Diet and host–microbial crosstalk in postnatal intestinal immune homeostasis

Abstract

Neonates face unique challenges in the period following birth. The postnatal immune system is in the early stages of development and has a range of functional capabilities that are distinct from the mature adult immune system. Bidirectional immune–microbial interactions regulate the development of mucosal immunity and alter the composition of the microbiota, which contributes to overall host well-being. In the past few years, nutrition has been highlighted as a third element in this interaction that governs host health by modulating microbial composition and the function of the immune system. Dietary changes and imbalances can disturb the immune–microbiota homeostasis, which might alter susceptibility to several autoimmune and metabolic diseases. Major changes in cultural traditions, socioeconomic status and agriculture are affecting the nutritional status of humans worldwide, which is altering core intestinal microbial communities. This phenomenon is especially relevant to the neonatal and paediatric populations, in which the microbiota and immune system are extremely sensitive to dietary influences. In this Review, we discuss the current state of knowledge regarding early-life nutrition, its effects on the microbiota and the consequences of diet-induced perturbation of the structure of the microbial community on mucosal immunity and disease susceptibility.

Key points

• Infant nutrition, including breast-milk, formula milk and solid weaning foods, is a key determinant of early microbial community structure that influences development of protective immunity and seems to affect health throughout life
• Diet-induced dysbiosis changes the species composition of the gut microbiota and leads to immune-mediated inflammatory and metabolic diseases
• Diet influences the postnatal development of innate and adaptive defences at the mucosal barrier surface and affects intestinal barrier function
• A triad of diet, the microbiota and the immune system regulates postnatal intestinal homeostasis and host physiology, which has consequences through to adulthood

Introduction

The 'hygiene hypothesis' proposed that an increased predisposition to allergies and the rise in the incidence of atopic diseases was linked to a lack of exposure to infectious agents, microorganisms and parasites during childhood that resulted in the development of the immune system being suppressed.^{1, 2} In the past few years, epidemiological studies further showed that children growing up on traditional farms with exposure to livestock and consumption of unprocessed cow's milk during their early years are resistant to these diseases.³ That errors in the development of the immune system are connected to improved sanitary conditions and the increased use of antibiotics, among other factors, is now evident. The gut microbiota is central to this phenomenon as it responds to changes in the environment and also affects the maturation and function of the immune system. Fluctuations in the composition of this microbiota are also caused by perturbations in diet.^{4, 5} This observation has led to the proposal of the 'diet hypothesis' that unifies changes in nutrition with gut microbiota and immune health (Figure 1).^{6, 7, 8}

Figure 1: The 'diet hypothesis'.

Diet, gut microbiota and host immunity are intimately connected and their bidirectional communication is central to maintaining intestinal and metabolic homeostasis. The commensal bacteria determine the nutritional value of food by fermenting dietary components to usable energy sources and by affecting nutrient uptake. Specific bacteria and microbial by-products influence the development and function of key components of mucosal immunity. The mucosal immune system shapes the commensal composition and location. Immune–microbial interactions via pattern-recognition receptors (TLRs, NODs) result in secretion of antimicrobial peptides, mucins and IgA, which maintains intestinal homeostasis and barrier function. The mucosal innate immune system also influences dietary energy absorption. Finally, perturbation of microbial community structure leads to dysbiosis, which can precipitate immune-mediated disorders such as IBD and metabolic diseases such as type 2 diabetes. Abbreviations: ILC, innate lymphoid cell; NOD, nucleotide oligomerization domain; T_H17 cell, type 17 T helper cell; TLR, Toll-like receptor; T_REG cell, regulatory T cell.

Figure 2: Diet, gut microbiota and dysbiosis.

Several features regulate the establishment and composition of the microbiota and their effect on the health and immune function of the host. Eubiosis or a normal microflora structure that protects against infections educates the immune system and contributes to nutrient digestion. Energy harvest is established by early intestinal colonization with specific microbes immediately after birth. An ordered process of subsequent colonization and expansion shaped by diet results in the establishment of distinct 'enterotypes', or clusters of microbial communities, that remains fairly stable in adults. Perturbations in the microbial community structure or dysbiosis are induced by factors such as diet, use of antibiotics or infection, which can alter susceptibility to several diseases.

Figure 3: The intestinal barrier.

 The intestinal barrier is made up of a single layer of epithelium consisting of intestinal epithelial cells and specialized Goblet cells, M cells and Paneth cells (present only in small intestine). Peyer's patches (found specifically in the ileum) and mesenteric lymph nodes develop prenatally when LTi are recruited to sites of the developing intestines called cryptopatches. Cryptopatches mature into isolated lymphoid follicles when pattern-recognition receptors (TLRs) are triggered by MAMPs, which then release IgA-producing plasma cells into the lamina propria. Dendritic cells in the Peyer's patches access microbes through M cells or directly from the lumen by extending dendrites through intestinal epithelial cells. These antigen-loaded dendritic cells can induce T-cell differentiation or T-cell-dependent B-cell maturation into germinal centres. Naive T cells (T_H0 cells) can differentiate into effector T_H1, T_H2 or T_H17 cells or into regulatory FOXP3⁺ T_REG cells or Tr1 cells. Microbial sensing by intestinal epithelial cells also marks the release of antimicrobial peptides and stimulation of intestinal epithelial cell proliferation in crypts. Abbreviations: IEL, intraepithelial lymphocyte; LTi, lymphoid tissue inducer cell; MAMP, microbe-associated molecular pattern; M cell, microfold cell; T_H, T helper cell; TLR, Toll-like receptor; Tr1, type 1 regulatory T cell; T_REG, regulatory T cell.



Figure 4: Development and maturation of the intestinal mucosal barrier and mucosal immune system.

Developmental changes in the prenatal, postnatal and adult intestine are summarized. Intestinal microbial colonization, as well as dietary components, induces maturation of the intestinal epithelium and initiates development of the mucosal immune system. Complex bidirectional interactions between gut microbiota, diet and the immune system itself regulate the establishment and maintenance of intestinal homeostasis and barrier function. Abbreviations: CRAMP, cathelin-related antimicrobial peptide; CRS, cryptidin-related sequence; TLR, Toll-like receptor; ±, cells might or might not be present; +, ++, +++, ++++, relative numbers of indicated cells.



Cultural diversity and geographical location contribute to dietary differences that result in distinct patterns of intestinal microbial colonization and disease susceptibility in different populations. The Western diet is generally low in fibre and high in processed foods, which adversely affects the intestinal microbial composition and leads to an obesity-prone metagenome.^{6, 8, 9} Conversely, the Japanese diet, which includes rice, beans and fermented foods,^{10, 11} and the diet of Eskimos in Greenland (which is typically high in fish and omega-3 fatty acids) promote resistance to chronic inflammatory diseases and heart diseases.^{12, 13, 14} In mouse experiments, offspring of mice fed a diet rich in omega-3 fatty acids have an altered gut microbiome and have enhanced production of the anti-inflammatory cytokine IL-10 in the colon and spleen, which protects the mice from an allergic challenge.¹⁵ The influence of nutrition on the microbiome and disease susceptibility is also specific to age. In newborn babies, the establishment and type of feeding has a considerable effect on the composition of the microbial community.¹⁶ In adults, both long-term dietary intake and short-term changes in macronutrients (for example, an animal or plant-product-based diet) influences microbial community structure and microbial gene expression profiles.⁴ The outcomes of the complex dynamic connections between the microbiota and the immune system are most important during the postnatal period and have consequences on host immunity and on metabolic homeostasis that reach well into adulthood.

 

In this Review, we discuss the effect of diet on host–microbial interactions in early life and highlight the key aspects of nutritional programming during the postnatal period in influencing the lifelong function of the immune system in health and disease.

Conclusions

The relationship between diet, microbiota and host immunity is being rapidly unravelled using a combination of epidemiological, immunological, metagenomic and metabolomic approaches. These studies are most pertinent at the postnatal period when dietary intake is closely tied to the development of both the gut microbiota and the immune system. In a study published in 2014, a prenatal placental microbiome was described that could be a source of the infants' first bacterial inoculum via intrauterine seeding.¹⁶⁵ Whether and how this low abundance yet metabolically rich microbiome directs the development of the immune system and the microbial community structure during gestation, as well as the effect of maternal nutrition on these processes, remains to be determined. A systems approach involving both animal studies and analysis of human cohorts are needed to unravel the complexities of microbiota–host crosstalk in early life. Animal models are invaluable and have provided a plethora of information and insights into the interplay between the immune system and host microbiota. However, it is important to caution that a direct correlation from animal studies to humans is not possible, particularly when interrogating immune developmental events in early life. For instance, in humans, αβ TCR⁺ T cells are seen in peripheral tissue at 10–12 gestational weeks; however, in mice, peripheral T cells are undetected in the fetus and their numbers only increase after birth,¹⁶⁶ which is suggestive of distinct developmental cues and immune requirements in human versus mouse neonates.

 

The interdependence of diet, immune and microbiota interactions and communications between the elements of this triad dictate intestinal mucosal homeostasis as well as metabolic well-being. The mechanisms by which these dialogues occur are only now being elaborated on and major gaps remain in our understanding of how specific nutrients and microbial metabolites regulate microbial composition, host metabolism and immunity. The use of specific dietary components in modulating the gut microbiota and subsequent immune function offers an attractive approach to deliver health benefits to a vulnerable population, such as paediatric and geriatric populations. As such, probiotics and prebiotics are being increasingly used to prevent and treat a variety of gastrointestinal and systemic diseases in infants.^{167, 168} Discoveries aimed at establishing specific features of the immune–microbiota crosstalk will provide useful insights for the development of preventive and therapeutic agents of multiple infectious, autoimmune and metabolic disorders.

 

Nature Reviews Gastroenterology & Hepatology | Review

Nitya Jain^1, & W. Allan Walker^2,

Published online 09 September 2014



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Mycobiota in gastrointestinal diseases

Abstract

New insights gained through the use of state-of-the-art technologies, including next-generation sequencing, are starting to reveal that the association between the gastrointestinal tract and the resident mycobiota (fungal community) is complex and multifaceted, in which fungi are active participants influencing health and disease. Characterizing the human mycobiome (the fungi and their genome) in healthy individuals showed that the gastrointestinal tract contains 66 fungal genera and 184 fungal species, with Candida as the dominant fungal genera. Although fungi have been associated with a number of gastrointestinal diseases, characterization of the mycobiome has mainly been focused on patients with IBD and graft-versus-host disease. In this Review, we summarize the findings from studies investigating the relationship between the gut mycobiota and gastrointestinal diseases, which indicate that fungi contribute to the aggravation of the inflammatory response, leading to increased disease severity. A model explaining the mechanisms underlying the role of the mycobiota in gastrointestinal diseases is also presented. Our understanding of the contribution of the mycobiota to health and disease is still in its infancy and leaves a number of questions to be addressed. Answering these questions might lead to novel approaches to prevent and/or manage acute as well as chronic gastrointestinal disease.

Key points

• The mycobiome (the resident fungal community and their genome), is a key component of the human microbiome
• Within a microbiome, there are interactions between and within species or genera among fungi and bacteria
• Alterations within the mycobiota are associated with different diseases
• The mycobiota might directly or indirectly interact with the host immune system
• Interactions between the mycobiota and host immune system can lead to exacerbation of gastrointestinal diseases such as IBD

Introduction

The association between fungi and gastrointestinal disease has been documented since the 18^th century, with a special focus on candidiasis. One of the first observations of this association was the study by Rosen von Rosenstein,¹ who described oral candidiasis that extended to the stomach and intestines. In addition, the first reported case of gastrointestinal candidiasis in an infant was described in this period.¹ Subsequent case reports published in the 19^th century documented Candida infection of the stomach, colon^{2, 3} and ileum.⁴ Candida gastrointestinal infections occur less frequently than oesophageal infection, with the stomach being the most common site of infection in the gastrointestinal tract.¹

 

Historically, fungi such as Candida were considered passive colonizers of the microbial community that could become pathogenic as the result of a change in the environment, for example the loss or reduction of bacterial neighbours (due to use of antibiotics) or suppression of immune defence (as a result of an immunosuppressive drug regimen). However, studies performed in the past decade have demonstrated that fungi have a complex, multifaceted role in the gastrointestinal tract and are active participants in directly influencing health and disease through fungal–bacterial, fungal–fungal and fungal–host interactions.

 

Advances in sequencing technology have provided the ability to profile the microbiome, with emphasis on the bacterial component. However, studies are now beginning to define the fungal component of the human microbiome (the mycobiome). A historical perspective of the interactions between fungi and the gastrointestinal tract and a description of the current state of research on the mycobiota as it pertains to the gastrointestinal tract in health and disease is provided in this Review.

 

Of note, a search of the mycobiome literature shows clear variability between different studies, which can be attributed to the lack of standardized methods to characterize the mycobiome. A multitude of differences occur across studies: sample types; collection times and protocols; DNA extraction methods; varying amplification targets; sequencing methods; differences in algorithms and online database composition; and variation in data cleaning steps and bioinformatics approaches. Therefore, development of standardized methods in microbiome (both bacterial and fungal) analyses is critical. Efforts to address standardization have been initiated and variables that influence microbiome research are being optimized.^{5, 6, 7}

 

Figure 1: Normal and abnormal interactions between fungi and the host immune system in gastrointestinal tissue.

APCs present fungal antigens as MHC class II conjugates to T-cell receptors on naive T cells. T cells then differentiate into T helper cells (T_H1 or T_H17), which secrete different proinflammatory and anti-inflammatory cytokines leading to recruitment of humoral and cellular factors of innate immunity. a | In healthy tissues, immune homeostasis is maintained by interdependent control exerted by T_H1 cytokines and T_REG cells. b | In patients with IBD, dysfunctional regulation of T_H1 or T_H17 pathways triggers an unregulated inflammatory response and recruitment of innate immune cells. Increases in cytokine levels can trigger oxidative tissue damage and recruitment of proteolytic peptides and enzymes, eventually manifesting as gastrointestinal disease. Furthermore, activation of the T_H2 pathway can lead to plasma cells detecting fungal cell wall antigens and producing antiglycan antibodies (ASCA, ALCA and ACCA). Abbreviations: ACCA, anti-chitobioside carbohydrate IgA antibodies; ALCA, anti-laminaribioside carbohydrate IgG antibodies; APC, antigen presenting cell; ASCA, anti-S. cerevisiae antibodies; mac, macrophage; NK, natural killer cell; NO, nitrogen oxide; PAMP, pathogen-associated molecular pattern; PRR, pattern-recognition receptor; ROS, reactive oxygen species; T₀, naive T cell; T_H1, type 1 T helper cell; T_H17, type 17 T helper; T_REG, regulatory T cell.

Conclusions

Studies performed to date on the role of the mycobiota in gastrointestinal diseases have just started to scratch the surface and demonstrate that the fungal community is a critical player in the pathogenesis of these diseases. Although studies performed so far have started to characterize the mycobiome in health and disease, and show potential links, it is important to note that such links reflect association rather than causation. Moreover, most studies have focused on the role of Candida and its effect on the host immune system. Focusing on one microbial kingdom (bacteria or fungi) whilst analysing the microbiome in a sample (for example, oral wash, gut biopsies or faecal pellets) provides limited insight.⁹⁶ To expand our knowledge and obtain deeper insight into the role of the microbiome in health and disease, future studies should also characterize the different microorganisms (bacteria, fungi and viruses) in the same sample types.

 

There is still a long way to go and several questions remain to be answered regarding the contribution of the gut mycobiota to the pathogenesis of gastrointestinal diseases (Box 1). Research funding to address these questions will be instrumental and will lead the way to develop novel approaches to prevent, manage and treat gastrointestinal disease.

Nature Reviews Gastroenterology & Hepatology | Review

Published online 11 November 2014

Pranab K. Mukherjee,^1, Boualem Sendid,^2, Gautier Hoarau,^2, Jean-Frédéric Colombel,^3, Daniel Poulain^2, & Mahmoud A. Ghannoum^1,

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Cells can fight viruses, even when stimulated to combat bacteria

Latest News > Biology >

Linda M. Stannard/University of Cape Town/Science Source

Rotaviruses like these might be vulnerable to our antibacterial defenses, a new study finds.

Viruses pull a lot of dirty tricks to dodge our immune defenses and make us sick, but now scientists have come up with a trick of their own. Researchers have discovered that prompting cells to combat bacteria can also help them fight off viruses, even though the cells presumably wouldn’t have the right weapons to do so. “This would be analogous to, in a football game, arming the defense with baseball bats,” says Andrew Gewirtz, a mucosal immunologist at Georgia State University in Atlanta. The finding could solve a vaccine mystery, as well as lead to new ways to combat infectious diseases.

Your cells don’t respond the same way to bacteria and viruses. They switch on different genes and release different mixtures of chemical messengers and protective molecules. That’s why Gewirtz and his colleagues were taken aback by the results of an experiment they performed 6 years ago. The researchers were testing whether an injection of flagellin, a protein that’s part of the tails (or flagella) some bacteria use to propel themselves, activates the body’s antibacterial defenses. Their findings showed that it did, enabling mice to subsequently survive what should have been a lethal dose of harmful intestinal bacteria.

The surprise came when Gewirtz’s team infected the mice with rotavirus, a common cause of severe diarrhea in young children. Even though the virus doesn’t have a flagellum, injecting the rodents with flagellin in advance protected them against the pathogen.

In their new study, published online today in Science, Gewirtz and his colleagues figured out why. The researchers determined which two pathogen-sensing molecules enable cells to recognize the injected flagellin. When the cells detect flagellin, they spur other cells to emit interleukin-22 (IL-22) and interleukin-18 (IL-18), molecular signals that help orchestrate a defensive response. That presumably would help kill off bacterial invaders, but why does it work against viruses?

The answer may lie in the habits of the rotavirus, which invades cells lining the small intestine. IL-22 makes intestinal cells more resistant to viral invasion, whereas IL-18 thwarts the virus by spurring cells it has already infected to commit suicide. So when these molecules are activated, they fight bacteria as well as rotavirus. Indeed, injecting mice with IL-22 and IL-18 triggered the same antiviral effect as flagellin, the team found.

Gewirtz says that this mechanism might work because “it’s not what the virus is used to.” Rotavirus evolved to evade the body’s antiviral defenses, but it can’t counteract the response activated by flagellin or the combination of IL-22 and IL-18.

“It’s a very nicely documented story,” says Roger Glass, a rotavirologist at the National Institutes of Health in Bethesda, Maryland. “They work through all possible explanations.” The crossover protection the authors observed is unexpected because the opposite often occurs, says immunologist and physician Robert Sabat of Charité University Medicine Berlin. For example, viral lung infections often leave patients more vulnerable to bacterial infections, not less.

Glass adds that the results might solve a mystery about the two new oral rotavirus vaccines introduced within the last decade. The vaccines contain weakened forms of the virus and are much more effective in developed countries than in developing countries, where rotavirus kills more than 400,000 children every year. Children in developing countries have probably been exposed to more flagella-carrying bacteria when they are vaccinated, he says. As a result, their cells might destroy the rotaviruses in the vaccine before they can develop immunity.

Researchers don’t expect the discovery to have much impact on global mortality from rotavirus infections. Treating children with IL-22 and IL-18 wouldn’t be feasible in developing countries where the virus is a major killer because of their limited medical facilities, Glass says. In developed countries, though, the combination might benefit children and adults whose immune systems are impaired because of cancer treatment or diseases like AIDS and who are vulnerable to rotavirus infections.

Sabat notes that researchers have already completed some clinical trials of IL-22 and IL-18 in cancer patients, and IL-18 did cause side effects such as fever, nausea, and difficulty breathing. However, he says, “a combination of IL-22 and low-dose IL-18 might be well tolerated.”

IL-22 and IL-18 might have other uses as well. “We think the system we’ve developed will be broadly applicable to other viral infections,” Gewirtz says. He and his colleagues are now testing whether the combination allows mice to resist a range of viruses, including norovirus, a gastrointestinal pathogen notorious for causing outbreaks on cruise ships.

 

Posted in Biology, Health

 

By Mitch Leslie                         

13 November 2014 2:00 pm

 

 

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Cells By the Number: Facts About the Building Blocks of Life

Developing nerve cells, with the nuclei shown in yellow.
Credit: Torsten Wittmann, University of California, San Francisco

Cells are the basic unit of life — and the focus of much scientific study and classroom learning. Here are just a few of their fascinating facets.

 

3.8 billion

 

That’s how many years ago scientists believe the first known cells originated on Earth. These were prokaryotes, single-celled organisms that do not have a nucleus or other internal structures called organelles. Bacteria are prokaryotes, while human cells are eukaryotes. Developing nerve cells, with the nuclei shown in yellow.

 

0.001 to 0.003

 

This is the diameter in centimeters of most animal cells, making them invisible to the naked eye. There are some exceptions, such as nerve cells that can stretch from our hips to our toes, sending electrical signals throughout the body.

 

Oxygen-transporting red blood cells.
Credit: Dennis Kunkel, Dennis Kunkel Microscopy, Inc.

1665

In that year, British scientist Robert Hooke coined the term cell to describe the porous, grid-like structure he saw when viewing a thin slice of cork under a microscope. Today, scientists study cells using a variety of high-tech imaging equipment as well as rainbow-colored dyes and a green fluorescent protein derived from jellyfish.

 

200

 

That’s how many different types of cells are in the human body, including those in our skin, muscles, nerves, intestines, blood and bones.

 

3 to 5

Believe it or not, that’s the approximate number of pounds of bacteria you’re carrying around, depending on your size. Even though bacterial cells greatly outnumber ours, they’re much smaller than our cells and therefore account for less than 3 percent of our body mass. Scientists are learning more about how our body bacteria contribute to our health.

 

24

This is the typical length in hours of the animal cell cycle, the time from a cell’s formation to when it splits in two to make more cells.

 

A snapshot of a phase of the cell cycle.
Credit: Jean Cook and Ted Salmon, UNC School of Medicine

120

 

That’s the approximate lifespan in days of a human red blood cell. Other cell types have different lifespans, from a few weeks for some skin cells to as long as the life of the organism for healthy neurons.

 

50 to 70 billion

 

Each day, approximately this many cells die in the human body as part of a normal process that serves a healthy and protective role. Those that die in the largest numbers are skin cells, blood cells and some cells that line structures like organs and glands.

 

Learn more:

 

Inside the Cell Booklet

 

Studying Cells Fact Sheet

 

This Inside Life Science article was provided to Live Science in cooperation with the National Institute of General Medical Sciences

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Does Stretching Increase Flexibility?

Credit: Pressmaster/Shutterstock.com

Many people think stretching is essential to improving flexibility. Runners stretch their hamstrings before hitting the pavement, gymnasts do hyper-splits during their warm-ups and yogis wind down their practice with some forward bends.

 

But does stretching really prevent tight hamstrings and stiff shoulders? And if so, how?

 

It turns out that scientists don't fully understand what happens during a stretch.

 

"Yoga will make you more flexible, but we don't know how," said Jules Mitchell, a yoga instructor and a master's degree candidate in exercise science at California State University, Long Beach.

 

It is clear that stretching doesn't actually make muscles permanently longer, experts agree. Instead, it may be that exercises such as reaching for your toes train the nervous system to tolerate a greater degree of muscle extension without firing off pain signals.

 

And traditional, passive stretches may not even be the best way to accomplish that task, the researchers say. [7 Common Exercise Errors and How to Avoid Them]

 

Muscle tissue

 

During a stretch, the muscle fibers and tendons (which attach the muscles to the bones) elongate, said Markus Tilp, a sports scientist and a biomechanist at the University of Graz, in Austria.

 

However, making a habit of stretching will not create a sustained lengthening of the muscle or fibers. Muscle tissue attaches at fixed points in the bone, so the entire muscle complex can't get permanently longer. And if one likens muscle tissue to a rubber band, it would not be a good thing for the muscle to get permanently stretched out, as that would mean a decrease in its elasticity, said Mitchell, who wrote her master's thesis on the science of stretch.

 

When animals are placed in casts that keep their muscles extended for a long time, their bodies do add additional sarcomeres, or the basic subunits of muscle fibers, but their muscles return to their original shape soon after the animal is removed from those constraints. And in those studies, it's not clear that the lengthened muscles improved the animal's flexibility.

 

In a June 2014 study in the journal Clinical Biomechanics, Tilp and colleague Andreas Konrad found no differences in people's muscles and tendons after six weeks of a static-stretching regimen.

 

So, if muscle fiber doesn't get longer as a result of stretching, why does stretching seem to increase people's flexibility?

 

Nervous system in control

The nervous system is the master conductor determining how far a person can stretch, said Brooke Thomas, a yoga instructor who discussed the science of stretching in a blog post on Breakingmuscle.com.

 

Nerve endings are dispersed throughout the muscle and tendon, and if a stretch doesn't feel safe for the muscle, those nerves will fire, registering pain and resistance, Thomas told Live Science.

 

These nerves "will say 'you better stop stretching, because if you stretch further, the muscle will maybe get damaged,'" Tilp told Live Science.

 

That's why a person under anesthesia, whose nerves are quieted, can be stretched through a full range of motion with no resistance. And healthy babies are born able to do the splits, because they haven't developed a blueprint for ranges of motion that feel unsafe, Mitchell said.

 

There's no doubt that Yoga practitioners who do triangle poses or splits for years will gradually be able to deepen their stretch. But that's because those repeated poses are retraining the nervous system to be quiet at deeper levels of stretch, a process known as stretch tolerance, Tilp said.

 

"You're not feeling this pain anymore, and that makes it possible for you to get into a deeper position with an even more flexed joint," TIlp said.

 

Increasing flexibility

 

Modern people spend all day sitting, so their nervous systems and muscles become habituated to a limited range of motion. [6 Ways to Make Sitting Healthier]

 

"The body adapts to the movements you most frequently make," Mitchell said. "The corollary to that is that the body adapts to the movements you don't make: It adapts by not making those movements anymore."

 

People who want more forgiving hamstrings or hip joints need to stand up, sit, squat, walk and change positions throughout the day, Mitchell said.

 

Passive stretches may not be the most effective way of increasing flexibility, Mitchell said. Although several studies found that passive-training regimens do modestly increase flexibility, it may be more effective to do something called proprioceptive neuromuscular facilitation (PNF), where people extend their muscles and then try to contract them from a lengthened position, Tilp said.

 

A study that will be published in the December 2014 issue of the Journal of Sports Medicine and Fitness found that gymnasts could increase their flexibility more after PNF stretching than after static stretches.

 

People aiming to increase their flexibility in their hamstrings may try doing forward bends and contracting their hamstrings at the same time as they are stretching. Alternately, people can try lying on their back and stretching the hamstrings with a yoga belt, and tightening the hamstrings at the same time as pulling their legs toward their face, Mitchell said.

 

It works because that kind of stretching loads the muscle with more force at a greater level of extension, which then tells the nervous system that the muscle can be strong and safe at that level of extension, she said.

 

Follow Tia Ghose on Twitter and Google+. Follow LiveScience @livescience, Facebook & Google+. Originally published on Live Science.

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  Author Bio

Tia Ghose

Tia has interned at Science News, Wired.com, and the Milwaukee Journal Sentinel and has written for the Center for Investigative Reporting, Scientific American, and ScienceNow. She has a master's degree in bioengineering from the University of Washington and a graduate certificate in science writing from the University of California Santa Cruz.

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Image of the Day: Problem Protein

The Scientist » Image of the Day

Aggregates of alpha-synuclein protein (pink) may contribute to nerve cell death in Parkinson's disease.

By The Scientist Staff | November 13, 2014



FLICKR, PARKINSON'S UK, NICOLA DRUMMOND

Parkinson's disease (PD) is a chronic progressive neurodegenerative movement disorder characterized by a profound and selective loss of nigrostriatal dopaminergic neurons. Clinical manifestations of this complex disease include motor impairments involving resting tremor, bradykinesia, postural instability, gait difficulty and rigidity. Current medications only provide symptomatic relief and fail to halt the death of dopaminergic neurons. A major hurdle in development of neuroprotective therapies are due to limited understanding of disease processes leading to death of dopaminergic neurons. While the etiology of dopaminergic neuronal demise is elusive, a combination of genetic susceptibilities and environmental factors seems to play a critical role. The majority of PD cases are sporadic however, the discovery of genes linked to rare familial forms of disease (encoding α-synuclein, parkin, DJ-1, PINK-1 and LRRK2) and studies from experimental animal models has provided crucial insights into molecular mechanisms in disease pathogenesis and identified probable targets for therapeutic intervention. Recent findings implicate mitochondrial dysfunction, oxidative damage, abnormal protein accumulation and protein phosphorylation as key molecular mechanisms compromising dopamine neuronal function and survival as the underlying cause of pathogenesis in both sporadic and familial PD. In this review we provide an overview of the most relevant findings made by the PD research community in the last year and discuss how these significant findings improved our understanding of events leading to nigrostriatal dopaminergic degeneration, and identification of potential cell survival pathways that could serve as targets for neuroprotective therapies in preventing this disabling neurological illness. (link)

 

 

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Complement — tapping into new sites and effector systems

Nature Reviews Immunology | Perspectives | Opinion

Martin Kolev,^{1, 2,} Gaelle Le Friec^{1, 2,} & Claudia Kemper^1,

Published online 14 November 2014

Abstract

Complement is traditionally known to be a system of serum proteins that provide protection against pathogens through direct cell lysis and the mobilization of innate and adaptive immunity. However, recent work indicates that the complement system has additional physiological roles beyond those in host defence. In this Opinion article, we describe the new modes and locations of complement activation that enable it to interact with other cell effector systems, such as growth factor receptors, inflammasomes and metabolic pathways. We propose that the location of complement activation dictates its function.

Introduction

 The complement system, which was discovered more than 100 years ago, is one of the oldest components of immunity and is central to the detection and destruction of invading pathogens^{1, 2, 3, 4, 5}. Complement is a system of fluid-phase proteins (found in the blood, lymph and interstitial fluids) and cell membrane-bound proteins. The serum-circulating proteins, which are generally synthesized in the liver, are mostly present in an inactive pro-enzyme state, and the membrane-bound proteins comprise receptors and regulators of complement activation fragments. The detection of microorganisms that have breached the host environmental barriers by fluid-phase complement components leads to the activation of the complement cascade and the elimination of the microbial target (Fig. 1a). The complement cascade can be activated by three pathways: the classical, alternative and lectin pathways^{1, 2, 3, 4, 5} (Fig. 1a). All activation pathways lead to the generation of the C3 and C5 convertase enzyme complexes, which cleave C3 into the anaphylatoxin C3a and the opsonin C3b, and C5 into the anaphylatoxin C5a and into C5b, respectively. Deposition of C5b onto a target initiates membrane attack complex (MAC) formation and target lysis¹. The opsonins and anaphylatoxins promote phagocytic uptake of pathogens by scavenger cells, and activate neutrophils, monocytes and mast cells, respectively^{1, 2, 3, 4, 5}. On the basis of these effector functions, complement has long been considered as an innate immune pathway.

 

Figure 1: Distinct location-directed functions of complement activation.

a | Liver-derived, systemically circulating complement forms the first line of defence against invading pathogens and can be activated through three pathways: the classical pathway, the lectin pathway and the alternative pathway, with the initial deposition of C3b on a surface also initiating a feedback amplification loop. Through the formation of C3 convertases (C4bC2a for the classical and lectin pathways, and C3bBb for the alternative pathway), these pathways culminate in the generation of the opsonin C3b and the anaphylatoxin C3a. Subsequent C5 convertase formation (C4bC2aC3b for the classical and lectin pathways, and C3bBbC3b for the alternative pathway) leads to C5b and anaphylatoxin C5a generation, with C5b initiating the formation of the membrane attack complex (MAC) and its insertion into target membranes. C3 and C5 can also be activated directly via activating proteases (see Box 1). Self tissue is protected from complement deposition through fluid-phase and cell-bound regulators; C1 inhibitor (C1-INH) inhibits the functions of C1r, C1s and mannan-binding lectin-associated serine protease 2 (MASP2). C3b (and C4b) are inactivated by the serine protease complement Factor I and one of several cofactor proteins (surface-bound CD46 and complement receptor type 1 (CR1) or fluid-phase Factor H and C4b-binding protein (C4BP)). Convertases are regulated through disassembly by regulators that have decay-accelerating activity — surface-bound CD55 and CR1 or fluid-phase Factor H and C4BP — and the formation of the MAC is controlled by CD59 and vitronectin (also known as S protein)¹¹³. b | Locally occurring complement activation is triggered when a cell-activating signal (such as T cell receptor (TCR) stimulation) initiates the generation and secretion of C3, C5, Factor B (FB) and Factor D (FD), leading to C3 and C5 convertase formation in the extracellular space and/or on the cell surface, and ultimately to the generation of the complement activation fragments C3a, C3b, C5b and C5a. C3a, C3b and C5a bind to their respective receptors on the T cell and induce cellular responses. Intracellular complement activation in resting CD4⁺ T cells (and possibly other cell types) occurs continuously through the action of the C3-cleaving protease cathepsin L. The resulting C3a fragment engages the intracellular lysosome-localized receptor C3aR, which sustains tonic mammalian target of rapamycin (mTOR) activation and T cell survival (resting T cells express C3aR only intracellularly). TCR activation induces cell-surface translocation (shuttling) of this intracellular C3 activation system (indicated by the dashed arrows), where engagement of surface C3aR and CD46 induce intracellular signalling events (for details on these signalling events, see Refs 11,35) that ultimately mediate upregulation of key growth factor receptors — including the receptors for interleukin-2 (IL-2), IL-7 and IL-12 (IL-2R, IL-7R and IL-12R, respectively) — as well as proliferation and the induction of effector function. Autocrine complement receptor activation in antigen-presenting cells (APCs) is triggered by Toll-like receptor (TLR) activation and mediates APC maturation and the expression of MHC class II and co-stimulatory molecules, as well as cytokine production. The sum of autocrine and paracrine effects of local complement activation during cognate APC and T cell interactions defines the functional outcome of T cell activity. Although not depicted here, the cell-surface expression of complement regulators affects these processes by regulating local complement activation^{9, 30, 36}. Furthermore, the C3 activation fragments inactive C3b (iC3b) and C3dg are deposited extracellularly on apoptotic cells and are then taken up by APCs; here, they regulate lysosomal fusion, processing of apoptotic cell debris and subsequent antigen presentation by an as yet undefined mechanism⁴⁸. MBL, mannose-binding lectin; P, properdin; T_H, T helper.

However, the discovery that receptors for complement activation fragments are expressed by almost all immune cells — including B cells and T cells — and that these cells can sense and convert the levels of complement activation into tailored responses⁶ led to the appreciation that complement directs both innate and adaptive immune responses. For example, complement receptor activation lowers the threshold for B cell activation, directs antigen handling by follicular dendritic cells (FDCs) and contributes to the maintenance of B cell tolerance and memory^{7, 8}. Similarly, complement has a non-redundant role in CD4⁺ and CD8⁺ T cell activation and function, either directly through stimulating complement receptor-mediated signalling events in T cells or indirectly through modulating antigen-presenting cell (APC) function^{9, 10, 11}. The appreciation of the role of complement in adaptive immunity coincided with the understanding that complement detects not only pathogenic microorganisms but also potentially harmful self molecules, such as those that are exposed by stressed, injured, apoptotic or necrotic tissues and cells⁴. The discovery that complement aids in the disposal of cellular debris and instructs the adaptive immune system provided the missing mechanistic explanations for the long-known but poorly understood finding that complement deficiencies predispose to autoimmune disease^{12, 13, 14, 15}.

 

Recent studies are also providing a new dimension to our understanding of complement. Unexpectedly, it was shown that complement can be activated not only at the cell surface, as traditionally thought, but also in intracellular compartments¹⁶. Moreover, it is now becoming clear that systemic serum complement has different functions from local immune cell-derived complement. Rather than being a mostly pro-inflammatory effector system, complement is emerging as a central player in cell and tissue development, homeostasis and repair. Studies of the molecular mechanisms underlying these new functions of complement have led to the discovery of new crosstalk between complement components and other cell effector systems, including growth factor receptors, inflammasomes, metabolic sensors and the Notch system. In this Opinion article, we propose a model to explain how the different locations of complement activation dictate its diverse functions and how complement engages other effector systems at these locations to regulate immune-related and non-immune-related processes.

 

Figure 2: Functional crosstalk between complement and other cell effector systems.

The functional crosstalk between the complement system and Toll-like receptors (TLRs) and the coagulation cascade has long been acknowledged. The recent developments in the field have led to the discovery of additional direct crosstalk with key effector systems, including the NOD-, LRR- and pyrin domain-containing protein 3 (NLRP3) inflammasome, carbohydrate receptors (such as dectin 1), Fc receptors for IgG (FcγRs), and cytokine and growth factor receptors, as well as the WNT and Notch systems. Cell populations in which this crosstalk occurs are indicated and, where identified, the signalling pathways driving the functional outcome of the crosstalk between complement and effector systems are shown. The regulation of the mammalian target of rapamycin (mTOR) metabolic sensing system by complement is not included here but the current knowledge about this crosstalk is summarized in Refs 23,39. '+' denotes upregulation; '−' denotes downregulation; AP-1, activator protein 1; APC, antigen-presenting cell; cAMP; cyclic AMP; DC, dendritic cell; DLL1, delta-like ligand 1; ER, endoplasmic reticulum; ERK, extracellular signal-regulated kinase; IL, interleukin; LRP, low-density lipoprotein receptor-related protein; MAC, membrane attack complex; MAPK, mitogen-activated protein kinase; MASP2, mannan-binding lectin-associated serine protease 2; MYD88, myeloid differentiation primary response protein 88; NF-κB, nuclear factor-κB; P2RX7, P2X purinoceptor 7; PI3K, phosphoinositide 3-kinase; SHIP, SH2 domain-containing inositol-5-phosphatase; SYK, spleen tyrosine kinase; R, receptor; SPAK, ST20/SPS1-related proline-alanine-rich protein kinase; T_H, T helper; TNF, tumour necrosis factor; T_Reg, regulatory T.

Figure 3: Complement at the nexus of the extensive crosstalk between cell effector systems.

The interaction between complement and other key cell effector systems involved in innate and adaptive immunity is multifactorial and in most cases bidirectional. Furthermore, the functional impact of complement on effector systems with primarily non-immune functions (for example, the Notch and WNT systems) is more substantial than previously thought, and indicates that complement contributes to normal development, and possibly to ageing and behaviour. We suggest that the emerging role of complement in core physiological metabolic pathways may be the crucial functional intersection point in this network. FcγR, Fc receptor for IgG; TLR, Toll-like receptor.

Conclusions and future perspectives

Complement has traditionally been defined as an innate and systemic system that functions in the defence against pathogens. However, it is now considered to be a central regulator of innate and adaptive immunity, with new functions that extend beyond protective immunity, including roles in cell generative, degenerative and regenerative processes. The finding that complement is activated within cells and not only engages intracellular complement receptors but also intersects with several other cell effector systems helps to explain its unexpectedly wide-reaching effects.

 

Nevertheless, there is still much to discover about this ancient system and key future questions include: how is intracellular complement generation and activation regulated? Does this novel pathway contribute to disease? Are additional complement components, including regulators, functionally active inside cells? In this regard, we have detected intracellular C5a (A. Fara and C. Kemper, unpublished observations) and several studies have reported intracellular expression of Factor D, complement receptor type 1 (CR1; also known as CD35) and the positive regulator properdin in resting cells^{89, 90}. Thus, one could envision the existence of an intracellular 'Complosome' — somewhat analogous to the inflammasome⁹¹ — that has novel functions in cell survival and activation. Furthermore, a unifying feature of the new roles and interactions for complement is their reliance on appropriate sensing of cellular integrity and balanced control of energy and substrate metabolism. Therefore, the emerging cooperation between complement and the metabolic pathway network may arise as a core intersection point for the diverse functions of complement in immunity and beyond (Fig. 3).

 

 

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