Microbiota from Alzheimer's patients induce deficits in cognition and hippocampal neurogenesis.

Alzheimer's disease is a complex neurodegenerative disorder leading to a decline in cognitive function and mental health. Recent research has positioned the gut microbiota as an important susceptibility factor in Alzheimer's disease by showing specific alterations in the gut microbiome composition of Alzheimer's patients and in rodent models. However, it is unknown whether gut microbiota alterations are causal in the manifestation of Alzheimer's symptoms. To understand the involvement of Alzheimer's patient gut microbiota in host physiology and behaviour, we transplanted faecal microbiota from Alzheimer's patients and age-matched healthy controls into microbiota-depleted young adult rats. We found impairments in behaviours reliant on adult hippocampal neurogenesis, an essential process for certain memory functions and mood, resulting from Alzheimer's patient transplants. Notably, the severity of impairments correlated with clinical cognitive scores in donor patients. Discrete changes in the rat caecal and hippocampal metabolome were also evident. As hippocampal neurogenesis cannot be measured in living humans but is modulated by the circulatory systemic environment, we assessed the impact of the Alzheimer's systemic environment on proxy neurogenesis readouts. Serum from Alzheimer's patients decreased neurogenesis in human cells in vitro and were associated with cognitive scores and key microbial genera. Our findings reveal for the first time, that Alzheimer's symptoms can be transferred to a healthy young organism via the gut microbiota, confirming a causal role of gut microbiota in Alzheimer's disease, and highlight hippocampal neurogenesis as a converging central cellular process regulating systemic circulatory and gut-mediated factors in Alzheimer's.

The gut microbiome and adult hippocampal neurogenesis: A new focal point for epilepsy?

Temporal lobe epilepsy (TLE) is a neurological disorder affecting millions of people worldwide and currently represents the most common form of focal epilepsy. Thus, the search for aetiological and pathophysiological parameters of TLE is ongoing. Preclinical work and post-mortem human studies suggest adult hippocampal neurogenesis as a potentially relevant factor in TLE pathogenesis. Although progress has been made in elucidating the molecular links between TLE and hippocampal neurogenesis, recent evidence suggests that additional peripheral mediators may be involved. The microbiota-gut-brain axis mediates bidirectional communication between the gut and the brain and could comprise a link between neurogenesis and TLE. In this review, we discuss emerging evidence highlighting a potential role for the gut microbiome in connecting TLE pathogenesis and hippocampal neurogenesis. We focus in particular on mechanisms associated with neuronal excitability, neuroinflammation and gut microbial metabolites. As the evidence does not yet support a direct link between gut microbiota-regulated hippocampal neurogenesis and TLE aetiology or pathophysiology, future studies are needed to establish whether current findings comprise circumstantial links or a potentially novel avenue for clinically relevant research.

Mnemonic discrimination of object and context is differentially associated with mental health.

Episodic memories are formed by hippocampal binding of the "what" and "where" features of everyday events. The hippocampus minimizes interference between related similar episodic memories by pattern separation. Stress and psychopathology are associated with lowered pattern separation. While current behavioral paradigms typically use correct rejections of single object or context lures rather than composite stimuli, it is not known if object and context pattern separation differentially associate with mental health. We reasoned that an object-in-context paradigm would be more sensitive to mental health state than current implementations, given increased task demands. We found that non-clinical depression and anxiety symptom severity were associated with reduced lure rejection for both object and context and that only the object domain was associated with a concomitant increase in lure overgeneralization. Therefore, we argue that reduced lure rejection and increased overgeneralization must not be conflated. Although our object-in-context paradigm was not more sensitive to variation in mental health, we show that lure rejection and overgeneralization rate in one domain (e.g. object) was affected by the status of the other domain (e.g. context target versus lure). Finally, as several metrics of pattern separation exist in the literature, we evaluated the association of different metrics with mental health.

The 'middle-aging' brain.

Middle age has historically been an understudied period of life compared to older age, when cognitive and brain health decline are most pronounced, but the scope for intervention may be limited. However, recent research suggests that middle age could mark a shift in brain aging. We review emerging evidence on multiple levels of analysis indicating that midlife is a period defined by unique central and peripheral processes that shape future cognitive trajectories and brain health. Informed by recent developments in aging research and lifespan studies in humans and animal models, we highlight the utility of modeling non-linear changes in study samples with wide subject age ranges to distinguish life stage-specific processes from those acting linearly throughout the lifespan.

Exercise mitigates a gut microbiota-mediated reduction in adult hippocampal neurogenesis and associated behaviours in rats.

Lifestyle factors, especially exercise, impact the manifestation and progression of psychiatric and neurodegenerative disorders such as depression and Alzheimer's disease, mediated by changes in hippocampal neuroplasticity. The beneficial effects of exercise may be due to its promotion of adult hippocampal neurogenesis (AHN). Gut microbiota has also been showed to be altered in a variety of brain disorders, and disturbances of the microbiota have resulted in alterations in brain and behaviour. However, whether exercise can counteract the negative effects of altered gut microbiota on brain function remains under explored. To this end, chronic disruption of the gut microbiota was achieved using an antibiotic cocktail in rats that were sedentary or allowed voluntary access to running wheels. Sedentary rats with disrupted microbiota displayed impaired performance in hippocampal neurogenesis-dependent tasks: the modified spontaneous location recognition task and the novelty suppressed feeding test. Performance in the elevated plus maze was also impaired due to antibiotics treatment. These behaviours, and an antibiotics-induced reduction in AHN were attenuated by voluntary exercise. The effects were independent of changes in the hippocampal metabolome but were paralleled by caecal metabolomic changes. Taken together these data highlight the importance of the gut microbiota in AHN-dependent behaviours and demonstrate the power of lifestyle factors such as voluntary exercise to attenuate these changes.