Bacterial diet affects the age-dependent decline of associative learning in Caenorhabditis elegans

  1. Satoshi Higurashi
  2. Sachio Tsukada
  3. Binta Maria Aleogho
  4. Joo Hyun Park
  5. Yana Al-Hebri
  6. Masaru Tanaka
  7. Shunji Nakano
  8. Ikue Mori
  9. Kentaro Noma

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Abstract

The causality and mechanism of dietary effects on brain aging are still unclear due to the long time scales of aging. The nematode Caenorhabditis elegans has contributed to aging research because of its short lifespan and easy genetic manipulation. When fed the standard laboratory diet, Escherichia coli , C. elegans experiences an age-dependent decline in temperature–food associative learning, called thermotaxis. To address if diet affects this decline, we screened 35 lactic acid bacteria as alternative diet and found that animals maintained high thermotaxis ability when fed a clade of Lactobacilli enriched with heterofermentative bacteria. Among them, Lactobacill us reuteri maintained the thermotaxis of aged animals without affecting their lifespan and motility. The effect of Lb. reuteri depends on the DAF-16 transcription factor functioning in neurons. Furthermore, RNA sequencing analysis revealed that differentially expressed genes between aged animals fed different bacteria were enriched with DAF-16 targets. Our results demonstrate that diet can impact brain aging in a daf-16 -dependent manner without changing the lifespan.

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  1. Version published to 10.7554/elife.81418 on eLife
  2. eLife

    Reviewer #2:

    This manuscript, "Lactobacilli in a clade ameliorate age-dependent decline of thermotaxis behavior in Caenorhabditis elegans," is focused on the impact of diet on age-dependent behavioral decline. The authors utilize a thermotaxis screen using different lactic acid bacteria (LAB) and identify strains of LAB with the ability to ameliorate age dependent decline in thermotaxis behavior. The study introduces some interesting results, including the finding that many LAB strains of the same clade can improve thermotaxis in older nematodes, despite disparate results on longevity. However, there were some questions remaining about methodology, and more importantly, there is very little evidence provided on what the molecular mechanism might be behind this phenomenon. Overall, this study contains interesting findings that are not developed thoroughly enough.

    Major Comments/Questions:

    1. How is LAB different from Ecoli? Does metabolic composition of LAB dictate its impact on thermotaxis behavior of worms? In the manuscript the authors argue that LAB are a "better" food source than E. coli. How does one define better for something as broad as a food source? There is a difference here but it is very unclear what aspects of LAB physiology may play a role.

    2. Does this phenomenon require eating LAB, or just perceiving it? The assays did not test whether perception of LAB diet is sufficient for its effect on thermotaxis, rather whether more time on LAB leads to better thermotaxis.

    3. Showing a potential daf-16 interaction is plausible, given that daf-16 interacts with many key pathways in the worm, but it is unclear whether this interaction is direct or indirect, or whether daf-16 is a major player in this pathway or just necessary for maintenance of health. What sensory pathways are activated when worms are fed on LAB diet, and how it finally interacts with daf-16?

    4. Similarly, the pha-4 and eat-2 data are interesting, but are not developed in any way. This is another avenue that could in principle lead toward a better mechanistic understanding.

  3. eLife

    Reviewer #1:

    These investigators examine how lactic acid producing E. coli impact age-related decline in neurological function through the use of temperature-food associative learning or thermotaxis. In particular, they screen a panel of different lactate producing E. coli and identify a particular clade of bacteria, Lactobacilli, that are able to suppress age-dependent decline in thermotaxis in a daf-16 dependent manner. Moreover, they uncouple improvement in neurological function from lifespan determination and locomotion. Overall, this group presents an interesting phenomenon regarding the effects of the lactic acid producing bacteria. However, it is not clear what is happening in the worm to elicit this neurological response and much work remains to determine this mechanism of action.

    While I can appreciate the careful nature of these worm behavioral assays including a host of different controls, these studies lack cellular and molecular details, which reduce my overall excitement for the story. It is interesting that a clade of lactic acid bacteria (LAB) can improve associative learning in C. elegans. However, I was very underwhelmed when I got to the final figure, which very briefly touched on molecular mechanism (only to give DAF-16 dependence). Since it has previously been shown that daf-16 mutant animals impact taste avoidance learning (Nagashima et al. PLOS Genetics, 2019), the dependence of DAF-16 and its role in associative learning seemed predictable. For future submissions, this previous study on DAF-16 should be referenced in the manuscript. Moreover, data regarding dietary restriction and the eat-2 mutation appear to be misinterpreted. Thus, more attention and analysis should be dedicated to the effects of dietary restriction on their paradigm. I thought that it was interesting that a clade of LAB consistently reduced expression of PHA-4 transcription factor and the authors might benefit for expanding upon this observation.

    In addition to molecular characterization, the manuscript provides little explanation at the cellular level. It is unclear what neurons or neuronal circuit are responsible for this phenomenon. Although mentioned in the discussion, this manuscript would benefit by close examination of the thermosensory circuit including the AFD and AIY neurons. How are these lactic acid producing E. coli ultimately signaling to the neurons? Do the LAB slow the rate of degeneration of either neuron? Is this phenomenon the result of lactic acid production or something else in the bacteria? Would it be possible to supplement lactic acid to worm media and produce the same result?

    This is an interesting phenomenon and requires more in-depth cellular and molecular characterization.

  4. Version published to 10.1101/2020.10.08.331256 on bioRxiv