing the lysosomal degradation of intracellular components, plays a crucial role in the maintenance and genetic integrity of Lgr5+ISC under physiological and stress conditions. Using conditional mice models lacking the autophagy gene Atg7 specifically in all intestinal epithelial cells or in Lgr5+ISC, we show that loss of Atg7 induces the p53-mediated apoptosis of Lgr5+ISC. Mechanistically, this is due to increasing oxidative stress, alterations to interactions with the microbiota, and defective DNA repair. Following irradiation, we show that Lgr5+ISC repair DNA damage more efficiently than their progenitors and that this protection is Atg7 dependent. Accordingly, we found that the stimulation of autophagy on fasting protects Lgr5+ISC against DNA damage and cell death mediated by oxaliplatin and doxorubicin treatments. Finally, p53 deletion prevents the death of Atg7-deficient Lgr5+ISC but promotes genetic instability and tumor formation. Altogether, our findings provide insights into the mechanisms underlying maintenance and integrity of ISC and highlight the key functions of Atg7 and p53.

Chronic stress is a strong modulator of cognitive processes, such as learning and memory. There is, however, great within-individual variation in how an animal perceives and reacts to stressors. These differences in coping with stress modulate the development of stress-induced memory alterations. The present study investigated whether and how chronic stress and individual emotionality interrelate and influence memory performances and brain neurogenesis in birds. For that, we used two lines of Japanese quail (Coturnix japonica) with divergent emotionality levels. Highly (E+) and less (E−) emotional quail were submitted to chronic unpredictable stress (CUS) for 3 weeks and trained in a spatial task and a discrimination task, a form of cue-based memory. E + and E− birds were also used to assess the impact of CUS and emotionality on neurogenesis within the hippocampus and the striatum. CUS negatively impacted spatial memory, and cell proliferation, and survival in the hippocampus. High emotionality was associated with a decreased hippocampal neurogenesis. CUS improved discrimination performances and favored the differentiation of newborn cells into mature neurons in the striatum, specifically in E+ birds. Our results provide evidence that CUS consequences on memory and neural plasticity depends both on the memory system and individual differences in behavior.

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Chronic stress and the gut microbiota appear to comprise a feed-forward loop, which contributes to the development of depressive disorders. Evidence suggests that memory can also be impaired by either chronic stress or microbiota imbalance. However, it remains to be established whether these could be a part of an integrated loop model and be responsible for memory impairments. To shed light on this, we used a two-pronged approach in Japanese quail: first stress-induced alterations in gut microbiota were characterized, then we tested whether this altered microbiota could affect brain and memory function when transferred to a germ-free host. The cecal microbiota of chronically stressed quails was found to be significantly different from that of unstressed individuals with lower α and β diversities and increased Bacteroidetes abundance largely represented by the Alistipes genus, a well-known stress target in rodents and humans. The transfer of this altered microbiota into germ-free quails decreased their spatial and cue-based memory abilities as previously demonstrated in the stressed donors. The recipients also displayed increased anxiety-like behavior, reduced basal plasma corticosterone levels and differential gene expression in the brain. Furthermore, cecal microbiota transfer from a chronically stressed individual was sufficient to mimic the adverse impact of chronic stress on memory in recipient hosts and this action may be related to the Alistipes genus. Our results provide evidence of a feed-forward loop system linking the microbiota-gut-brain axis to stress and memory function and suggest that maintaining a healthy microbiota could help alleviate memory impairments linked to chronic stress.