Pregnancy related diseases are notorious for the potential threat they pose on the lives of both the mother and the child. Most of them are also very difficult to treat. A number of factors lead to the complicacy of the situation and many times out of control. e.g., one of the reasons behind the high risk of preterm labour and neonatal mortality is bacterial vaginosis (bacterial infection of the vagina). Therefore, prenatal care offers one of the greatest challenges in the field of medical practice. Safe methods are prerequisite to have fruitful and effective solution as the therapeutic protocols undertaken would influence the lives of the mother and babies both on short and long term basis. The prevention methods should then focus on the use of natural and safer drugs and probiotics can definitely be the choice under the current scheme of events. A host of scientific and medical studies signify the importance of the use of probiotics in reducing pregnancy associated complications.

Facilitating glucose metabolism in pregnant women:

There were previous reports to demonstrate that a balanced metabolism of glucose can reduce many of the pregnancy associated risks and provide both the mother and the infant health benefits on long term basis. A study headed by Dr. Kirsi Laitinen showed that the administration of L. rhamnosus and B. lactis strains modulated the plasma glucose content and provided health benefits to women during the period of pregnancy and even after it. It also resulted in decreased glycated Hb levels in the blood. The study also provided the first ever evidence of improvement in consistent human glucose metabolism thereby presenting the clinical evidences of effective cross communication between the hosts and the microbiome in the metabolism of glucose. Another thrust point of the use of probiotics in this case is the length of the period of benefit. Some of the studies have shown the effect of probiotics to be extending well upto 7 years. The probiotics can induce the sufficient modifications in the composition of the intestinal microbiota to cause the required metabolic changes. The probiotics aid in nondigestible polysaccharides thereby increasing the pool of glucose that can be absorbed. They also stimulate the transcription of lipase activity increasing genes and help in storage of glucose in the adipose tissues. The probiotics also induce the NF-κB and CD14 pathways that result in activation of the innate immunity through the TLR which can be of particular interest with respect to lower insulin resistance. According to a recent study, the gut microbiota composition has been found to be a deciding factor in energy metabolism. Cani et al. showed an inverse correlationship between the levels of fat feeding in individuals with the Bifidobacterium content. It was also found that a higher number of Bifidobcterium enhanced glucose tolerance. The use of probiotics in the modulations of microbial composition of the gut to attain a changed immunological response by the intestine may provide a novel means of glucose metabolism regulation. This approach is also cost effective considering the critical events of pregnancy where it can provide relief.

Reduction in bacterial vaginosis:

The infection of the vaginal tracts by pathogenic bacteria is a major cause of pregnancy associated complications like preterm labour and increased rate of neonatal mortality in women throughout the world. The use of therapeutic interventions like antibiotics has been partially beneficial and could not curb incidences of preterm birth. Studies have revealed the near absence of vaginal lactobacilli in cases of bacterial vaginosis and the ensuing question is whether the probiotics can reverse this trend given the potential of probiotics to inhibit their pathogenic counterparts. Indeed it has been found that the beneficial microbes can restore back the microflora and increases the possibility of a good and healthy pregnancy term. Therefore, the reason behind the use of probiotics in such cases has a strong background. The group of Giuseppe et al. suggested that after post administration some of the strains of lactobacilli can have safe vaginal colonization whereby they can remove and kill the pathogenic bacteria like Gardnerella vaginalis. The probiotics can also perturb the inflammatory responses in immune system to good effect that alleviate problems of preterm birth. In addition, the beneficial bacteria aids in the degradation of lipids increase the levels of cytokines. These factors help in the promotion of embryo development. Taken together, the probiotics can definitely be an answer to the problems of vaginal bacteriosis.

Lowering of infant diseases:

The post birth neonatal health is a reason of great concern as atopic diseases like eczema is quite prevalent and increased cases are being reported throughout the world. Breast feeding (the basic source of nutrition in infants) have been found to be effective in combating this problem although the exact means by which it provides the protection is unknown. Whether probiotics can increase the inhibitory response to the disease is a matter of great interest. Samuli Rautava, MD, Turku University Hospital, Finland carried out a study with 62 pairs of mother-infant. According to the work, probiotic administration to pregnant mother enhanced the immuno potential of the breast milk as was evident from the increased levels of TGF-β2 in probiotic recipient mothers. As a result cases of atopic eczema were reduced significantly in infants where the mother received probiotic supplements. As reported in the Journal of Allergy and Clinical Immunology, it is observed that infants with higher concentration of cord blood IgE were most likely to be benefitted from such supplementation. Our understanding of the mechanism behind the use of probiotics in treatment of infant atopic diseases is paltry and a deeper insight into it is needed. This is revealed by the work of Wickens et al. that proposes that the L. rhamnosus receiving group showed lesser atopic eczema severity as compared to the group that received Bifidobacterium animalis strain. However, there are existing reports of the beneficial effects of using Lactobacilli to prevent infant eczema and it only augurs well for the inhibition of the disease.

Scientist like Reid suggests a high safety record for the probiotic use during pregnancy. Hence, Probiotics possess all the beneficial traits to be exploited as a safer means of therapeutic intervention in pregnancy related complications and other adverse effects like maternal metabolism and infant health.

According to the Department of Health and Human Services (US), Rheumatoid arthritis (RA) affects nearly 2 million (~1% of the population). Autoimmunity (when antibodies are generated against self antigens of the body) is the reason behind RA. RA causes inflammatory responses with acute pain of the joints, degradation of cartilage and even destruction of the bone and hence is associated with considerable disability and problems in life quality. Available therapeutics like monoclonal antibodies provide only but non-persistent relief from the disease symptoms. There is therefore, a definite need for safer and long term benefit producing therapies that can provide relief from the arthritic pain. The disease gains severity with an imbalance between the levels of pro-inflammatory and anti-inflammatory cytokines. There were previous data to suggest that the microbes in the GI tract, systemic and mucosal immune responses and the arthritic development share a relationship. The use of probiotics in the treatment and relief of arthritic and unnatural inflammatory responses has a bright future.

Probiotics in the relief of arthritis:

There are existing evidences of the beneficial effects of probiotics in the relief of acute symptoms in RA. The probiotic products can cause its effects-directly or indirectly. The direct effects are exerted within the gastro-intestinal tract locally that involves the alteration of the inhabitant microbiota and the synthesis of compounds like vitamins. The indirect effects on the other hand are caused outside their domain of colonization, viz., lungs, skin, joints which may be brought about by a change in the immunological responses. The group of Marteau proposed that arthritis mediated inflammation may be alleviated with the use of probiotics. Researchers have observed that in juvenile arthritis, the defense mechanism of the gut is severely compromised. In a study by Malin et al. thirty juvenile arthritis patients were administered with Lactobacillus GG for a period of two weeks and the gut defences were observed. The oral dosage of Lactobacillus GG could reinstate barrier processes of the mucosa in the disorder. The gastro-intestinal tract induced inflammation becomes a linkage between inflammatory disorders of the GI tract and arthritis. According to Vanderhoof, decrease in immune response and permeability of the GI tract is caused due to the consumption of probiotics. David R. Mandel, MD Rheumatology & Osteoporosis, Mayfield Village, Ohio suggests adjunctive treatment of the probiotic B. coagulans as safe and effective to be administered to patients with RA. According to the work of Kano et al. L. delbrueckii strain fermented milk intake could sufficiently reduce collagen associated arthritis. The same study demonstrated that RA patients on a diet of uncooked vegetables supplemented with lactobacilli showed signs of decreased arthritic symptoms. While other groups have found suppression in collagen-mediated arthritis with the intake of L. casei concomitantly elucidating a reduction in paw swelling, infiltration of the lymphocyte and cartilage destruction. In a completed clinical trial conducted by the Lawson Health Research Institute in collaboration with St. Joseph’s Health Care London, it was hypothesized that administration of selective strains of probiotics like L. rhamnosus and L. reuteri can improve the state of inactivity in RA patients by relieving them of their acute painful symptoms.

Probiotic mediated immuno-modulation in RA:

The major route of activity of the probiotic bacteria in relieving the situation of acute inflammatory disorders and arthritis is through the alteration of the immune system. Studies have shown that the specific dosage of probiotics bacteria like Lactobacillus GG could induce the proliferation of lymphocytes (both B and T cells) with a resultant decrease to mitogen sensitivity. The probiotics also cause a balance between the inflammatory (pro- and anti-) cytokines. Lactobacillus GG administration could increase the production of the anti-inflammatory interleukin 10 (IL-10) while lactobacilli intake enhanced the Th1 production as also reduced IgE antibody generation. Various preparations (live or heat inactivated) of the bacteria produced similar effect irrespective of the time of treatment. The reason behind such similarity is elusive though. Data indicate that feeding patients with fermented products supplemented with lactobacilli could produce greater beneficial effects than the oral intake of the bacteria alone. This further confirms the earlier reports of probiotic effect well past its colonization and adhesion in the GI tract. L. casei oral administration results in reduced production of interferon-γ and an enhanced level of IL-2. Although, earlier results demonstrated that live L. casei administered infants showed greater IgA serum titers than the one who had taken the heat killed forms of the bacteria. But the results with Lactobacillus GG suggest the form of the microorganism is not important and that any component of the cells might as well be involved in the beneficial effects. Indeed some researchers have shown that the heat inactivated Lactobacillus GG cytoplasmic extracts could inhibit the mononuclear cells in humans. Thus, the probiotic cells have in possession some anti-proliferative factors which are heat stable in nature. There are also possibilities of potential immuno-alteration by secreted bacterial components. This theory is supported by the observation that Lactobacilli degraded casein inhibits the activation of T-cells and downregulates the IL-2 transcript levels and PKC compartmentalization. Lactobacillus strains reduce the levels of pro-inflammatory cytokines. Some of the common members affected being IFN-γ, TNFα and IL-12. But they do not alter the levels of the cytokines like TGF-β or IL-10 which results in anti-inflammatory responses in RA. In a recent report, it was shown that in patients receiving probiotics, IgA and IgM immunoglobulin levels increased significantly as compared to the control group who did not receive it. In a study conducted by the group of Seon So, L. casei inhibits collagen induced arthritis by reducing Th1 effector actions. The intake of the bacteria resulted in the reduction of proinflammatory cytokines (IL-2, IL-12, TNF-α, IFN-γ, IL-6, etc) through CD4+ T-cells with a decrease in levels of immunoregulatory IL-10. All these cytokines are Collagen type-II reactive molecules. The administration also prevented the NF-κB translocation into the nucleus.

Therefore, the potential of the probiotic strains to modulate the immune system has provided sufficient basis to use them as effective modes of therapeutic interventions in combating abnormal inflammations such as those observed in arthritis.

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The human body needs throughout the life, a steady and appropriate supply of minerals through the diet. The minerals form an integral part of a large number of vitamins, proteins, transport chains and enzymes.  A good number of minerals are essential to that effect-some in higher amount (macro-elements) while others in relatively lesser quantities (micro-elements). Irrespective of the quantity, their significance cannot be weighed down. In the United States, the RDA (Recommended Dietary Allowances) forms the guidelines for the proper intake of minerals. Some of the important minerals required in our diet include iron, calcium, magnesium, phosphorous, zinc, copper, cobalt, iodine, fluoride. Although the mineral intake is important for the proper maintenance of our physiological activities, in a good percentage of the human population the threshold value for the intake and metabolism of the minerals is not met. Therefore, efforts are on to facilitate better utilization of the minerals in our body.

Factors affecting mineral absorption:

Mineral absorption and utilization by the human body depends on its physiological, hormonal and biochemical status. The mineral sources being divergent in nature their possible bioavailability needs to be checked before use. There are factors acting both in favor and against optimum mineral absorption. Stability maintenance, state of ingested mineral, if a potential transporter is present for the mineral, small sized particles, reduced intestinal motility and solubility are some of the factors facilitating absorption. While there are factors like high transit time, fats, fiber, some acids, precipitation of minerals in presence of alkalis which inhibit mineral absorption.

Problems faced during mineral deficiency:

Although the minerals are required in very trace amounts, their deficiency or depletion from the human body may give rise to a lot of diseased conditions. The two of the classic examples are formation of anemia due to iron deficiency and osteoporosis as a result of lack of calcium and phosphorous. In due course of time lack of minerals results into various forms of degenerative diseases some of which may be chronic in nature. In our daily lives we ourselves experience these mineral deficiencies when we feel fatigued and problems with memory or slower rate of metabolism. Some of the symptoms might be too subtle to experience but in the long run causes greater problems. Supplementation with mineral nutrients has helped ease some of these problems but could not eradicate the problem fully. Since, the excess minerals administered to the body were not being absorbed properly.

There are also conditions in the body when the minerals are required in higher amounts. One such state is the metabolic acidity wherein a greater supply for the minerals is wanted to balance out the acidic condition and restore back the alkalinity of the body.  The minerals like potassium, magnesium and calcium provides the buffering activity that is needed to keep the food entering the body buffered and maintain the normal physiological pH at ~7.3. If the diet doesn’t supply the adequate buffering agents in terms of these minerals, the bones and teeth will be at risk of getting depleted of the minerals.

Role of probiotics in facilitating mineral absorption:

The indigestible carbohydrates like oligofructose, galactooligosaccharides and inulin have been found to cause enhanced mineral retention and absorption by the human body. Significant improvement in mineral absorption was also observed for sugar alcohols and starches. These carbohydrate compounds are able to bind and sequester the minerals and these carbohydrate-mineral complexes pass unabsorbed through the small intestine onto the colon when the minerals are released from the complex and absorbed. The probiotics can act on the nondigestible carbohydrates and gives rise to short chain fatty acids. The SCFAs so formed can affect an increased absorption of minerals like Mg2+ and Ca2+. As also the acidic condition that results from the formation of lactic acid, butyric acid or propionic acid can enhance the ionization of minerals that in turn results in passive diffusion according to the work of Cummings et al. Researchers like Resta, Feng and Christakos have demonstrated that the SCFAs can stimulate Vitamin D receptor expression on the eukaryotic cells.  Now there were previous reports to suggest that in mammals Vitamin D can regulate the metabolism of calcium and hence ensures its proper absorption from the diet. The research also showed that the parts in probiotics can cause increased vitamin D receptor expression both independent and dependent of SCFAs. The signaling pathways involved in the regulation of transport of calcium are PKC and MAPK. In addition, the probiotics can cause increased transport of SCFA within the intestinal epithelia through the induction of their major transporters like monocarboxylate transporter 1 (MCT1) according to Lee et al. which promotes increase in cellular energy and VDR expression and proteins involved in calcium binding like calreticulin, Sp100. The calcium transporter, TRPV6 is also markedly induced by probiotic bacteria. In cereal foods, phytate binds and complexes the minerals. According to reports, trace mineral elements like iron, copper, zinc are highly reduced in diet with rich phytate content. The endogenous phytase is generally lacking in humans. Therefore, supply of probiotics to provide the required phytase could alleviate the problem.

What lies ahead?

The idea is to create a balance between the prebiotics and probiotics to overcome the problem of lack of mineral absorption. The future research should focus on the finding and characterization of more inulin like carbohydrates that can chelate and sequester the essential minerals. However, the prebiotics can bring along with them the problem of non-availability of minerals in certain regions of the body. The probiotics that can work on these otherwise nondigestible carbohydrates can bring relief in such situation. Therefore, the right combination of prebiotic-probiotic has to found out. But there are existing reports that suggest that the probiotic bacteria can cause sufficient improvement in mineral absorption even in the absence of the prebiotics. Efforts should be made to identify from the pool of probiotic bacterial strains the ones suitable for the purpose of mineral absorption. Strains could be so designed as to induce the increased production of mineral transporter genes. Nevertheless, the probiotics can definitely be used in improved absorption of minerals from the diet.

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The inability of individuals to degrade and digest the disaccharide lactose leads to a state known as lactose intolerance. A large proportion of the world population suffers from lactose intolerance. This often results in symptoms such as bloating, nausea, vomiting, diarrhea and abdominal cramps. It has also been reported that a prime reason for the inflammatory bowel disease (IBD) is the consumption of milk by lactose intolerant individuals. Generally, a person may be called lactose intolerant if he breathes hydrogen>20ppm or his blood glucose level increases by <1.12 mmol/L after an intake of 50gm of lactose. There are increasing reports of the beneficial effects that the probiotic products may provide to alleviate the problem of lactose intolerance. Although, there remains certain ambiguities in their proper use due to lack of knowledge among the common people. e.g., individuals with lactose intolerance are able to digest the yoghurt lactose with greater efficiency as compared to the utilization of milk lactose. But the reasons were unknown for such discrepancies in response to the same substrate. In absence of feasible treatment regimes, the earlier efforts to combat the problem involved avoiding lactose containing dietary products.

Source of lactose in the diet:

Since a large number of the human population suffers from the ailment, the obvious question arises is the lactose containing diets indispensable. Lactose is a disaccharide sugar molecule (made from a single molecule each of glucose and galactose) that forms an inseparable part of milk and other milk based products. For a complete human diet, milk plays an integral part. Therefore, methods of lactose utilization need to be developed rather than removing it from the parts of the nutrients.

The problem and reason behind lactose intolerance:

It has been observed that the individuals suffering from lactose intolerance lack the enzyme, lactase. Lactase is a glycosidic hydrolase and belongs to the β-galactosidase family of enzymes that is required to convert lactose into glucose and galactose which can be absorbed into the bloodstream after their passage through the small intestinal wall. The lactase protein is encoded by the gene LCT.  Although the LCT gene is expressed quite effectively in infants, it becomes dormant in adults due to weaning. In some adults the gene has been found to harbor mutations causing lactose persistence (ability to utilize lactose). The effect is brought about in an autosomal dominant manner where mutation in a single allele is sufficient to produce the effect. Also, some scientists have established that a transcription factor MCM6 sits on the promoter of LCT gene and actively regulates its transcription. Mutations in MCM6 have been linked to lactose intolerance.

In persons lacking active lactase, the undigested sugar goes into the colon in an intact form where it is acted upon by the colon residing bacteria. These bacteria can metabolize the lactose with a number of gaseous end products like carbon dioxide, hydrogen, etc. which is the reason behind many of the associated symptoms of lactose intolerance. There are also end products of fermentation and unutilized sugars that causes increased osmotic pressure in the colon. According to the researchers, Scrimshaw and Johnson there are several other factors besides the lactase deficiency and its derivative effects that might add to the complexity of the diseased state. Some of the factors according to their study include age, ethnicity and possibly sex coupled with the factors like the ingredients of the meal taken alongwith lactose, the amount of lactose intake at a specific point in time, the transit time through the gastro-intestinal tract and the speed of gastric emptying. There are also possibilities of probable interactions or cross talks among these factors which may only elevate the severity of the condition.

Solution to lactose intolerance with probiotics:

So, what can be the solution to the problem of lactose intolerance? People have tried doing away with lactose containing dietary products but that is not a permanent and wise solution considering the fact that those food supplements are quite necessary for our health. Among others the β-galactosidase enzyme in the form of drugs or encapsulations has been tried. But due to the extreme conditions within the human GI tract it does not met with the due success. Even if it provided relief, it was only for a brief period and the solution seemed to be transient in nature. However, researchers like Gallagher have long before demonstrated that the people suffering from lactose maldigestion for some unknown reason were able to utilize yoghurt lactose but not the milk lactose. It also resulted in lower hydrogen breath. Gradually it was found that the probiotic bacteria present in the yoghurt could exert such beneficial trait. Milk containing L. acidophilus has shown similar results. Several of the non-pathogenic bacterial strains, e.g., S. thermophilus, L. bulgaricus could produce lactase. This effect is well demonstrated both in children and adults. Therefore, the probiotics could be an obvious choice by the ailing individuals. In such host they could exert the action of their lactase along the gut lumen to facilitate digestion and alleviate lactose intolerance. This has been well shown in both adults and children. Infection of the intestine caused by Giardia lambia could result in lactose intolerance among children and probiotics have been used to restore the activity of lactase in such children. Besides, the effect brought about by the bacterial β-galactosidase, there are other beneficial results obtained by the activity of probiotics in bringing lactose tolerance within the host.  They also provide delayed gastric emptying and reduced time of orocecal transit and at times both. Also, since the microbes are able to delay the passage of lactose through the GI tract, the lactase deficient people get more time to digest lactose. This can be explained by the finding that yoghurt with no probiotic lactase can effectuate a prolonged transit time to some extent.  Probiotics containing fermented products could cause delayed gastric emptying due to higher viscosity and a lowered pH as compared to normal milk.

However, it is noteworthy to mention that the bacterial lactase has the highest activity at pH of 6-8. But within the human body it has to encounter a wide array of pH. Nonetheless, it has been found that bacterial lactase can resist these differences in pH and a good enough amount of it remains active. Some researchers have found that the lactases from certain strains of bacteria are more effective. Efforts should be made to identify, isolate and characterize the probiotic β-galactosidase that can withstand a wider range of pH and still remain active. Through genetic engineering it is also possible to produce more robust lactase producing strains. In any case probiotics seem to be the only hope in lactose intolerance alleviation at present. The US National Institutes of Health has successfully carried out different clinical trials on the use of probiotics in lactose intolerance.

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